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Cochrane Database of Systematic Reviews
Beta-blockers for congestive heart failure in children (Review)
Alabed S, Sabouni A, Al Dakhoul S, Bdaiwi Y, Frobel-Mercier AK
Alabed S, Sabouni A, Al Dakhoul S, Bdaiwi Y, Frobel-Mercier AK.

Beta-blockers for congestive heart failure in children.
Cochrane Database of Systematic Reviews 2016, Issue 1. Art. No.: CD007037.
DOI: 10.1002/14651858.CD007037.pub3.
www.cochranelibrary.com
Beta-blockers for congestive heart failure in children (Review)

Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Analysis 1.1. Comparison 1 Echocardiographic evaluation, Outcome 1 Left ventricular ejection fraction (LVEF). . . 29
Analysis 1.2. Comparison 1 Echocardiographic evaluation, Outcome 2 Left ventricle fractional shortening (LVFS). . 30
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 39
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Beta-blockers for congestive heart failure in children (Review) i

[Intervention Review]
Beta-blockers for congestive heart failure in children
Samer Alabed1 , Ammar Sabouni2 , Suleiman Al Dakhoul3 , Yamama Bdaiwi4 , Anne-Kristina Frobel-Mercier5
1 Department of Cardiovascular Science, The University of Sheffield, Sheffield, UK. 2 Kasr Al-Ainy School of Medicine, Cairo University,
Cairo, Egypt. 3 Department of Medicine, The Wirral University Teaching Hospitals, Upton, Wirral, UK. 4 Faculty of Medicine,
Damascus University, Damascus, Syrian Arab Republic. 5 Quantitative Clinical Pharmacology, AstraZeneca, Mölndal, Sweden
Contact address: Samer Alabed, Department of Cardiovascular Science, The University of Sheffield, Sheffield, UK. s.alabed@nhs.net,
s.alabed@sheffield.ac.uk.
Editorial group: Cochrane Heart Group.

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 1, 2016.
Citation: Alabed S, Sabouni A, Al Dakhoul S, Bdaiwi Y, Frobel-Mercier AK. Beta-blockers for congestive heart failure in children.
Cochrane Database of Systematic Reviews 2016, Issue 1. Art. No.: CD007037. DOI: 10.1002/14651858.CD007037.pub3.
ABSTRACT
Background
Beta-blockers are an essential part of standard therapy in adult congestive heart failure and therefore, are expected to be beneficial
in children. However, congestive heart failure in children differs from that in adults in terms of characteristics, aetiology, and drug
clearance. Therefore, paediatric needs must be specifically investigated. This is an update of a Cochrane review previously published in
2009.
Objectives
To assess the effect of beta-adrenoceptor-blockers (beta-blockers) in children with congestive heart failure.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and
LILACS up to November 2015. Bibliographies of identified studies were checked. No language restrictions were applied.
Selection criteria
Randomised, controlled, clinical trials investigating the effect of beta-blocker therapy on paediatric congestive heart failure.
Data collection and analysis
Two review authors independently extracted and assessed data from the included trials.
Main results
We identified four new studies for the review update; the review now includes seven studies with 420 participants. Four small studies
with 20 to 30 children each, and two larger studies of 80 children each, showed an improvement of congestive heart failure with beta-
blocker therapy. A larger study with 161 participants showed no evidence of benefit over placebo in a composite measure of heart failure
outcomes. The included studies showed no significant difference in mortality or heart transplantation rates between the beta-blocker
and control groups. No significant adverse events were reported with beta-blockers, apart from one episode of complete heart block.
A meta-analysis of left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) data showed a very small improvement
with beta-blockers.
However, there were vast differences in the age, age range, and health of the participants (aetiology and severity of heart failure;
heterogeneity of diagnoses and co-morbidities); there was a range of treatments across studies (choice of beta-blocker, dosing, duration
Beta-blockers for congestive heart failure in children (Review) 1
of treatment); and a lack of standardised methods and outcome measures. Therefore, the primary outcomes could not be pooled in
meta-analyses.
Authors’ conclusions
There is not enough evidence to support or discourage the use of beta-blockers in children with congestive heart failure, or to propose
a paediatric dosing scheme. However, the sparse data available suggested that children with congestive heart failure might benefit from
beta-blocker treatment. Further investigations in clearly defined populations with standardised methodology are required to establish
guidelines for therapy. Pharmacokinetic investigations of beta-blockers in children are also required to provide effective dosing in future
trials.
PLAIN LANGUAGE SUMMARY
Beta-blockers for children with congestive heart failure
Background
The term congestive heart failure describes a disorder in which the heart is unable to sufficiently and efficiently pump blood through
the body. Depending on the severity of the condition, this causes breathlessness and fatigue due to insufficient oxygen supply, and an
accumulation of fluids in tissues and organs.
In children, congestive heart failure is mainly due to congenital heart defects. Drug treatment, depending on the specific condition, may
be used for long-term control of heart failure, or to bridge the time until corrective surgery. For dilated or restrictive cardiomyopathy,
a disorder with high mortality, heart transplantation remains the only option when drug treatment fails.
Beta-blockers have proven beneficial and even life-saving in adults with congestive heart failure and therefore, are part of the standard
treatment. For children, similar benefits could be expected, but beta-blockers are used, if at all, off-label (i.e. they are not recommended
for children). Since the causes for heart failure are different in children than they are in adults, the main effect and adverse events may
differ. Dosing might also have to be specifically adapted for different age groups.
Study characteristics
This review summarises and discusses the available information on the use of beta-blockers in children with congestive heart failure.
Seven studies, with a total of 420 children were included in the review.
Key results
Beta-blocker therapy improved heart failure in four small studies with less than 30 participants each, and two larger studies with 80
participants each. However, the largest trial, with 161 participants, did not show a significant effect of the investigated beta-blocker
over placebo.
None of the studies reported any severe beta-blocker-related adverse events, apart from one child who had a heart rhythm disturbance.
Conclusions
There were not enough data to recommend or discourage the use of beta-blockers in children with congestive heart failure. However,
the current available data suggest that children with heart failure might benefit from beta-blocker treatment. Further investigations are
required to establish guidelines for therapy.
Description of the condition

Heart failure (HF) is the insufficiency of the heart to pump enough
BACKGROUND
blood to the organs of the body; subsequently, blood accumulates Previous studies have shown that for some drugs, the pharmacoki-
in dependent areas such as the lungs or lower limbs. Heart failure netics in children differ fundamentally from those in adults, so
is a progressive deterioration that causes premature myocardial cell require special dosing, and lead to a different treatment response
death (Katz 2009). Affected people have symptoms of shortness (Kearns 2003). The need for adapted paediatric dosing schemes
of breath, fatigue and oedema (Jessup 2009). When fluid starts for carvedilol has been previously reported (Läer 2002). Popula-
accumulating in body organs, the condition is called congestive tion pharmacokinetic analyses and subsequent simulations indi-
heart failure. cate that infants in particular, require substantially higher weight
The aetiology of congestive heart failure in childhood differs fun- normalised doses to achieve the same drug exposure as adults
damentally from that in adulthood. In adults, coronary heart dis- (Albers 2008).
ease, hypertension, acquired valvular defects, arrhythmias and my- It is also important to note the numerous differences in the co-
ocardial infarction are the leading causes of HF. However, in chil- morbidities between paediatric and adult populations. For exam-
dren, the main contributors to the aetiology of HF are congen- ple, Webster 2006 recorded renal comorbidity in about 8% of
ital heart defects (CHD; Kay 2001; Klein 2003; Picchio 2008; heart failure patients younger than one year, but in about 31%
Webster 2006). Congenital heart defects have an incidence of 4 of adult patients. Pulmonary comorbidity was present in about
to 50 per 1000 live births (Pierpont 2007), and were once consid- 23% of adults, compared to 35% in children, which is of special
ered the main cause of perinatal mortalities (Gilboa 2010). About importance, since bronchoconstriction is an adverse event of beta-
half of the children with CHD present with a defect that requires blocking agents.
interventional treatment, and half of these serious defects result
in congestive heart failure. The yearly incidence of heart failure
from structural defects is about one to two per 1000 live births How the intervention might work
(Kay 2001). The majority of these children suffer from cardiac
failure secondary to shunt lesions that lead to a considerable vol- In adults, beta-blockers counter the sympathetic system effects,
ume load of both the right and left ventricle. In this patient group, and as a result, slow down the heartbeat, reduce arrhythmias, de-
pharmacotherapy might be indicated for either long-term control crease myocardial contractility, and diminish myocardial apopto-
of heart failure to bridge the time until corrective cardiac surgery sis and fibrosis (Bautista-Hernandez 2011). Similar results may
is possible, or to treat heart failure remaining after correction. A be achieved in paediatric patients (Erdo an 2009). A correlation
much smaller group of children suffers from cardiac failure with between the plasma norepinephrine levels and the severity of heart
a low systemic output, due to cardiomyopathy or cardiac damage failure has been established (Ross 1987). In accordance, carvedilol
resulting from a different disease process, such as inflammation has been shown to decrease neurohormonal activation in paedi-
and subsequent loss of cardiac myocytes. The prognosis in this atric patients (Giardini 2003).
patient group is poor, with a five-year mortality rate of up to 80%
(Arola 1997).
Why it is important to do this review
Therapeutic management of heart failure in children lacks evi-
dence-based national and international guidelines (Beggs 2008).
Description of the intervention Medical management of paediatric heart failure includes; digoxin,
In adults, beta-adrenergic blocking agents (beta-blockers) have furosemide, hydrochlorothiazide and spironolactone, in addition
been proven successful in the treatment of congestive heart failure. to ACE inhibitors and beta-blockers (WHO 2015). When phar-
According to the European Society of Cardiology, beta-blocking macotherapy fails to provide efficacy, heart transplantation be-
agents, combined with diuretic and angiotensin-converting en- comes an option. However, transplantation is very difficult in chil-
zyme (ACE) inhibitor are standard therapy; they are also recom- dren, due to the chronic shortage of suitable donor organs. If a pa-
mended for the treatment of Classes II to IV of the New York tient lives to undergo the operation, life expectancy increases, but
Heart Association (class of recommendation = I; level of evidence stays low on an absolute scale. Morales, et al found an overall sur-
= A; NYHA 1994). This is because they have been shown to reduce vival rate of only 54% at 10 years, with a risk of rejection of 61%
both morbidity and mortality (Al-Gobrani 2013; ESC Guidelines during the first year after transplantation (Morales 2007). Also,
2005; Hunt 2006). In children, the Canadian Cardiovascular So- the immunosuppression therapy that is an essential part of the
ciety recommends the addition of a beta-blocker such as carvedilol, treatment after cardiac transplantation poses considerable long-
metoprolol, or bisoprolol to an established regimen of diuretics, term risks (Kulikowska 2008).
digoxin, and an ACE inhibitor in moderate to severe cases only Beta-blockers are life-saving standard therapy in adults with con-
(Kantor 2013). However, as heart failure in children differs from gestive heart failure. However, it is not sufficiently known whether
that in adults, positive effects of beta-blockers in paediatric heart safety and efficacy are similar in children. In general, pharmacoki-
failure cannot be readily expected. netics and pharmacodynamics of a drug might differ strongly be-

tween adults and different paediatric populations; therefore, spe- Types of interventions
cific investigations are required. We included studies investigating any kind of beta-blocker, as
The kind and severity of adverse effects in adults and in children either monotherapy, or in combination with other medication.
may also differ substantially. An example is provided in a clinical Control groups received placebo or standard therapy for heart
study by Buitelaar, et al, who investigated pindolol in children failure (i.e. diuretics, digoxin, ACE inhibitors). We did not apply
with attention-deficit hyperactivity disorder: the children experi- any restrictions to dose or route of application.
enced intense hallucinations and nightmares with a massive nega-
tive impact on their daily functioning. While nightmares are a well
known adverse effect, they are regarded as mild events in adults. Types of outcome measures
The severity of symptoms eventually led to discontinuation of the
pindolol treatment arm (Buitelaar 1996).
It is the aim of this review to give an overview of the available Primary outcomes
literature on clinical effects and side effects of beta-blockers in 1. Mortality or referral for heart transplantation
children, in order to provide evidence for therapeutic decisions. 2. Improvement of congestive heart failure, expressed by
If the quality of data proves insufficient for this, we will explore rating systems such as the New York Heart Association (NYHA)
the needs in this area as a basis for future clinical trials. This is an classification (NYHA 1994), the Ross Score (Ross 1992), or
update of a systematic review previously published in 2009 (Frobel standardised assessment by participants, parents, or doctors
2009). 3. Adverse events reported by study investigators and by
participants
Secondary outcomes
OBJECTIVES 1. Echocardiographic evaluation of left ventricular ejection

fraction (LVEF) or fractional shortening (LVFS)
Our objective was to summarise the evidence from randomised 2. Markers of the state of disease (e.g. levels of brain
controlled trials (RCT) on the effectiveness and safety of beta- natriuretic peptide (BNP))
blockers in children with congestive heart failure. 3. Cardiovascular parameters (heart rate and blood pressure)
Search methods for identification of studies

METHODS
Electronic searches
Criteria for considering studies for this review The original review searched the Cochrane Central Register of
Controlled Trials (CENTRAL) in The Cochrane Library, MED-
LINE (Ovid), EMBASE (Ovid), and LILACS up to January 2008
(Appendix 1). We updated the searches on 9 November 2015
Types of studies (Appendix 2). We did not apply any language restrictions.
All randomised, controlled, clinical trials investigating the effects
of beta-blocker therapy on paediatric participants with congestive Searching other resources
heart failure. We also searched the citation lists of relevant publications, but did
not identify any possibly relevant material that was not already
contained in the results of the database searches.
Types of participants
The participants of the included studies were children suffering
from congestive heart failure (infants and toddlers, aged 28 days Data collection and analysis
to 23 months), according to the classification system of the Euro-
pean Medicines Agency, and children up to 18 years of age (EMEA
2001). Studies specifically investigating neonates or preterm in- Selection of studies
fants, i.e. infants younger than 28 days, were not included (EMEA Two review authors (AF, SL) in the original review and two review
2001). authors in the updated review (SD, AS) independently reviewed

titles and abstracts of the search results. We excluded all publica- We investigated all included trials for unpredicted outlying meth-
tions that were reviews, retrospective, or observational study de- ods.
signs, were not randomised, or did not focus on beta-blockers,
children and congestive heart failure.
Statistical heterogeneity
We used visual inspection and both the Chi² and the I² statistics
Data extraction and management
to investigate statistical heterogeneity. We used the I² statistic to
Two review authors in the original review (AF, SL) and three re- quantify statistical inconsistency and assess the impact of hetero-
view authors in the updated review (SA, SD, AS) independently geneity in the meta-analysis. We set an I² greater than 50% to
extracted and collated data from the included trials, using a stan- demonstrate high heterogeneity.
dardised, agreed data extraction form.
Assessment of reporting biases

Assessment of risk of bias in included studies
A funnel plot test was not suitable as the number of included
We assessed the methodological quality (risk of bias) of included studies was less than ten (Sterne 2011).
trials, using the methods detailed in Chapter six of the Cochrane
Handbook for Systematic Reviews of Interventions to identify the dif-
ferent sources of bias (Higgins 2011). We rated the risk of selection Data synthesis
bias by assessing randomisation and allocation concealment. We
We used the Cochrane Review Manager software to perform data
also rated performance, detection and attrition bias by assessing
analysis (RevMan 5.3).
blinding to treatment, blinding to outcome assessment and losses
to follow-up.
Subgroup analysis and investigation of heterogeneity
Measures of treatment effect There were not enough data to carry out the intended subgroup
analyses (age, dose, aetiology and severity of heart failure, type of
We followed the recommendations of the Cochrane Handbook for
Systematic Reviews of Interventions Sections 9.2 and 9.4 for mea- beta-blocker, and additional organ disease).
suring the effects of different data types (Higgins 2011).
For continuous outcomes, we had planned to calculate mean dif-
ferences (MD) and 95% confidence intervals (CI), and for di-
chotomous outcomes, odds ratios (OR) and 95% CI. RESULTS
Unit of analysis issues

Description of studies
Our primary outcomes were mortality rates, heart failure improve-
ment, and adverse events. Our unit of analysis was the partici-
pant. We did not encounter any cluster trials, studies with multi-
ple treatment groups or cross-over trials. Results of the search
The search for the first version of this review identified 677 refer-
ences (Alabed 2009). After review of titles and abstracts, we identi-
Dealing with missing data fied six references to be of potential interest to the review. Based on
Wherever possible, we extracted data relevant to intention-to-treat the full text of these papers, we included three studies, published
analyses. in four papers (Azeka 2002; Buchhorn 2001; Shaddy 2007); we
excluded two papers, reporting on two studies (Kajimoto 2006;
Suwa 1996).
Assessment of heterogeneity We identified 388 new references in the updated literature review.
We included two studies (Ghader 2009; Huang 2013), and two
conference proceedings (Ahuja 2013; Ontoseno 2014). Figure 1
Methodological heterogeneity
shows a flow chart of the updated search.

Figure 1. Study flow diagram.

After a one-week run-in with standard therapy, which was then
Included studies
continued in both treatment arms, ten infants underwent up-
Ahuja 2013 is an abstract of an open-label, randomised controlled titration with propranolol, aiming for a heart rate of 110 to 120
per minute, or a target dose of 2 mg/kg/day.
trial presented at the Annual Conference of the Paediatric Car-
Participants were studied at the end of run-in and at the end of
diac Society of India. Eighty infants with ventricular septal de-
the titration period. This resulted in an average treatment du-
fect (VSD) awaiting surgery received either propranolol (1 to 2
ration of 17 days. The outcomes recorded were modified Ross
milligramme per kilogramme bodyweight per day (mg/kg/day))
with conventional heart failure therapy (i.e. digoxin and diuretics) Score, haemodynamic parameters (echocardiography), heart rate
or conventional therapy alone. There was no information about variability (24-hour Holter electrocardiogram (ECG)), and neu-
rohormonal parameters.
treatment duration. The median follow-up was seven months and
Ghader 2009 was a randomised, double blind, placebo-controlled
ranged from 1 to 32 months.
trial of metoprolol in children with mild to moderate heart fail-
Primary outcomes studied included death, VSD closure surgery
ure. Particpants had structural heart disease such as VSD, patent
or hospitalisation for heart failure or chest infection. Secondary
outcomes were worsening of heart failure and adverse events such ductus arteriosus (PDA), or mitral regurgitation (MR), and symp-
as bronchospastic disease and arrhythmias. toms of heart failure such as failure to thrive, sweating, recurrent
pneumonia, or exercise intolerance, despite being on cardiac med-
Unsuccesful attempts have been made to get information beyond
ication. Thirty children, aged 3 months to 10 years, were recruited
the abstract from the study authors.
from paediatric clinics in Sari, Iran.
Azeka 2002 was a randomised, double blind, placebo-controlled
The intervention group included 16 children who received a single
monocentre trial that investigated the effects of carvedilol in a
population of 22 children with low-output cardiac failure due to daily dose of metoprolol 1 mg/kg/day for three months in addition
to heart failure medication such as digoxin, ACE inhibitors and
idiopathic dilated cardiomyopathy.
diuretics. The control group received a placebo for three months
The age of the participants ranged from 3.2 months to 10 years.
in addition to the same conventional heart failure therapy as the
participants had severe heart failure (NYHA Class IV) with ejec-
interventional group.
tion fractions below 30%, despite receiving at least two months of
Outcomes studied were echocardiography parameters including:
standard treatment (i.e. digoxin, diuretics, ACE inhibitors), and
were waiting for heart transplantation. cardiac index, E-point septal separation (EPSS), left-ventricular
ejection fraction (LVEF). Other reported outcomes were: maximal
After a titration period, carvedilol was given over six months, with
velocity of early diastolic filling (E-wave), maximal velocity of late
a target dose of 0.2 mg/kg/day, given in two daily doses. The eight
diastolic filling (A-wave), the ratio of E-and A-waves (E/A) and
participants in the placebo group and the 14 participants in the
myocardial performance index (MPI).
carvedilol group all received additional standard treatment.
Huang 2013 was a randomised, open-label study comparing add-
Participants were studied at baseline and at the end of the six-
month full-dose period. Outcome measures included were: death on carvedilol to conventional therapy. Both intervention and con-
trol groups received the conventional therapy of digoxin and ACE
from cardiovascular causes, modified NYHA Class, decrease in use
inhibitors. The intervention group received additional carvedilol.
of conventional medication, delisting for heart transplantation,
The starting dose of carvedilol was 0.1 mg/kg/day and was dou-
left ventricular ejection fraction, fractional shortening, left ven-
bled every two weeks to the highest tolerated level. The tolerated
tricular diastolic index (left ventricular diastolic diameter per body
dose was maintained for six months.
surface area), and left ventricular systolic index (left ventricular
systolic diameter per body surface area). The study recruited 89 children aged 1 month to 10 years. Twelve
participants were lost to follow-up without any given reasons. The
Buchhorn 2001 conducted a randomised, open, monocentre trial
final analysis included 40 participants in the intervention group
on propranolol in 20 infants with cardiac failure.
and 37 participants in the control group.
The participants were up to three-months old, with heart failure
Outcomes studied included: Ross Score, improvement of heart
due to congenital heart disease with left-to-right shunts and pul-
failure at six months post-treatment (improvement was defined
monary over-circulation. Modified Ross Score exceeded six points,
despite standard therapy (i.e. digoxin and diuretics). The Ross as a higher than 5% increase in left-ventricular ejection fraction
(LVEF) or improvement of heart functional grade), haemody-
Score was modified in this trial by giving participants who required
namic parameters, echocardiography including: left ventricular di-
a nasogastric feeding tube a score of four points. The original sys-
astolic diameter, left ventricular systolic diameter, LVEF, left ven-
tem assigns zero or one point for a feeding duration of less or more
tricular fractional shortening, and brain natriuretic peptide (BNP)
than 40 minutes respectively, and zero to two points, depending
levels.
on the volume consumed per feeding (Ross 1992).

Ontoseno 2014 was an abstract of a double blind, randomised continued in all study arms.
controlled trial presented at the the 5th Congress of the Asia- Baseline values and results after the six-month maintenance phase
Pacific Paediatric Cardiac Society in India. Thirty children with were evaluated for a composite measure that included functional
congestive heart failure secondary to congenital heart disease were assessment, participant or parent global assessment, and major
randomised to either carvedilol alone or to conventional therapy clinical events.
with ACE inhibitors and diuretics. Treatment duration was three Baseline characteristics of the included studies can be found in
months, however, doses were not reported. The outcomes reported Table 1. Study design characteristics of the included studies can
were pulse rate, respiratory rate, and hepatomegaly. be found in the Characteristics of included studies tables.
Shaddy 2007 was a randomised, double blind, placebo-controlled,
multicentre trial of carvedilol in 161 children with symptomatic
systolic heart failure of mixed aetiology. In the majority of partic- Excluded studies
ipants (59%), the condition underlying heart failure was dilated Kajimoto 2006 and Suwa 1996 were excluded since mixed data
cardiomyopathy; in 27%, it was congenital heart disease with a from children and adults were presented, making it impossible to
systemic ventricle that was not a left ventricle; and in 14%, it was draw conclusions only on the paediatric population.
congenital heart disease with a dysfunctional systemic left ventri-
cle. In the updated search, six papers were excluded as they were either
Participants from birth to 18 years of age were included; the me- not randomised (Bajcetic 2008; Blume 2006; Kantor 2010; Li
dian age ranged from 1.8 to 3.6 years in the different treatment 2008; Xiauhoi 2014), or heart failure was secondary to muscle
arms. The children showed chronic symptomatic heart failure due dystrophy (Kwon 2012; Matsumura 2010), or thalassaemia (Ajami
to systemic ventricular systolic dysfunction, with an ejection frac- 2010; Kojury 2014), as these diagnoses are fundamentally different
tion below 40%, despite receiving at least one month of standard from the conditions in the included studies.
treatment (i.e. individually prescribed treatment that always con-
tained ACE inhibitors). Risk of bias in included studies
The carvedilol dose was slowly increased over several weeks, aim-
Methodological quality varied considerably across the included
ing for a target dose of 0.4 mg/kg/day in the low dose treatment
studies and added to the heterogeneity already introduced by the
arm (53 participants) and 0.8 mg/kg/day in the high dose arm
major differences in characteristics of the study populations (see
(53 participants), given in two daily doses over six months. The
Discussion below). A summary of the ’Risk of bias’ assessment can
remaining participants received placebo. Standard treatment was
be found in Figure 2 and Figure 3.

Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.

Figure 3. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
Allocation
Losses to follow-up were reported and accounted for in all of
All included studies used randomisation to define treatment and the studies, apart from the conference abstracts (Ahuja 2013;
control arms. However, apart from Huang 2013 and Shaddy 2007, Ontoseno 2014); there was insufficient information available in
none of the included studies elaborated on the sequence generation the abstracts about this item.
method used. While Shaddy 2007 reported extensively on haemodynamic and
Allocation concealment method was unclear in all but Shaddy neurohumoral parameters in the different treatment arms, the
2007. number of participants was different for each parameter tested;
making it impossible to compare these outcomes to those of the
other trials. The reason for this inconsistency was neither com-
Blinding mented upon nor became clear from the ’flow of individuals’ chart
Three of the included trials were placebo-controlled and double showing drop-outs and exclusions.
blinded (Azeka 2002; Ghader 2009; Shaddy 2007). Three studies Huang 2013 reported that 12 of the 89 randomised children were
were open-label, without placebo-control (Ahuja 2013; Buchhorn lost to follow-up. It was not clear to which group they had been
2001; Huang 2013). These studies compared beta-blockers (with assigned nor for what reasons they were lost to follow-up. These
conventional therapy) to conventional therapy alone. One RCT 12 children were not accounted for in the final analysis. The in-
was double blind and controlled by conventional therapy without complete outcome data are a high risk of bias in Huang 2013.
placebo (Ontoseno 2014).
Buchhorn 2001 stated that blinding would have been pointless
since participants receiving beta-blocker treatment could have Selective reporting
been easily identified by looking at changes in mean heart rate. No protocols of the included studies were available to us to inves-
With regard to this, there might have been at least partial unblind- tigate selective reporting.
ing, although unreported, in Azeka 2002, Ghader 2009, Ontoseno
2014, and Shaddy 2007 when heart rate was recorded.
Other potential sources of bias
In Buchhorn 2001, there was a statistically significant mean age
Incomplete outcome data
difference between the treatment and control arms (P = 0.03; mean
age 9.2 years; standard deviation (SD) ± 4.5 weeks in the treatment Primary outcomes
arm; mean age 5.3 years; SD ± 2.4 weeks in the control arm). As
younger infants will still have higher pulmonary vascular resistance
and hence less shunt, this difference in age may have contributed 1. Mortality or heart transplantation
to the improvement in the treatment group and biased the results.
There were no significant differences in mortality or heart trans-
This is a weakness of the trial.
plantation rates between the intervention and control groups. Four
Sample size calculation was either not given or not sufficiently
participants (29%) died in the carvedilol group, compared to two
transparent in any of the included studies. None of the included
participants (25%) in the control group. Only one case progressed
studies commented on whether there were power calculations
to heart transplantation (7%) in the carvedilol group, compared
preceding recruitment. Shaddy 2007 specified the rates of im-
to two participants (25%) in the placebo arm (Azeka 2002).
provement and worsening of heart failure they assumed likely for
The end points all-cause mortality, cardiovascular mortality, all-
carvedilol and placebo treatment, and that led to the target sample
cause mortality or heart failure hospitalisation and all-cause mor-
size of 150 participants. However, they presented no references
tality or cardiovascular hospitalisation did not differ significantly
for these numbers, nor do they comment on how far rates of im-
between treatment and control groups (Shaddy 2007).
provement, or worsening, of heart failure related to adults can be
Ahuja 2013 compared death and referral for heart surgery between
assumed to apply to children. As described in the background part
propranolol and conventional therapy. Both outcomes failed to
of this review, childhood congestive heart failure differs from heart
show a statistically significant difference.
failure in adults in that it is predominantly a consequence of con-
Mortality or referral to heart transplantation was not reported in
genital heart defects, rather than a sequela of coronary artery dis-
Buchhorn 2001; Ghader 2009; Huang 2013, or Ontoseno 2014.
ease, hypertension, myocardial infarction, or the like. Therefore,
the pathophysiology that leads to congestive heart failure is likely
to be different between adult and paediatric participants; e.g. an 2. Improvement of heart failure
impaired function of the right ventricle is more common in chil-
Ahuja 2013, Azeka 2002, Buchhorn 2001, and Huang 2013 found
dren than in adults. This implies that Shaddy 2007 based their
an improvement in heart failure under beta-blocker therapy. In
statistical calculations on inadequate assumptions concerning the
contrast, Shaddy 2007 was not able to show a significant effect with
comparability of paediatric and adult data.
carvedilol compared to placebo. Results were not pooled as the
The NYHA classification has been established to assess heart dis-
included studies used different outcome measures (Ross, NYHA
ease in adults, but cannot be easily transferred to infants (Ross
or composite measures) to assess heart failure improvement.
1992). Therefore, Buchhorn 2001 and Huang 2013 used the Ross
In the available abstract, Ahuja 2013 reported that 11 out of 40
Score to grade the severity of heart failure. Although the youngest
participants in the control group, compared to 2 out of 40 in the
participants in the Azeka 2002 trial clearly were infants (age range
carvedilol group, experienced a worsening of heart failure. No Ross
3.2 months to 10 years), the authors used a modified NYHA classi-
Scores where reported in the abstract.
fication for the whole study population, as described in a previous
In the carvedilol group, Azeka 2002 fount that some participants
publication (Bruns 2001). However, this is adapted to school-age
had a significant improvement in NYHA Class and therefore,
children, not younger ones, and it is not clear how this system was
could be removed from the transplantation waiting list (one partic-
used in infants. Shaddy 2007 used both the Ross and the NYHA
ipant (7%) improved to Class II, eight participants (57%) to Class
systems, depending on the age of the individual participant.
I). In the placebo arm, the remaining four participants (50%) did
The Ross score has to be viewed cautiously as a measure of im-
not improve in NYHA Class (Class IV).
provement of heart failure with beta-blocker therapy, as it incor-
In Buchhorn 2001, propranolol-treated infants showed a signif-
porates heart rate as a parameter. While a decrease of tachycar-
icant improvement in clinical symptoms according to the Ross
dia may indicate improvement of heart failure, this does not ap-
Score. At baseline, the condition of the participants of the pro-
ply with beta-blocker treatment, since beta-blockers decrease heart
pranolol group was classified as moderate (mean 8.3; SD ± 1.9
rate in all participants, regardless of clinical improvement. There-
points), and improved to mild (mean 3.3; SD ± 2.3 points) by the
fore, a beta-blocker-induced heart rate reduction may have biased
end of the propranolol titration period. At baseline, Ross Score
all studies that used the Ross score (Buchhorn 2001; Huang 2013;
points in the control group were a mean of 7.2; SD ± 2.4 points,
Shaddy 2007).
and increased to a mean of 8.3; SD ± 1.9 points at the end of the
Ghader 2009, Ahuja 2013 and Ontoseno 2014 did not report a
investigation period. Both counts were classified as moderate con-
Ross score or NYHA classification.
gestive heart failure (range for mild = three to six points; moderate
= seven to nine points).
In Huang 2013, the carvedilol group had a mean baseline Ross
Score of 6.7; SD ± 2.2 points, and a mean of 5.9; SD ± 2.8 points
Effects of interventions at the end of the six-month trial. This reflected an improvement

in Ross Score of 0.8 (12%) and was statistically significant. The quency of cardiovascular adverse events in the carvedilol and
control group did not demonstrate a significant change in heart placebo arms. The most common adverse events in all study arms
failure. were upper respiratory tract infections, vomiting, and cough.
Shaddy 2007 found that 56% of the participants in both the Of the ten infants treated with propranolol in Buchhorn 2001, two
placebo and carvedilol group (combined high and low dose arms) developed bradycardia at higher dosages and therefore, received a
improved in a composite measure of heart failure outcomes (30 dose lower than the target of 2 mg/kg/day. No negative effects on
of 54 participants in the placebo group; 58 of 103 participants ventricular function or haemodynamics were observed.
in the carvedilol group). The severity of heart failure stayed un- No information regarding safety of beta-blockers was found in
changed in eight participants (15%) of the placebo arm and in Ahuja 2013, Ghader 2009, or Ontoseno 2014.
20 participants (19%) of the treatment arm, and worsened in 16
participants (30%) of the placebo arm and 25 participants (24%)
of the treatment arm. The Ross Scores, NYHA classification, and Secondary outcomes
assessment by participants, parents or doctors contributed to the
composite measure but were not reported separately.
Neither Ghader 2009 nor Ontoseno 2014 reported Ross Scores, 4. Echocardiographic evaluation
NYHA classification, or other composite measures. Azeka 2002, Huang 2013, and Shaddy 2007 reported left ventric-
ular ejection fraction (LVEF) and left ventricle fractional short-
ening (LVFS). The common outcome measures made it possible
3. Adverse Events to perform meta-analyses. Ghader 2009 reported LVEF, but only
All of the participants treated with carvedilol in Azeka 2002 toler- included participants with no systolic dysfunction, so these data
ated the target dose (0.2 mg/kg/day) well. No side effects typical were not included in the meta-analyses.
of anti-adrenergic drugs were observed. The pooled results of LVEF showed a very small improvement in
In Huang 2013, none of the participants taking carvedilol demon- the beta-blocker compared to the control arm (MD 5.99%; 95%
strated renal or hepatic impairment. One participant on carvedilol CI 1.88 to 10.11; Analysis 1.1; Figure 4). However, this result
experienced lower respiratory tract infection and complete atri- became statistically insignificant using a random-effects analysis
oventricular block. Another participant experienced a leptotrichia (MD 7.56%; 95% CI -0.45 to 15.57). The I² was 69%, demon-
infection. strating high heterogeneity (Azeka 2002; Huang 2013; Shaddy
Shaddy 2007 found no significant difference between the fre- 2007).
Figure 4. Forest plot of comparison: 1 Echocardiographic evaluation, outcome: 1.1 Left ventricular ejection
fraction (LVEF).
The pooled LVFS changes showed a small improvement (MD

3.79%; 95% CI 0.92 to 6.66; I² = 31%; Analysis 1.2; Figure 5),
which remained statistically significant in a random-effects analysis
(Azeka 2002; Huang 2013; Shaddy 2007).

Figure 5. Forest plot of comparison: 1 Echocardiographic evaluation, outcome: 1.2 Left ventricle fractional
shortening (LVFS).
Buchhorn 2001 reported fractional area change (FAC), which did

not differ significantly between the propranolol and the control methods, data quality, and outcome reporting. Therefore, we were
group. only able to pool the results for two outcomes, and we were unable
No echocardiographic evaluations were reported in the two con- to provide robust evidence for the effectiveness of beta-blockers in
ference abstracts (Ahuja 2013; Ontoseno 2014). children with congestive heart failure.
5. Markers of the state of disease Summary of main results

Plasma brain natriuretic peptide (BNP) baseline and post-treat-
No significant differences in mortality and heart transplantation
ment concentrations were reported in Huang 2013 and Shaddy
rates were reported between the beta-blocker and control groups
2007. The baseline BNP levels in the carvedilol were higher in
in Ahuja 2013; Azeka 2002; or Shaddy 2007.
Huang 2013 (median 9356 pg/mL) than in Shaddy 2007 (median
Four studies reported an improvement in heart failure with beta-
91 pg/mL), and may reflect a different stage of heart failure in the
blocker therapy (carvedilol and propranolol; Ahuja 2013; Azeka
two trials. Therefore, we did not pool the results.
2002; Buchhorn 2001; Huang 2013). Improvement was measured
In Huang 2013, BNP levels decreased by 30% in the carvedilol
with the NYHA classification, Ross Scores or composite measures.
group compared to 20% in the control group. In Shaddy 2007,
However, effectiveness of carvedilol could not be shown in a larger
BNP levels only decreased significantly in the placebo group.
trial that included 161 children aged 3 months to 17 years (Shaddy
2007).
6. Cardiovascular parameters; Haemodynamics No severe adverse events were reported in any of the studies, apart
Azeka 2002 did not report heart rate; blood pressure changes were from one episode of complete atrioventricular block in Huang
not significant. 2013.
In Buchhorn 2001, the mean heart rate was significantly reduced There was a small pooled improvement in echocardiographic pa-
with propranolol (mean HR 118/minute; SD ± 10/minute), com- rameters (LVEF and LVFS; Azeka 2002; Huang 2013; Shaddy
pared to the control group (mean HR 142/minute; SD ± 11/ 2007). Studies in adults showed similar changes in ejection frac-
minute; P < 0.001). tion and were associated with clinical improvement (van Campen
Ontoseno 2014 reported a significantly lower pulse rate in the 1998; Chatterjee 2013). However, EF changes between 5-10%
beta-blockers’ group, compared to the diuretics + ACE inhibitors’ can also be explained by inter-observer variety, test-retest reliabil-
group. ity, difference in EF calculation methods and random variation
In Shaddy 2007, the heart rate was significantly reduced with (Mahmarian 1991; Galderisi 2011). Small changes in EF rates
carvedilol treatment (combined doses; mean HR 89.2/minute; SD might thus not be clinically significant.
± 30.3/minute), compared to placebo (mean HR 106/minute; SD The abstract published by Ontoseno 2014 only reported heart and
± 21.8/minute; P = 0.04). respiratory rate and was of limited benefit to this review.
No haemodynamics were reported in Ahuja 2013, Ghader 2009,
or Huang 2013.
Overall completeness and applicability of

evidence
DISCUSSION
The main outcome of interest was reduction of mortality and heart
We included seven studies that examined 420 paediatric partic- transplantation rates, and improvement of heart failure with beta-
ipants, which were extremely heterogenous in study population, blocker treatment. These outcomes could not be pooled from the

included studies because there was strong heterogeneity of study in favour of beta-blocker treatment in children with heart failure.
populations, designs, and outcome measures used for heart failure. At the same time, no additional adverse effects from these higher
The aetiologies of heart failure varied between studies. Partici- doses were reported, apart from one episode of complete atrioven-
pants had a background of dilated cardiomyopathy in Azeka 2002 tricular block in Huang 2013.
and Huang 2013, and congenital heart disease in Ahuja 2013, The inconclusiveness of the data available from randomised con-
Buchhorn 2001, Ghader 2009, and Ontoseno 2014. Shaddy 2007 trolled trials contrasts with current clinical practice, as beta-block-
included a mixed population with dilated cardiomyopathy and ers are used in paediatric cardiology and have been reported in sev-
congenital heart disease. Participant age and age range of the in- eral observational investigations to be beneficial (Buchhorn 1998;
dividual study populations also differed across trials. Gachara 2001; Rusconi 2004; Shaddy 1999; Williams 2002).
There was heterogeneity in the study medication. Ahuja 2013 and
Buchhorn 2001 investigated propranolol, Ghader 2009 studied
metoprolol, and Azeka 2002, Huang 2013, Ontoseno 2014, and
Shaddy 2007 investigated carvedilol, but examined different doses. Quality of the evidence
Treatment duration varied widely as well; it was only 17 days in
All seven included studies are RCTs. All included studies stated
Buchhorn 2001, three months in Ghader 2009 and Ontoseno
that they were randomised trials but only Shaddy 2007 and Huang
2014, six months in Azeka 2002 and Huang 2013, and eight
2013 adequately reported the randomising. Allocation sequence
months in Shaddy 2007.
generation was only described by Shaddy 2007.
Similarly, outcome measures were not standardised; they differed
Four trials were double blinded (Azeka 2002; Ghader 2009;
between the trials and were largely incomparable. Although in
Shaddy 2007; Ontoseno 2014) and three were open-label (Ahuja
each case some variant of a heart failure classification system was
2013; Buchhorn 2001; Huang 2013).
used, it differed in any two of the included trials.
Four of the trials were small and had sample sizes that ranged
The ’high dose’ of carvedilol used (0.8 mg/kg/day) by Shaddy
between 20 and 30 participants (Azeka 2002; Buchhorn 2001;
2007, which is about the daily dose used in adults for the treatment
Ghader 2009; Ontoseno 2014). Sample size calculations were not
of heart failure (0.7 mg/kg/day, assuming a body weight of 73 kg),
sufficiently transparent in these small studies, nor in Shaddy 2007,
might have led to sub-therapeutic plasma levels in the paediatric
which was much larger (161 participants) but failed to prove a
population, since drug clearance is highly dependent on organ
significant effect of carvedilol over placebo.
maturation and fluctuates during childhood. This hypothesis of
Two trials were only published as conference proceedings (Ahuja
under-dosing in Shaddy 2007 is supported by the discussion of
2013; Ontoseno 2014). This limited both the information avail-
the authors themselves, who detected trough carvedilol concen-
able and the ’Risk of bias’ assessment in these studies. The
trations that were lower than those known to result in adults; this
Ontoseno 2014 abstract contributed particularly limited data for
is supported other, earlier publications (Läer 2002). Specifically,
this review, due to the scarce information reported in the abstract.
Albers 2008 suggested that in children, a fourfold increased dose
Attempts were made to contact the authors of these studies with-
(3 mg/kg/day instead of 0.7 mg/kg/day) of carvedilol is required
out success. Once published, we will include data from the full
to achieve plasma levels comparable to those in adults.
report of these studies in an updated version of this review.
However, Azeka 2002 was able to show a significant effect of
carvedilol with a dose as low as 0.2 mg/kg/day. It is possible that
this was due to the severity of the condition; all participants in this
study had severe heart failure (NYHA Class IV), which is likely
to imply compromised liver function, possibly resulting in an im- Potential biases in the review process
paired hepatic metabolism of carvedilol and therefore, increased None known.
drug exposure. Again, it is also possible that the improvement in
the Azeka trial was observed because the study population was a
subgroup with quite a different aetiology of heart failure than the
populations in the other studies. For instance, 100% of the partic- Agreements and disagreements with other
ipants in Azeka 2002 had a systemic left ventricle, while this was studies or reviews
the case for only 73% (118 out of 161) of the participants in the
Prijic 2014 is a systematic review and meta-analysis of beta-block-
Shaddy trial, which again highlights the above mentioned hetero-
ers in children with systolic dysfunction. This review identified
geneity of study populations, particularly with regard to aetiology
eight studies, four of which were RCTs (Azeka 2002; Huang 2013;
of congestive heart failure (Shaddy 2007).
Kwon 2012; Shaddy 2007), and four that were retrospective analy-
Higher doses have been used in more recent studies using
sis (Kantor 2010; Xiauhoi 2014), or non-randomised trials (Blume
carvedilol; Huang 2013 used 0.8 mg/kg/day of carvedilol and
2006; Li 2008). Three of the included studies in Prijic 2014 in-
Ahuja 2013 used up to 2 mg/kg/day. These trials found results
cluded participants with heart failure secondary to either muscular

dystrophy (Kwon 2012), or endocardial fibroelastosis (Li 2008; Implications for research
Xiauhoi 2014), and therefore differ from our review population.
Further randomised controlled clinical trials investigating beta-
Prijic 2014 only searched PubMed and The Cochrane Library for
blockers in children with congestive heart failure are required.
included trials, which might be the reason why three of our in-
Specifically, there is a need for pharmacokinetic investigations of
cluded studies were not included in their review (Ahuja 2013;
beta-blockers in children to ensure that treatment yields appro-
Ghader 2009; Ontoseno 2014). In addition, Prijic 2014 per-
priate therapeutic drug levels. More specific information on the
formed meta-analyses despite the clinical heterogeneity, which was
pharmacokinetics of beta-blockers in children is indispensable to
thought to be inappropriate in our review.
ensure that optimal dosing is chosen in future clinical trials. In
Prijic 2014 concluded that carvedilol significantly reduces the risk
addition, outcome measures have to be defined with particular
of death and heart transplantation in children with heart failure.
care, in order to make sure that the results of future trials are as
The number needed to treat to prevent one death was 14. Our
clear and informative as possible.
review agrees that beta-blockers might be beneficial in children.
However, we did not perform a meta-analysis to quantify their
effect.
ACKNOWLEDGEMENTS
AUTHORS’ CONCLUSIONS The authors of the updated review thank the authors of the original
version of this review Stephanie Läer, Klaus G Schmidt and Martin
Implications for practice Hulpke-Wette.
There was not enough evidence to support or discourage the use The authors would like to thank Nicole Martin from the Cochrane
of beta-blockers in children, or to propose a paediatric dosing Heart Group for her precious help with the literature searches and
scheme. However, the existing sparse data suggest that children retrieving the full texts of studies.
with congestive heart failure might benefit from treatment with
beta-blockers. We thank Henry Li for his help with a paper published in Chinese.
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Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Ahuja 2013
Methods Single centre, randomised, open-label trial.
Participants 80 infants were included.

Inclusion criteria: Infants with symptoms of heart failure with a moderate to severe VSD
awaiting surgery. Infants had at least 15 days of conventional heart failure therapy with
diuretics and digoxin before inclusion in the study
Exclusion criteria: Immediate indication for surgery for VSD, coarctation of aorta or
PDA. Infants with pulmonary artery hypertension, uncontrolled heart failure, significant
failure to thrive, Down’s syndrome, hospitalisation for pneumonia or heart failure, severe
anaemia, renal or hepatic dysfunction, hypersensitivity or contraindication to propra-
nolol
Interventions Intervention group: propranolol 1 mg/kg/day and increased to a maximum of 2 mg/kg/

day if tolerated. In addition to conventional heart failure therapy
Control group: conventional therapy with diuretics and digoxin similar to the interven-
tion group
Outcomes Primary outcomes: death, VSD closure surgery or hospitalisation for heart failure or
chest infection.
Secondary Outcome: worsening of heart failure and adverse events such as bronchospastic
disease and arrhythmias
Notes Abstract only; no full report.
Risk of bias Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Unclear risk Randomisation mentioned, but method
bias) not specified. Only abstract available
Allocation concealment (selection bias) Unclear risk Only abstract available.
Blinding (performance bias and detection High risk open label.

bias)
All outcomes
Blinding of participants and personnel High risk open label.

(performance bias)
All outcomes
Blinding of outcome assessment (detection High risk open label.

bias)
All outcomes

Ahuja 2013 (Continued)
Incomplete outcome data (attrition bias) Unclear risk Only abstract available.
All outcomes
Selective reporting (reporting bias) Unclear risk Only abstract available.
Azeka 2002
Methods Monocentre, parallel design.
Participants Sao Paulo, Brazil

22 participants: 14 (4 male/10 female; 29/71%) in treatment group; 8 (7 male/1 female;
88/13%) in control group
Age range: 3.2 months to 10 years
Mean age: in treatment arm 2.1 (95% CI 1.4 to 2.8) years; in control arm 3.7 (1.1 to 6.
2) years
Inclusion criteria: idiopathic DC; EF < 30%; listed for transplantation; 2 months of
standard treatment insufficient
Exclusion criteria: active myocarditis; sustained ventricular tachycardia or heart block not
controlled by antiarrhythmic intervention or pacemaker; systemic arterial hypertension;
progressive systemic diseases causing cardiomyopathy; clinically important hepatic or
renal disease; haemodynamic instability with adrenergic agonist or antagonist treatment
or ventilatory mechanical support
Baseline severity of HF: NYHA Class IV (all participants)
Co-diagnoses (extracardial): not specified
Interventions Study medication: carvedilol

Dosing: initial dose 0.01 mg/kg/day; weekly doubling of dose to 0.16 mg/kg/day; target
dose 0.2 mg/kg/day; given in two doses
Medication control group: placebo
Co-medication: all participants received digoxin, diuretics and ACE inhibitors
Treatment length, overall: 6 months + titration period (mean (95% CI)) treatment arm:
59.8 (37.4 to 82.2) days; control arm: 61.7 (35.8 to 87.7) days
Treatment length, full dose: 6 months
Outcomes Death from cardiovascular reasons

Modified NYHA Class
Decrease in use of conventional medication
Delisting for heart transplantation
Left ventricular ejection fraction
Fractional shortening
Left ventricular diastolic index (diameter per body surface area)
Left ventricular systolic index (diameter per body surface area)
Notes

Azeka 2002 (Continued)
Random sequence generation (selection Unclear risk Randomisation mentioned, but method not specified.
bias)
Allocation concealment (selection bias) Unclear risk Allocation concealment not mentioned.
Blinding (performance bias and detection Low risk Double blind.

bias)
All outcomes
Blinding of participants and personnel Low risk Double blind.

(performance bias)
All outcomes
Blinding of outcome assessment (detection Unclear risk Blinding of outcome assessors not mentioned.
bias)
All outcomes
Incomplete outcome data (attrition bias) Unclear risk No discontinuation of treatment in either group;
All outcomes nine participants lost to follow-up due to death or trans-
plantation
Selective reporting (reporting bias) Low risk No study protocols available.
Buchhorn 2001
Methods Monocentre, parallel design.
Participants Göttingen, Germany

20 participants: 10 (4 male/6 female; 40/60%) in treatment group; 10 (4 male/6 female;
40/60%) in control group
Age range: infants up to 3 months
Mean age (± SD): treatment arm 9.2 ± 4.5 weeks; control arm 5.3 ± 2.4 weeks
Inclusion criteria: congenital heart disease and severe heart failure due to left-to-right
shunts; modified Ross score > 6 points despite digitalis and diuretic therapy
Exclusion criteria: not specified
Baseline severity of HF: modified Ross score (mean ± SD): treatment arm: 8.3 ± 1.9;
control arm: 7.2 ± 2.4 (after 1 week run-in on standard therapy)
Co-diagnoses (extracardial): trisomy 21 (6 cases), duodenal stenosis (2) cheilog-
nathopalatoschises (1), tuberous sclerosis (1)
Interventions Study medication: propranolol

Dosing: initial dose 1.0 mg/kg/day; titration until HR 110 to 120/min
target dose 2 mg/kg/day; mean dose 1.6 ± 0.6 mg/kg/day
Medication control group: standard therapy (co-medication, see below)
Co-medication: all participants received standard therapy, i.e. digoxin and diuretics; 1
week run-in period on standard therapy
Treatment length, overall: average of 17 days titration period (results were obtained
during the first month of treatment)

Buchhorn 2001 (Continued)
Treatment length, full dose: final observations at the end of titration period
Outcomes Modified Ross score

Haemodynamic parameters (echocardiography)
Heart rate variability (24h Holter ECG)
Neurohormonal parameters
Notes
Random sequence generation (selection Unclear risk Randomisation mentioned, but method not specified.
bias)
Allocation concealment (selection bias) Unclear risk Not applicable.
Blinding (performance bias and detection High risk Treatment and assessment both open.
bias)
All outcomes
Blinding of participants and personnel High risk Open design.

(performance bias)
All outcomes
Blinding of outcome assessment (detection High risk Open design.

bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk Treatment arm: one participant stopped treatment titra-
All outcomes tion due to sepsis, but data were included
Selective reporting (reporting bias) Unclear risk No study protocols available.
Ghader 2009
Methods Randomised controlled trial
Participants Recruited from paediatric clinics in Sari, Iran.

30 participants aged 3 months to 10 years. Followed up for 3 months.
Inclusion criteria: children with heart failure due to left ventricle volume overload struc-
tural heart disease.
Exclusion criteria: Surgery candidates with a EF of less than 50%, children with brady-
cardia (heart rate less than 60) and pulmonary artery pressure > 60 mm Hg.
Interventions Intervention group: Metoral (metoprolol) dose = 1 mg/kg/day, daily single dose for 3
months. participants continued to receive previous medication: digoxin ± ACE inhibitors

Ghader 2009 (Continued)
± diuretics
Control group: Placebo made in Mazandaran University, Pharmacology Ward. Given
as daily single dose for 3 months with continuation of previous medication: digoxin ±
ACE inhibitors ± diuretics
Outcomes Haemodynamic parameters (echocardiography): left ventricular ejection fraction, E-

point septal separation, cardiac index, maximal velocity of early diastolic filling and
myocardial performance index
Notes
Random sequence generation (selection Unclear risk randomisation is mentioned, sequence generation not
bias) specified
Allocation concealment (selection bias) Unclear risk Not specified.
Blinding (performance bias and detection Low risk The study is mentioned to be ’double-blinded’; details of
bias) blinding not mentioned
All outcomes
Blinding of participants and personnel Low risk The study is mentioned to be ’double-blinded’; details of
(performance bias) blinding not mentioned
All outcomes
Blinding of outcome assessment (detection Unclear risk The study is mentioned to be ’double-blinded’; details
bias) of blinding not mentioned but outcomes measured are
All outcomes objective and carry low risk of bias
Incomplete outcome data (attrition bias) Low risk Complete outcome data for main outcomes of study, no
All outcomes attrition nor exclusions reported from the analysis, no
loss to follow-up
Huang 2013
Methods Randomised controlled trial
Participants Paediatric participants hospitalised with dilated cardiomyopathy. Total of 89 participants

included. participants aged 1 month to 10 years.
Inclusion criteria: Grade 2 or 3 heart function on the modified Ross criteria, left ven-
tricular ejection fraction less than 45% and having received one month of conventional
treatment with ACE inhibitors, digoxin, and diuretics
Exclusion criteria: severe atrioventricular regurgitation or ventricular outflow obstruc-

Huang 2013 (Continued)
tion. ECG abnormalities including persistent or symptomatic ventricular arrhythmia,

atrioventricular block or sinus node dysfunction. Systolic blood pressure lower than 85
mm Hg for participants older than 6 years, 75 mm Hg for participants 1 to 6 years-old,
or 65 mm Hg for participants younger than 1 year; a resting heart rate lower than 60
beats/min for participants older than 6 years, 80 beats/min for participants 1 to 6 years-
old, or 100 beats/min for participants younger than 1 year. Participants with renal or
hepatic insufficiency or over sensitivity to beta-blockers were also excluded
Interventions Intervention group: Carvedilol added to conventional drug treatment including digoxin,
angiotensin-converting enzyme (ACE) inhibitor, and a diuretic.
The starting dose was 0.1 mg/kg/day, which was doubled every 2 weeks to the highest
tolerated dose. Carvedilol was given for 6 months
Control group: Conventional drug treatment without carvedilol
Outcomes Ross score and improvement of heart failure at 6 months post treatment. Improvement
was defined as more than 5% increase in LVEF or improvement of heart functional
Grade
Haemodynamic parameters (echocardiography): left ventricular diastolic diameter, left
ventricular systolic diameter, LVEF, and left ventricular fractional shortening.
BNP levels
Notes
Random sequence generation (selection Low risk Randomised based on hospital number.
bias)
Allocation concealment (selection bias) Unclear risk Not specified.
Blinding (performance bias and detection High risk Open design.

bias)
All outcomes
Blinding of participants and personnel High risk Open design.

(performance bias)
All outcomes
Blinding of outcome assessment (detection High risk Open design.

bias)
All outcomes
Incomplete outcome data (attrition bias) High risk 12 participants were lost to follow-up (13.48%) without
All outcomes any reasons given. No intention-to-treat analysis

Ontoseno 2014
Methods Radomized, controlled, double blind study
Participants 30 children with congestive heart failure secondary to left-to-right shunt congenital heart
disease (VSD and PDA)
Interventions Intervention: Carvedilol

Control: ACE inhibitor and diuretics
Outcomes Heart rate, respiratory rate, and hepatomegaly
Notes Abstract only; no full report.
Random sequence generation (selection Unclear risk randomisation is mentioned, sequence

bias) generation not specified
Allocation concealment (selection bias) Unclear risk No mentioned in abstract.
Blinding (performance bias and detection Unclear risk No details in abstract.

bias)
All outcomes
Blinding of participants and personnel Low risk Double blind study.

(performance bias)
All outcomes
Blinding of outcome assessment (detection Unclear risk No details in abstract.

bias)
All outcomes
Incomplete outcome data (attrition bias) Unclear risk No details in abstract.

All outcomes
Selective reporting (reporting bias) Unclear risk No details in abstract.
Shaddy 2007
Methods 26 centres, parallel design
Participants USA
161 participants: 106 (53 at each dose level) in treatment group; 55 in control group
Gender (male/female): 83/78 (52/48%)
Age range: 0 to 18 years
Median (interquartile range) age: ’high dose’ arm: 2.8 (1.1 to 10.2) years; ’low dose’ arm:
3.6 (1.2 to 12.8) years; control arm: 1.8 (0.8 to 6.1) years
Inclusion criteria: chronic symptomatic heart failure due to systemic ventricular systolic
Shaddy 2007 (Continued)
dysfunction; NYHA Class or Ross score II, II or IV for at least 1 month (neonates: 2
weeks); EF < 40% within 4 weeks of randomisation; 1 month (neonates: 2 weeks) of
stable standard treatment insufficient
Exclusion criteria: NYHA or Ross Class I; transplantation or corrective surgery antici-
pated during 8 months after study entry; sustained or symptomatic uncontrolled ventric-
ular dysrhythmias; presence of certain cardiac conditions or endocrine disorders (speci-
fied); cardiomyopathy caused by certain conditions (specified); active myocarditis; un-
acceptable blood pressures and heart rates (specified); renovascular or pulmonary hy-
pertension unresponsive to vasodilator agents; obstructive pulmonary or reactive airway
diseases; disorders that could impair drug absorption, metabolism or excretion; severe
illness that could preclude participation or survival; no consent given; child-bearing po-
tential without adequate contraception; sensitivity or allergy to adrenoceptor-blockers;
use of investigational drugs in specified time before randomisation; use of beta-blockers
within 2 months of randomisation; use of certain other drugs (specified) within 2 weeks
of randomisation
Baseline severity of HF: NYHA Class - percentage of all participants: NYHA II = 71%;
NYHA III = 27%; NYHA IV = 0.1%
Co-diagnoses (extracardial): not specified
Interventions Study medication: carvedilol

Dosing:
’low dose’ treatment arm: initial dose 0.05 mg/kg/day; every other week doubling of
dose; target dose 0.4 mg/kg/day (25 mg/d for participants > 62.5 kg);
’high dose’ treatment arm: initial dose 0.1 mg/kg/day; every other week doubling of
dose; target dose 0.8 mg/kg/day (50 mg/d for participants > 62.5 kg);
all doses distributed to two applications
Medication control group: placebo
Co-medication: all participants received ’standard heart failure therapy’, including ACE
inhibitors
Treatment length, overall: 8 months
Treatment length, full dose: 6 months
Outcomes Primary outcome:

effect on composite measure of clinical heart failure outcomes
Secondary outcomes:
individual components of the composite measure; echocardiographic parameters; scored
drug levels of carvedilol in the population;
BNP levels; safety and tolerability
Notes clinicaltrials.gov Identifier: NCT00052026
Random sequence generation (selection Low risk Adequate randomisation; study arms stratified for left or
bias) non-left systemic ventricle
Allocation concealment (selection bias) Low risk Randomisation code assigned by pharmacist.

Shaddy 2007 (Continued)
Blinding (performance bias and detection Low risk Double blind.

bias)
All outcomes
Blinding of participants and personnel Low risk Double blind.

(performance bias)
All outcomes
Blinding of outcome assessment (detection Unclear risk Blinding of outcome assessors not mentioned.
bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk Intention-to-treat analysis shows no significant differences
All outcomes with regard to completion, withdrawal, death and trans-
plantation; 20% to 25% discontinuation in each treatment
arm
Selective reporting (reporting bias) Unclear risk No study protocols available. Trial registered on clinicaltri-
als.gov but no outcomes were provided
ACE = angiotensin converting enzyme, BNP = brain natriuretic peptide, CI = confidence interval, DC = dilated cardiomyopathy , ECG
= electrocardiogram, EF = ejection fraction, HF = heart failure, HR = heart rate, kg = kilogramme, mg/kg/day = milligrammes per
kilogramme bodyweight per day, NYHA = New York Heart Association, PDA = patent ductus arteriosus, SD = standard deviation,
VSD = ventricular septal defect
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Ajami 2010 Particants inclusion criteria not met. Heart failure secondary to thalassaemia
Bajcetic 2008 Not a randomised trial.
Blume 2006 Not a randomised trial.
Kajimoto 2006 Age of the study population ranges from 7 to 27 years without any sub-grouping for different ages, therefore, no
conclusions can be drawn with regard to a paediatric population
Kantor 2010 Retrospective analysis. Not a randomised trial.
Kojury 2014 Particants inclusion criteria not met. Heart failure secondary to thalassaemia
Kwon 2012 Particants inclusion criteria not met. Heart failure secondary to muscular dystrophy

(Continued)
Li 2008 Not a randomised trial. Heart failure secondary to endocardial fibroelastosis
Matsumura 2010 Particants inclusion criteria not met. Heart failure secondary to muscular dystrophy
Suwa 1996 Age of the study population ranges from 14 to 68 years without any sub-grouping for different ages, therefore,
no conclusions can be drawn with regard to a paediatric population
Xiauhoi 2014 Retrospective analysis. Not a randomised trial.

DATA AND ANALYSES
Comparison 1. Echocardiographic evaluation
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Left ventricular ejection fraction 3 207 Mean Difference (IV, Fixed, 95% CI) 5.99 [1.88, 10.11]
(LVEF)
2 Left ventricle fractional 3 207 Mean Difference (IV, Fixed, 95% CI) 3.79 [0.92, 6.66]
shortening (LVFS)
Analysis 1.1. Comparison 1 Echocardiographic evaluation, Outcome 1 Left ventricular ejection fraction
(LVEF).
Review: Beta-blockers for congestive heart failure in children
Comparison: 1 Echocardiographic evaluation
Outcome: 1 Left ventricular ejection fraction (LVEF)
Mean Mean
Study or subgroup Beta-Blocker Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Azeka 2002 14 16.8 (17.45) 8 -2 (8.2) 14.6 % 18.80 [ 8.04, 29.56 ]
Huang 2013 40 7.7 (16.1) 37 5 (17.4) 30.1 % 2.70 [ -4.81, 10.21 ]
Shaddy 2007 53 14.2 (13.25) 55 9.8 (16) 55.3 % 4.40 [ -1.13, 9.93 ]
Total (95% CI) 107 100 100.0 % 5.99 [ 1.88, 10.11 ]

Heterogeneity: Chi2 = 6.50, df = 2 (P = 0.04); I2 =69%
Test for overall effect: Z = 2.85 (P = 0.0043)
Test for subgroup differences: Not applicable
-20 -10 0 10 20
Favours [control] Favours [beta-blockers]

Analysis 1.2. Comparison 1 Echocardiographic evaluation, Outcome 2 Left ventricle fractional shortening
(LVFS).
Review: Beta-blockers for congestive heart failure in children
Comparison: 1 Echocardiographic evaluation
Outcome: 2 Left ventricle fractional shortening (LVFS)
Mean Mean
Study or subgroup Beta-Blocker Control Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Azeka 2002 14 6.9 (10.2) 8 -1.5 (7.87) 14.2 % 8.40 [ 0.77, 16.03 ]
Huang 2013 40 4.4 (9.84) 37 3.4 (11.08) 37.5 % 1.00 [ -3.70, 5.70 ]
Shaddy 2007 53 9.7 (9.84) 55 5.1 (12) 48.4 % 4.60 [ 0.47, 8.73 ]
Total (95% CI) 107 100 100.0 % 3.79 [ 0.92, 6.66 ]

Heterogeneity: Chi2 = 2.90, df = 2 (P = 0.23); I2 =31%
Test for overall effect: Z = 2.58 (P = 0.0097)
Test for subgroup differences: Not applicable
-10 -5 0 5 10
Favours [control] Favours [beta-blockers]
ADDITIONAL TABLES
Table 1. Baseline characteristics
Study ID Study arm Number Age - mean Gender (male) Weight - kg LVEF (%) Underly-
month (SD) (SD) ing heart con-
ditions
Ahuja 2013 Control 40 5.15± 2.6 75% 4.79 ±1.09 NA Ventricular sep-
tal defect
Propranolol 40 5.5 ±3.17 65% 4.71±1.43 NA (VSD)
Azeka 2002 Control 8 44.4 (13.2 to 87.50% 12.1 (7.3 to 16. 19.4 (15.9 to Dilated car-
74.4) 8) 22.8) diomyopathy
Carvedilol 14 25.2 (16.8 to 28.50% 9.2 (7.7-10.8) 16.7 (14.2-19.

33.6) 2)
Buchhorn Control 10 1.2 (±0.5) 40% 3.4 (0.5) NA Congenital

2001 heart disease.
Propranolol 10 2.1 (±1) 40% 3.8 (0.9) NA

Table 1. Baseline characteristics (Continued)
Ghader 2009 Control 14 31 ±35 36% 10.8 (6) 68.4 (2.6) Structural heart
disease such as
VSD
and patent duc-
tus arteriosus
Metoprolol 16 32.9±37 38% 10.8 (5.7) 68.2 (2.8) (PDA)
Huang 2013 Control 37 55.2 ± 54.6 56.70% NA 38.7 ± 11.5 Dilated Car-
diomyopathy
Carvedilol 40 63.7 ± 58.8 57.50% NA 35.8 ± 10.7
Ontoseno Control 15 NA NA NA NA Left to right

2014 shunt (VSD
Carvedilol 15 NA NA NA NA and PDA)
Shaddy 2007 Control 55 22 (9 to 73) 54.50% NA 25.1 (9.0) Dilated

cardiomyopa-
thy and congen-
Carvedilol 53 43 (14 to 154) 52.80% NA 28.1 (7.0) ital heart disease
APPENDICES
Appendix 1. Search strategies 2008
CENTRAL in The Cochrane Library 2008, issue 1

#1 MeSH descriptor Heart Failure, Congestive explode all trees
#2 MeSH descriptor Ventricular Dysfunction explode all trees
#3 heart next failure
#4 cardiac next failure
#5 (ventric* near/6 dysfunction* )
#6 (ventric* near/6 function* )
#7 MeSH descriptor Heart Defects, Congenital explode all trees
#8 (congenital* near/3 heart )
#9 (congenital near/3 cardiac )
#10 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9)
#11 MeSH descriptor Adrenergic beta-Antagonists explode all trees
#12 betablocker*
#13 beta-blocker*
#14 (beta* near/3 block* )
#15 (Beta and (Adrenergic near/6 block* ) )
#16 acebutolol
#17 atenolol
#18 alprenolol
#19 betaxolol
#20 bisoprolol
#21 bupranolol
#22 carvedilol
#23 carteolol
#24 celiprolol
#25 esmolol
#26 labetalol
#27 metoprolol
#28 nadolol
#29 nebivolol
#30 oxprenolol
#31 penbutolol
#32 pindolol
#33 practolol
#34 propranolol
#35 sotalol
#36 timolol
#37 (#11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20)
#38 (#21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29)
#39 (#30 or #31 or #32 or #33 or #34 or #35 #36)
#40 (#37 or #38 or #39)
#41 child*
#42 (pediatr* or paediatr* )
#43 adolesc*
#44 infant*
#45 (#41 or #42 or #43 or #44)
#46 (#10 and #40 and #45)
MEDLINE (Ovid)
1 exp Heart Failure/
2 exp Ventricular Dysfunction/
3 heart failure.tw.
4 cardiac failure.tw.
5 (ventric$ adj6 dysfunction$).tw.
6 (ventric$ adj6 function$).tw.
7 exp Heart Defects, Congenital/
8 (congenital$ adj3 heart).tw.
9 (congenital$ adj3 cardiac).tw.
10 or/1-9
11 exp Adrenergic beta-Antagonists/
12 betablocker$.tw.
13 (beta$ adj3 block$).tw.
14 (beta and (adrenergic adj6 block$)).tw.
15 Acebutolol.tw.
16 atenolol.tw.
17 alprenolol.tw.
18 betaxolol.tw.
19 bisoprolol.tw.
20 bupranolol.tw.
21 carvedilol.tw.
22 carteolol.tw.
23 celiprolol.tw.
24 esmolol.tw.
25 labetalol.tw.
26 metoprolol.tw.
27 nadolol.tw.
28 oxprenolol.tw.
29 penbutolol.tw.
30 pindolol.tw.
31 practolol.tw.
32 propranolol.tw.
33 sotalol.tw.
34 timolol.tw.
35 or/11-34
36 10 and 35
37 limit 36 to “all child (0 to 18 years)”
38 (child$ or infant$ or pediatr$ or paediatr$ or adolesc$).tw.
39 38 and 36
40 37 or 39
41 randomized controlled trial.pt.
42 controlled clinical trial.pt.
43 Randomized controlled trials/
44 random allocation/
45 double blind method/
46 single-blind method/
47 or/41-46
48 exp animal/ not humans/
49 47 not 48
50 clinical trial.pt.
51 exp Clinical trials as topic/
52 (clin$ adj25 trial$).ti,ab.
53 ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ti,ab.
54 placebos/
55 placebo$.ti,ab.
56 random$.ti,ab.
57 research design/
58 or/50-57
59 58 not 48
60 59 not 49
61 comparative study.pt.
62 exp evaluation studies/
63 follow up studies/
64 prospective studies/
65 (control$ or prospectiv$ or volunteer$).ti,ab.
66 or/61-65
67 66 not 48
68 67 not (49 or 60)
69 49 or 60 or 68
70 40 and 69
EMBASE (Ovid)
1 exp Heart Failure/
2 Heart Ventricle Function/
3 Heart Right Ventricle Function/
4 Heart Left Ventricle Function/
5 heart failure.tw.
6 cardiac failure.tw.
7 (ventric$ adj6 dysfunction$).tw.
8 (ventric$ adj6 function$).tw.
9 exp Congenital Heart Disease/
10 (congenital$ adj3 heart).tw.
11 (congenital$ adj3 cardiac).tw.
12 or/1-11
13 exp Beta Adrenergic Receptor Blocking Agent/
14 betablocker$.tw.
15 (beta$ adj3 block$).tw.
16 (beta and (adrenergic adj6 block$)).tw.
17 Acebutolol.tw.
18 atenolol.tw.
19 alprenolol.tw.
20 betaxolol.tw.
21 bisoprolol.tw.
22 bupranolol.tw.
23 carvedilol.tw.
24 carteolol.tw.
25 celiprolol.tw.
26 esmolol.tw.
27 labetalol.tw.
28 metoprolol.tw.
29 nadolol.tw.
30 oxprenolol.tw.
31 penbutolol.tw.
32 pindolol.tw.
33 practolol.tw.
34 propranolol.tw.
35 sotalol.tw.
36 timolol.tw.
37 or/13-36
38 12 and 37
39 exp child/
40 exp adolescent/
41 (child$ or infant$ or pediatr$ or paediatr$ or adolesc$).tw.
42 or/39-41
43 38 and 42
44 clinical trial/
45 random$.tw.
46 randomized controlled trial/
47 trial$.tw.
48 follow-up.tw.
49 double blind procedure/
50 placebo$.tw.
51 placebo/
52 factorial$.ti,ab.
53 (crossover$ or cross-over$).ti,ab.
54 (double$ adj blind$).ti,ab.
55 (singl$ adj blind$).ti,ab.
56 assign$.ti,ab.
57 allocat$.ti,ab.
58 volunteer$.ti,ab.
59 Crossover Procedure/
60 Single Blind Procedure/
61 or/44-60
62 43 and 61
LILACS
betablocker$ or beta-blocker$ or Adrenergic beta-Antagonist$ or Acebutolol or atenolol or alprenolol or Betaxolol or Bisoprolol or
bupranolol or carvedilol or carteolol or celiprolol or Esmolol or labetalol or metoprolol or Nadolol or oxprenolol or penbutolol or
pindolol or practolol or propranolol or sotalol or timolol [Palavras] and child$ or infant$ or adolesc$ [Palavras] and random$ or trial$
or study or clinical or placebo$ or prospective$ [Palavras]
Appendix 2. Search strategies 2015
CENTRAL in The Cochrane Library 2015, issue 11

#1MeSH descriptor: [Heart Failure] explode all trees
#2MeSH descriptor: [Ventricular Dysfunction] explode all trees
#3heart next failure
#4cardiac next failure
#5(ventric* near/6 dysfunction*)
#6(ventric* near/6 function*)
#7MeSH descriptor: [Heart Defects, Congenital] explode all trees
#8(congenital* near/3 heart)
#9(congenital near/3 cardiac)
#10#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9
#11MeSH descriptor: [Adrenergic beta-Antagonists] explode all trees
#12betablocker*
#13beta-blocker*
#14(beta* near/3 block*)
#15(Beta and (Adrenergic near/6 block*))
#16acebutolol
#17atenolol
#18alprenolol
#19betaxolol
#20bisoprolol
#21bupranolol
#22carvedilol
#23carteolol
#24celiprolol
#25esmolol
#26labetalol
#27metoprolol
#28nadolol
#29nebivolol
#30oxprenolol
#31penbutolol
#32pindolol
#33practolol
#34propranolol
#35sotalol
#36timolol
#37#11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or
#29 or #30 or #31 or #32 or #33 or #34 or #35 or #36
#38child* or pediatr* or paediatr* or adolesc* or infant*
#39#10 and #37 and #38
MEDLINE (Ovid)
1. exp Heart Failure/
2. exp Ventricular Dysfunction/
3. heart failure.tw.
4. cardiac failure.tw.
5. (ventric$ adj6 dysfunction$).tw.
6. (ventric$ adj6 function$).tw.
7. exp Heart Defects, Congenital/
8. (congenital$ adj3 heart).tw.
9. (congenital$ adj3 cardiac).tw.
10. or/1-9
11. exp Adrenergic beta-Antagonists/
12. betablocker$.tw.
13. (beta$ adj3 block$).tw.
14. (beta and (adrenergic adj6 block$)).tw.
15. Acebutolol.tw.
16. atenolol.tw.
17. alprenolol.tw.
18. betaxolol.tw.
19. bisoprolol.tw.
20. bupranolol.tw.
21. carvedilol.tw.
22. carteolol.tw.
23. celiprolol.tw.
24. esmolol.tw.
25. labetalol.tw.
26. metoprolol.tw.
27. nadolol.tw.
28. oxprenolol.tw.
29. penbutolol.tw.
30. pindolol.tw.
31. practolol.tw.
32. propranolol.tw.
33. sotalol.tw.
34. timolol.tw.
35. or/11-34
36. 10 and 35
37. limit 36 to “all child (0 to 18 years)”
38. (child$ or infant$ or pediatr$ or paediatr$ or adolesc$).tw.
39. 38 and 36
40. 37 or 39
41. randomized controlled trial.pt.
42. controlled clinical trial.pt.
43. randomized.ab.
44. placebo.ab.
45. drug therapy.fs.
46. randomly.ab.
47. trial.ab.
48. groups.ab.
49. 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48
50. exp animals/ not humans.sh.
51. 49 not 50
52. 40 and 51
53. (2008* or 2009* or 2010* or 2011* or 2012* or 2013* or 2014*).ed.
54. 52 and 53
EMBASE (Ovid)
1. exp heart failure/
2. heart ventricle function/
3. heart right ventricle function/
4. heart left ventricle function/
5. heart failure.tw.
6. cardiac failure.tw.
7. (ventric$ adj6 dysfunction$).tw.
8. (ventric$ adj6 function$).tw.
9. exp congenital heart disease/
10. (congenital$ adj3 heart).tw.
11. (congenital$ adj3 cardiac).tw.
12. or/1-11
13. exp beta adrenergic receptor blocking agent/
14. betablocker$.tw.
15. (beta$ adj3 block$).tw.
16. (beta and (adrenergic adj6 block$)).tw.
17. Acebutolol.tw.
18. atenolol.tw.
19. alprenolol.tw.
20. betaxolol.tw.
21. bisoprolol.tw.
22. bupranolol.tw.
23. carvedilol.tw.
24. carteolol.tw.
25. celiprolol.tw.
26. esmolol.tw.
27. labetalol.tw.
28. metoprolol.tw.
29. nadolol.tw.
30. oxprenolol.tw.
31. penbutolol.tw.
32. pindolol.tw.
33. practolol.tw.
34. propranolol.tw.
35. sotalol.tw.
36. timolol.tw.
37. or/13-36
38. 12 and 37
39. exp child/
40. exp adolescent/
41. (child$ or infant$ or pediatr$ or paediatr$ or adolesc$).tw.
42. or/39-41
43. 38 and 42
44. random$.tw.
45. factorial$.tw.
46. crossover$.tw.
47. cross over$.tw.
48. cross-over$.tw.
49. placebo$.tw.
50. (doubl$ adj blind$).tw.
51. (singl$ adj blind$).tw.
52. assign$.tw.
53. allocat$.tw.
54. volunteer$.tw.
55. crossover procedure/
56. double blind procedure/
57. randomized controlled trial/
58. single blind procedure/
59. 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58
60. (animal/ or nonhuman/) not human/
61. 59 not 60
62. 43 and 61
63. (2008* or 2009* or 2010* or 2011* or 2012* or 2013* or 2014*).dd.
64. (2008* or 2009* or 2010* or 2011* or 2012* or 2013* or 2014*).em.
65. 63 or 64
66. 62 and 65
LILACS
betablocker$ or beta-blocker$ or Adrenergic beta-Antagonist$ or Acebutolol or atenolol or alprenolol or Betaxolol or Bisoprolol or
bupranolol or carvedilol or carteolol or celiprolol or Esmolol or labetalol or metoprolol or Nadolol or oxprenolol or penbutolol or
pindolol or practolol or propranolol or sotalol or timolol [Words] and child$ or infant$ or adolesc$ [Words] and random$ or trial$ or
study or clinical or placebo$ or prospective$ [Words]
WHAT’S NEW
Last assessed as up-to-date: 9 November 2015.
Date Event Description
15 April 2015 New citation required but conclusions have not changed Four new studies included. No change to conclusion.
21 March 2014 New search has been performed Updated search run in November 2015

HISTORY
Protocol first published: Issue 2, 2008
Review first published: Issue 1, 2009
Date Event Description
4 March 2013 Review declared as stable Authors are unable to update
20 March 2009 Amended Amended ’External sources of support’ section.
19 March 2008 Amended Converted to new review format
CONTRIBUTIONS OF AUTHORS
Samer Alabed: selection of studies, data extraction and analysis, review writing and editing.
Ammar Sabouni: selection of studies, data extraction and analysis.
Suleiman Dakhoul: selection of studies, data extraction and analysis.
Yamama Bdaiwi: co-writing review.
Anne-Kristina Frobel-Mercier: author of original review and specialist feedback.
DECLARATIONS OF INTEREST
None known for the authors of the updated version of the review.
SOURCES OF SUPPORT
Internal sources
• None, Other.
External sources
• This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Heart
Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic
Reviews Programme, NIHR, NHS or the Department of Health, UK.

DIFFERENCES BETWEEN PROTOCOL AND REVIEW
In the original review, the review authors had planned to extract data for the following outcomes: acceptability of treatment, physical
fitness measures, participant perceived quality of life, and economic costs. However, the studies identified did not give enough data to
report these outcomes. In this updated version, the review authors decided not to further pursue reporting these outcomes. In addition,
no subgroup analysis could be performed as available data were limited.
INDEX TERMS
Medical Subject Headings (MeSH)

Adrenergic beta-Antagonists [∗ therapeutic use]; Carbazoles [therapeutic use]; Heart Failure [∗ drug therapy]; Metoprolol [therapeutic
use]; Propanolamines [therapeutic use]; Propranolol [therapeutic use]; Randomized Controlled Trials as Topic
MeSH check words

Adolescent; Child; Child, Preschool; Humans; Infant; Infant, Newborn


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Cochrane Database of Systematic Reviews

Beta-blockers for congestive heart failure in children (Review)

Alabed S, Sabouni A, Al Dakhoul S, Bdaiwi Y, Frobel-Mercier AK

Alabed S, Sabouni A, Al Dakhoul S, Bdaiwi Y, Frobel-Mercier AK.

Beta-blockers for congestive heart failure in children (Review)

Beta-blockers for congestive heart failure in children (Review) i

Beta-blockers for congestive heart failure in children

Editorial group: Cochrane Heart Group.

PLAIN LANGUAGE SUMMARY

Beta-blockers for children with congestive heart failure

Description of the condition

Beta-blockers for congestive heart failure in children (Review) 3

OBJECTIVES 1. Echocardiographic evaluation of left ventricular ejection

Search methods for identification of studies

Beta-blockers for congestive heart failure in children (Review) 4

Assessment of reporting biases

Unit of analysis issues

Beta-blockers for congestive heart failure in children (Review) 5

Beta-blockers for congestive heart failure in children (Review) 6

Beta-blockers for congestive heart failure in children (Review) 7

Beta-blockers for congestive heart failure in children (Review) 8

Beta-blockers for congestive heart failure in children (Review) 9

Beta-blockers for congestive heart failure in children (Review) 11

The pooled LVFS changes showed a small improvement (MD

Beta-blockers for congestive heart failure in children (Review) 12

Buchhorn 2001 reported fractional area change (FAC), which did

5. Markers of the state of disease Summary of main results

Overall completeness and applicability of

Beta-blockers for congestive heart failure in children (Review) 13

Beta-blockers for congestive heart failure in children (Review) 14

Beta-blockers for congestive heart failure in children (Review) 17

Beta-blockers for congestive heart failure in children (Review) 18

Characteristics of included studies [ordered by study ID]

Methods Single centre, randomised, open-label trial.

Participants 80 infants were included.

Interventions Intervention group: propranolol 1 mg/kg/day and increased to a maximum of 2 mg/kg/

Notes Abstract only; no full report.

Risk of bias Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk Only abstract available.

Blinding (performance bias and detection High risk open label.

Blinding of participants and personnel High risk open label.

Blinding of outcome assessment (detection High risk open label.

Beta-blockers for congestive heart failure in children (Review) 19

Selective reporting (reporting bias) Unclear risk Only abstract available.

Methods Monocentre, parallel design.

Participants Sao Paulo, Brazil

Interventions Study medication: carvedilol

Outcomes Death from cardiovascular reasons

Risk of bias Risk of bias

Bias Authors’ judgement Support for judgement

Beta-blockers for congestive heart failure in children (Review) 20

Blinding (performance bias and detection Low risk Double blind.

Blinding of participants and personnel Low risk Double blind.

Selective reporting (reporting bias) Low risk No study protocols available.

Methods Monocentre, parallel design.

Participants Göttingen, Germany

Interventions Study medication: propranolol

Beta-blockers for congestive heart failure in children (Review) 21

Outcomes Modified Ross score

Risk of bias Risk of bias

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk Not applicable.

Blinding of participants and personnel High risk Open design.