Physical activity interventions for people with congenital heart disease

TLDR: The evidence is very uncertain about the effect of physical activity and exercise interventions on HRQoL, and three types of intervention were identified: physical activity promotion; exercise training; and inspiratory muscle training.

Abstract: Background Congenital heart disease (ConHD) affects approximately 1% of all live births. People with ConHD are living longer due to improved medical intervention and are at risk of developing non-communicable diseases. Cardiorespiratory fitness (CRF) is reduced in people with ConHD, who deteriorate faster compared to healthy people. CRF is known to be prognostic of future mortality and morbidity: it is therefore important to assess the evidence base on physical activity interventions in this population to inform decision making. Objectives To assess the effectiveness and safety of all types of physical activity interventions versus standard care in individuals with congenital heart disease. Search methods We undertook a systematic search on 23 September 2019 of the following databases: CENTRAL, MEDLINE, Embase, CINAHL, AMED, BIOSIS Citation Index, Web of Science Core Collection, LILACS and DARE. We also searched ClinicalTrials.gov and we reviewed the reference lists of relevant systematic reviews. Selection criteria We included randomised controlled trials (RCT) that compared any type of physical activity intervention against a 'no physical activity' (usual care) control. We included all individuals with a diagnosis of congenital heart disease, regardless of age or previous medical interventions. DATA COLLECTION AND ANALYSIS: Two review authors (CAW and CW) independently screened all the identified references for inclusion. We retrieved and read all full papers; and we contacted study authors if we needed any further information. The same two independent reviewers who extracted the data then processed the included papers, assessed their risk of bias using RoB 2 and assessed the certainty of the evidence using the GRADE approach. The primary outcomes were: maximal cardiorespiratory fitness (CRF) assessed by peak oxygen consumption; health-related quality of life (HRQoL) determined by a validated questionnaire; and device-worn 'objective' measures of physical activity. Main results We included 15 RCTs with 924 participants in the review. The median intervention length/follow-up length was 12 weeks (12 to 26 interquartile range (IQR)). There were five RCTs of children and adolescents (n = 500) and 10 adult RCTs (n = 424). We identified three types of intervention: physical activity promotion; exercise training; and inspiratory muscle training. We assessed the risk of bias of results for CRF as either being of some concern (n = 12) or at a high risk of bias (n = 2), due to a failure to blind intervention staff. One study did not report this outcome. Using the GRADE method, we assessed the certainty of evidence as moderate to very low across measured outcomes. When we pooled all types of interventions (physical activity promotion, exercise training and inspiratory muscle training), compared to a 'no exercise' control CRF may slightly increase, with a mean difference (MD) of 1.89 mL/kg-1/min-1 (95% CI -0.22 to 3.99; n = 732; moderate-certainty evidence). The evidence is very uncertain about the effect of physical activity and exercise interventions on HRQoL. There was a standardised mean difference (SMD) of 0.76 (95% CI -0.13 to 1.65; n = 163; very low certainty evidence) in HRQoL. However, we could pool only three studies in a meta-analysis, due to different ways of reporting. Only one study out of eight showed a positive effect on HRQoL. There may be a small improvement in mean daily physical activity (PA) (SMD 0.38, 95% CI -0.15 to 0.92; n = 328; low-certainty evidence), which equates to approximately an additional 10 minutes of physical activity daily (95% CI -2.50 to 22.20). Physical activity and exercise interventions likely result in an increase in submaximal cardiorespiratory fitness (MD 2.05, 95% CI 0.05 to 4.05; n = 179; moderate-certainty evidence). Physical activity and exercise interventions likely increase muscular strength (MD 17.13, 95% CI 3.45 to 30.81; n = 18; moderate-certainty evidence). Eleven studies (n = 501) reported on the outcome of adverse events (73% of total studies). Of the 11 studies, six studies reported zero adverse events. Five studies reported a total of 11 adverse events; 36% of adverse events were cardiac related (n = 4); there were, however, no serious adverse events related to the interventions or reported fatalities (moderate-certainty evidence). No studies reported hospital admissions. Authors' conclusions This review summarises the latest evidence on CRF, HRQoL and PA. Although there were only small improvements in CRF and PA, and small to no improvements in HRQoL, there were no reported serious adverse events related to the interventions. Although these data are promising, there is currently insufficient evidence to definitively determine the impact of physical activity interventions in ConHD. Further high-quality randomised controlled trials are therefore needed, utilising a longer duration of follow-up.

Figures

Table 1. ’Summary of findings’ table

Table 1. ’Summary of findings’ table

Table 1. ’Summary of findings’ table

Full text

ORE Open Research Exeter
TITLE
Physical activity interventions for people with congenital heart disease (protocol)
AUTHORS
Williams, CA; Wadey, C; Pieles, G; et al.
JOURNAL
Cochrane Database of Systematic Reviews
DEPOSITED IN ORE
29 October 2019
This version available at
http://hdl.handle.net/10871/39378
COPYRIGHT AND REUSE
Open Research Exeter makes this work available in accordance with publisher policies.
A NOTE ON VERSIONS
The version presented here may differ from the published version. If citing, you are advised to consult the published version for pagination, volume/issue and date of
publication

Cochrane Database of Systematic Reviews
Physical activity interventions for people with congenital
heart disease (Protocol)
Williams CA, Wadey C, Pieles G, Stuart G, Taylor RS, Long L
Williams CA, Wadey C, Pieles G, Stuart G, Taylor RS, Long L.
Physical activity interventions for people with congenital heart disease.
Cochrane Database of Systematic Reviews 2019, Issue 8. Art. No.: CD013400.
DOI: 10.1002/14651858.CD013400.
www.cochranelibrary.com
Physical activity interventions for people with congenital heart disease (Protocol)
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
iPhysical activity interventions for people with congenital heart disease (Protocol)
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

[Intervention Protocol]
Physical activity in terventions for people with congenital
heart disease
Craig A Williams
1
, Curtis Wadey
1
, Guido Pieles
2
, Graham Stuart
2
, Rod S Taylor
3
, Linda Long
3
1
Children’s Health and Exercise Research Centre, University of Exeter, Exeter, UK.
2
National Institute for Health Research (NIHR)
Cardiovascular Biomedical Research Centre, Bristol Heart Institute, Bristol, UK.
3
Institute of Health Research, University of Exeter
Medical School, Exeter, UK
Contact address: Craig A Williams, Children’s Health and Exercise Research Centre, University of Exeter, St Luke’s Campus, Heavitree
Road, Exeter, Devon, EX1 2LU, UK.
C.A.Williams@exeter.ac.uk.
Editorial group: Cochrane Heart Group.
Publication status and date: New, published in Issue 8, 2019.
Citation: Williams CA, Wadey C, Pieles G, Stuart G, Taylor RS, Long L. Physical activity interventions for people with congenital
heart disease. Cochrane Database of Systematic Reviews 2019, Issue 8. Art. No.: CD013400. DOI: 10.1002/14651858.CD013400.
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effectiveness and safety of physical activity promotion and exercise training interventions in individuals with congenital
heart disease.
B A C K G R O U N D
Due to improved medical interventions children with complex
congenital he art disease (ConHD) are now living into adulthood,
presenting new challenges for health care professionals as this pop-
ulation is now at risk of acquiring non-communicable ‘lifestyle’
diseases (NCDs) (
Giannakoulas 2009; Khairy 2010). It has been
reported that people with ConHD fail to meet the minimum
requirements for physical activity (
Reybrouck 2005; McCrindle
2007
); and that the prevalence of obesity is increasing (Andonian
2019
). This significantly increases the chance of developing NCDs
such as coronary heart disease, type II diabetes mellitus, and breast
and colon cancers (
Lee 2012). Patients with ConHD also have
reduced cardiorespiratory fitness (CRF) (
Amedro 2017); this has
been significantly linked with mortality and surgical outcomes in
this population (
Inuzuka 2012 ; d’Udekem 2017). It is crucial,
therefore, that people with ConHD increase their physical activ-
ity in line with the current guidelines of 60 minutes of moderate
to vigorous physical activity (MVPA) daily for young people and
150 minutes of MVPA weekly in adults (
Department of Health
2011
). However, there is currently no consensus on how best to
improve physical activity and physical fitness for all ages and dis-
ease severities in people with ConHD. The aim of this review is
to collate and summarise the randomised controlled trial evidence
for physical activity promotion and exercise training interventions
in people with ConHD.
Description of the condition
ConHD is a developmental abnormality of the heart or intratho-
racic vessels (or both) and can include both str uctural and electri-
cal abnormalities of the heart (
Mitchell 1971). The pathophysiol-
ogy is complex, from shunting lesions to single ventricles - for a
three-part review see
Rhodes 2008, Sommer 2008a and Sommer
2008b
. The birth prevalence of ConHD has been stable for over
1Physical activ ity interventions for people with congenital heart disease (Protocol)
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

a decade, plateauing around 9.1 in every 1000 live births (95%
confidence interval (CI) 9.00 to 9.20). As a result, e ach year 1.35
million children are born with ConHD globally (
van der Linde
2011
). Medical innovation has cut infant mortality significantly:
in 1987/88 over 30% of ConHD mortality was in children aged
less than four years old; in 2004/05 this had fallen to less than
10%, with the highest proportion of deaths occurring in geriatrics
(
Khairy 2010). This has led to a significant shift in th e prevalence
of ConHD in adulthood: in 2010 it was estimated that adults ac-
counted f or two-thirds of the ConHD population (
Marelli 2014).
Pregnant women with ConHD are six times more likely to die
during labour (OR 6.7, 95% CI 2.9 to 15.4); and their children are
at an increased risk of inheriting ConHD (
Blue 2012; Opotowsky
2012
).
People with ConHD suffer reduced life expectancy, which can
be primarily attributed to cardiac sequelae such as progressive
heart failure and sudden cardiac death (
Zomer 2012; Diller 2015).
Health-related quality of life for those with ConHD has been
reported as lower compared to h ealthy controls, specifically in
the domains of physical functioning and general health (
Gratz
2009
; Dulfer 2013). Furthermore, CRF is impaired in children
and adults with ConHD, with large heterogeneity both within a
condition and between different conditions of ConHD (
Kempny
2011; Diller 2015). CRF also declines more steeply throughout
childhood and adolescence compared with age-matched controls,
which may have implications for adults as lower fitness levels
have been linked to a poorer prognosis (
Amedro 2017; d’Udekem
2017
). Fortunately, regular physical activity, such as a 10-week
walking programme, has been shown to improve CRF, physical
activity and quality of life in this population (
Dua 2010).
Description of the in tervention
Physical activity consists of any bodily movement involving skele-
tal muscles that results in an increased energy expenditure, whereas
exercise training is a planned and structured period of physical
activity with the intention to maintain or improve physical fit-
ness components (
Caspersen 1985). Although MVPA guidelines
exist for healthy adults, children and adolescents (
Department of
Health 2011
), there are no national or international MVPA guide-
lines for people with ConHD. However, a recommendation by
the American Heart Association supports an active lifestyle and
use of recreational sports and exercise training to enhance the lives
of children and adult ConHD patients (
Longmuir 2013). Impor-
tantly the risks of exercise in an adult ConHD population have
been well documented but not at a paediatric le vel. In a study of
25,790 adults with ConHD, a total of 1189 deaths were reported
with only 17 (0.01%) patients dying of sudden cardiac death of ar-
rhythmic origin during physical activity (Koyak 2012). This high-
lights the relative safety of physical activity in this population.
How the inter vention might work
Physical functioning is a domain of health-related quality of life
and can be defined as limitations in mobility activities, such as
walking specified distances. Physical functioninghas been reported
to be lower in pe ople with ConHD compared to healthy con-
trols (
Gratz 2009). By increasing a patient’s cardiorespiratory or
muscular fitness, or both, an intervention may improve self-re-
ported physical functioning as patients will be able to undertake
daily activities more efficiently (
Gratz 2009). The use of cardiopul-
monary exercise testing (CPET), using different exercise modal-
ities (running, cycling) and measuring oxygen uptake and mus-
cular strength testing, are both practical and accurate assessments
of physical functioning. We may include less objective measures,
such as the 6-minute walk test and multistage fitness test, within
the review if the re is a lack of ’gold standard’ testing, but we will
analyse the data separately. Self-reported physical functioning can
be assessed using validated questionnaires, examples of which are
provided later in this protocol. We will consider both objectively
measured and self-reported physical functioning in our review.
Physical activity and exercise tr aining have been shown to have
direct benefits at the molecular level on skele tal muscle, the en-
dothelium and the my ocardium. Muscle fibre adaptations, mito-
chondrial activity, stem cell proliferation and an increase in ni-
tric oxide bioavailability are just some positive molecular adapta-
tions seen after exercise training (
Adams 2017). These underlying
mechanisms are proposed to contribute to increased health-related
quality of l ife, exercise capacity and a decrease in morbidity and
mortality (
Adams 2017).
Why it is important to do thi s review
Physical fitness is known to be lower in people with ConHD and
deteriorates with age faster compared to heal thy people (
Kempny
2011
; Amedro 2017). This has significant implications as CRF
is predictive of medium-term mortality rates (
Inuzuka 2012),
and is considered the most important factor in determining a
positive outcome post surgical intervention (Fontan procedure)
(
d’Udekem 2017).
Currently there is a dearth of evidence to adequately inform what
should be the optimal physical activity and exercise interventions
for people with ConHD (
Gomes-Neto 2016). Consequently, exer-
cise is not adequately discussed in paediatric cardiac cl inics; this is
primarily attributed to a lack of training and knowledge of the cur-
rent e xercise recommendations for people with ConHD (
Williams
2017). We hope by conducting this review to inform health care
policy and highlight future avenues for research for those afflicted
by a heart condition.
O B J E C T I V E S
2Physical activ ity interventions for people with congenital heart disease (Protocol)
Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Frequently asked questions

Q1. What are the contributions in this paper?

This is a protocol for a Cochrane Review ( Intervention ). The objectives are as follows: 

Q2. What will be the main purpose of this study?

The authors will also aim to undertake univariate meta-regression to explore heterogeneity and examine potential treatment effect modifiers. 

Q3. How many deaths were reported in a study of 25,790 adults with condyl?

In a study of 25,790 adults with ConHD, a total of 1189 deaths were reported with only 17 (0.01%) patients dying of sudden cardiac death of arrhythmic origin during physical activity (Koyak 2012). 

Q4. What is the main reason why people with condylarthria have reduced life?

People with ConHD suffer reduced life expectancy, which can be primarily attributed to cardiac sequelae such as progressive heart failure and sudden cardiac death (Zomer 2012; Diller 2015). 

Q5. What is the effect of the Fontan procedure on the health of children and adolescents?

Physical activity levels in children and adolescents are reduced after the Fontan procedure, independent of exercise capacity, and are associated with lower perceived general health. 

Q6. How will the authors minimise the risk of bias in included studies?

The authors will minimise selective reporting, which could overestimate the effects of an intervention, by contacting authors for unpublished data. 

Q7. What is the risk of bias in a study?

Their analysis of bias due to deviations from intended interventions will assess the effect of assignment to the intervention at baseline, sometimes known as the ‘intention-to-treat effect’. 

Q8. What is the typical care for a person with congenital heart disease?

Usual care typically comprises regular check-ups, drug treatment as required and dependent on congenital heart disease status, and general advice for a healthy and active lifestyle. 

Q9. How will the authors adjust cluster RCTs’ sample sizes?

The authors will adjust cluster RCTs’ sample sizes or standard errors using the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions using an estimate of the intracluster correlation co-efficient (ICC) derived from the trial, from a similar trial or from a study of a similar population. 

Q10. What are the five considerations used to assess the quality of a body of evidence?

The authors will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence as it relates to the studies that contribute data to the meta-analyses for the pre-specified outcomes. 

Q11. How will the authors determine the statistical model to be used for meta-analysis?

The authors will use a threshold of I² greater than 50% (considered to represent substantial heterogeneity (Deeks 2017) for both dichotomous and continuous outcomes to determine the statistical model to be used for meta-analysis. 

Q12. What will the authors do to investigate the effects of the randomisation unit?

The authors will also acknowledge heterogeneity in the randomisation unit, and perform a subgroup analysis to investigate the effects of the randomisation unit if necessaryDealing with missing dataThe authors will contact investigators or study sponsors to verify key study characteristics and obtain missing numerical outcome data where possible (for example when a study is identified as abstract only). 

Q13. What is the reason why a study is excluded from the review?

The authors anticipate most studies will provide usual care; however, where a study does not provide standard care the authors will not exclude it from the review as this may be because of a trial being conducted in a less economically developed region, where there is no provision for usual care. 

Q14. who is the lead researcher in a contractual research partnership between the university of bristol?

GEP is lead researcher in a contractual research partnership between the University of Bristol and Canon Medical Systems UK Ltd. investigating cardiac function during exercise in children. 

Q15. Who will independently screen titles and abstracts for inclusion from all the potential trials the authors identify?

Two review authors (CAW and CW) will independently screen titles and abstracts for inclusion from all the potential trials the authors identify from the search. 

Q16. Why will the authors present all reported events in the review?

Due to the dearth of available data, the authors will present all reported events (regardless of whether they were considered to be ’adverse’ or ’serious adverse’ events) in the review (by individual adverse event type) and in the ’Summary of findings’ table (> 12 months post intervention).