Challenges and Opportunities in Pediatric Heart Failure

and Transplantation
Update on Pharmacological Heart
Failure Therapies in Children
Do Adult Medications Work in Children and if Not, Why Not?
Joseph W. Rossano, MD; Robert E. Shaddy, MD

eart failure is a serious problem in children with acquired

and congenital heart disease (CHD). In 2006, there were
nearly 14000 hospitalizations related to heart failure in pediatric patients.1 The disease is also costly, not only in terms of
lives lost with a 20-fold increase in hospital mortality compared with children without heart failure but also in terms
of morbidities, prolonged hospitalizations, and dramatically
high hospital charges.13 However, it is not clear that there
has been an overall improvement in the outcomes of children
with heart failure. Although the risk-adjusted hospital mortality has declined, several single-center and multicenter studies
of dilated cardiomyopathy (DCM) failed to demonstrate any
change in survival over several decades.47
Multiple large, prospective, multicenter, randomized, controlled trials in adult heart failure patients have demonstrated
the survival advantage of -blockers, angiotensin-converting
enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists.812 However, many drugs shown to be beneficial in the treatment of heart failure in adults have not been
proven to be effective in children.4,1317 There are many potential reasons for this. One potential reason is that the medications are actually beneficial, but the design and populations
included in prior studies were not sufficient to demonstrate the
benefit. However, there are other problems that may have more
to do with the potential differences between adults and children with heart failure and their response to medications that
treat heart failure. These issues are the focus of this review.

Challenges in Study Design in

Pediatric Heart Failure
One potential explanation for the negative findings of many
pediatric heart failure studies is that the medications actually
work, but the challenges in study design and study implementation make it difficult, if not impossible, to see the beneficial
treatment effect. Prospective pediatric heart failure drug trials are almost universally underpowered to detect a difference
between treatment arms, particularly if the study is using a
primary end point of symptoms or survival rather than a surrogate end point such as a biomarker or an echocardiographic
end point. Many of the problems related to this underpowering

of these types of trials are unavoidable and related to the markedly lower incidence of heart failure in children.
The pediatric carvedilol study, a multicenter, randomized,
controlled trial, involved 161 children with chronic symptomatic heart failure from systemic ventricular dysfunction, with
enrollment from 26 centers over 5 years.14 Approximately 60%
of these patients had DCM, and the remainder had some form of
CHD. Most were in New York Heart Association or Ross heart
failure class II, and very few were in class IV. The primary end
point, which was a composite measure of clinical heart failure, was no different between carvedilol- and placebo-treated
patients, although more than half of the patients in both groups
improved. Secondary end points such as death or transplantation were also similar in both groups. Importantly, only 8
patients (5%) suffered cardiovascular mortality.
Conversely, a large, prospective, randomized trial of
carvedilol in adult heart failure patients included 2289 patients
with New York Heart Association class III or IV.9 In this study,
mortality was observed in 320 patients (14%). Only 70% of
the patients were alive by 21 months after randomization
in the placebo group. In the adult trial, the large number of
patients combined with a high event rate allowed the differences between carvedilol and placebo to be readily apparent,
and trial enrollment was stopped early secondary to benefit noted on interim analysis. Because of the differences in
events and the number of patients enrolled, it is not surprising
that the pediatric study failed to observe a difference even if
there is a difference in reality (type II error). Assuming that
carvedilol is beneficial for the patient population studied in the
pediatric trial, it would take >6000 patients followed up for 2
years (assuming a 10% mortality in placebo-treated patients
at 2 years) to demonstrate a 20% improvement in survival.
Given that <200 patients were enrolled from 26 US centers in
5 years, it is very unlikely that the study will be repeated with
a larger cohort of patients. These challenges with prospective,
randomized, controlled trials highlight the issue of relying
on these types of studies as the sole evidence of therapeutic
efficacy. Comparative effectiveness research using observational studies from well-designed registries or large databases
can provide complementary data to randomized, controlled

From the Cardiac Center, Childrens Hospital of Philadelphia, Philadelphia, PA; and Department of Pediatrics, Perelman School of Medicine, University
of Pennsylvania, Philadelphia.
Correspondence to Joseph W. Rossano, MD, The Childrens Hospital of Philadelphia, Division of Cardiology, 34th St and Civic Center Blvd, Room 6NE
40, Philadelphia, PA 19104. E-mail rossanoj@email.chop.edu
(Circulation. 2014;129:607-612.)
2014 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org

DOI: 10.1161/CIRCULATIONAHA.113.003615

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607

608CirculationFebruary 4, 2014
trials and, in some cases, replace randomized, controlled trials when the trials would be unethical or impractical.1820 For
example, the Interagency Registry for Mechanically Assisted
Circulatory Support (INTERMACS) has served as the platform for US Food and Drug Administration postapproval
studies.21 Thus, for many pediatric diseases, including heart
failure, assessment of therapeutic efficacy should not rely
solely on randomized, controlled trials but rather should take
into account the totality of evidence from well-conducted preclinical and clinical studies.
The use of surrogate end points is common in pediatric trials secondary to the low number of clinically important events
such as death. However, there is a real risk of error in concluding the benefit or lack thereof of therapies on the basis of
these surrogate end points. Early trials of -blockers in adult
heart failure patients failed to meet the primary end point of
improvement in exercise tolerance, although an improvement
in ejection fraction was noted.22,23 Although it may be tempting to conclude that an improvement in symptoms or exercise
tolerance from a medication would be sufficient to reasonably
conclude that mortality would also be improved, this should
be done with caution. Inotropic medications such as dobutamine and milrinone improve cardiac output and heart failure
symptoms.2428 However, these medications have also been
associated with increased mortality in heart failure patients
from multiple studies in adults.2933 There are limited data
on the association of inotropic medications with mortality in
pediatric heart failure, and these medications are often used as
a bridge to transplantation.3437
Another significant issue in trials of medications for pediatric heart failure patients is deciding which patients should be
included. The carvedilol study included patients with cardiomyopathy and CHD and patients with systemic left ventricles
(LVs) and systemic right ventricles. As detailed below, there

are significant differences between the right ventricles and LVs

in heart failure that may account for some of these differences.
Additionally, DCM is a heterogeneous disorder that can arise
from a variety of sources, including infections, inflammatory
disorders, metabolic disorders, mitochondrial disease, and
mutations in a variety of myocardial genes.38 Some of these
sources may respond well to angiotensin-converting enzyme
inhibitors and -blockers, whereas others may not. For example, patients with Duchenne muscular dystrophy, who have an
abnormality of the cytoskeletal protein dystrophin, seem to
have a favorable response to angiotensin-converting enzyme
inhibitors and -blockers from several observational studies
and small clinical trials.3942 Although it would be ideal to perform large-scale clinical trials in children with DCM of the
same underlying origin, the majority of pediatric patients with
DCM are idiopathic. Thus, trials finding no overall net benefit
in all patients with DCM may be overlooking an important
subset of patients who do benefit from the medications but
are not discernible because they represent a relatively small
proportion of patients in the study.

Different Responses to Medications

Ones response to a drug depends on many factors. These
factors are compounded when one considers the variable
responses that can be seen in a growing child at different stages
of development. There are age- and development-dependent
changes in how medicines are distributed in and eliminated
from the body (pharmacokinetics). There are also age- and
development-dependent changes in the response to medicines (pharmacodynamics). Furthermore, there are age- and
development-dependent changes in the adverse effects of
medicines, both short and long term. With the use of population pharmacokinetics in the pediatric carvedilol trial, it was
demonstrated that steady-state concentrations of carvedilol

Table. Summary of Trials of -Blockers, Angiotensin-Converting Enzyme Inhibitors, and Angiotensin II Antagonists in Patients
With a Systemic Right Ventricle
Agent

TGA/ccTGA

Follow-Up, mo

MRI*

Vo2max

NYHA Class

Pro/Retro

Lindenfeld et al51

Carvedilol

ccTGA

Giardini et al52

Carvedilol

Both

ND

ND

Pro

12

Pro

-Blocker

Josephson et al

Various

TGA

36

ND

ND

Retro

Doughan et al54

Various

TGA

31

ND

ND

Retro

Hechter et al16

Various

TGA

14

24

ND

Retro

Robinson et al

Enalapril

TGA

12

ND

ND

Pro

Therrien et al56

Ramipril

TGA

17

12

ND

Pro

Dore et al15

Losartan

Both

29

3.5

ND

ND

Pro

Lester et al

Losartan

TGA

ND

ND

Pro

53

ACE inhibitor
55

ATII antagonist
57

ACE indicates angiotensin-converting enzyme; ATII, angiotensin II; ccTGA, congenitally corrected transposition of the great arteries; MRI, magnetic resonance
imaging; ND, not determined; NYHA, New York Heart Association; Pro, prospective study design; Retro, retrospective study designs; , significant improvement; , no
significant change.
*Right ventricular ejection fraction as determined by MRI.
Determined in a minority of patients.
Right ventricular ejection fraction as determined by echocardiography.
Reprinted from Winter etal50 with permission from the publisher. Copyright 2009 BMJ Publishing Group Ltd & British Cardiovascular Society.

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Rossano and Shaddy Heart Failure Therapies in Children 609

appeared to be lower in this group of pediatric patients compared with historical data in adult patients, suggesting that
higher doses of carvedilol in children may be needed to
achieve the same effect as in adults.14 A subsequent formal
pharmacokinetic study of carvedilol in children found that
significantly higher doses and possibly more frequent dosing
are necessary to reach the same exposure as in adults.43 Thus,
one reason that heart failure drugs may not work the same in
children and adults is attributable to differences in absorption, metabolism, or excretion. A joint statement from the US
Food and Drug Administration, Center for Drug Evaluation
and Research, and Center for Biologics Evaluation and
Research recommends the following: (1) a combined pharmacokinetic and pharmacodynamic approach to ensure that
achieving a given exposure to a medication results in the
desired therapeutic effect; (2) the development, validation,
and use of different end points for specific age and developmental subgroups; and (3) long-term studies to determine
possible effects on skeletal, behavioral, cognitive, sexual, and
immunity maturation and development.44

Different Diseases
As noted above, the causes of heart failure in children are
diverse, including CHD and structurally normal hearts with

heart muscle disease (cardiomyopathy). Overall, 60% to 70%

of heart failure admissions in children occur with some form
of CHD.1 For the purposes of this review, we limit the discussion of heart failure to those patients with signs or symptoms
of heart failure resulting from systemic ventricular systolic
dysfunction. In the pediatric carvedilol trial, in a comparison
of those with a systemic LV with those whose systemic ventricle was not a morphological LV, there was a statistically
significant difference between the percentage of patients who
had an improved outcome (64%) in the systemic LV groups
compared with those without a systemic LV (35%), suggesting a differential response to carvedilol on the basis of the
morphology of the systemic ventricle.
Thus, it is possible that children with heart failure caused by
systolic LV dysfunction may benefit from carvedilol or other
-adrenergic receptor blocker therapy. However, this would
assume that the causes of systolic LV dysfunction in a child
are similar to those in an adult. This assumption may not be
correct. In adults with nonischemic cardiomyopathy, there is
a high incidence of comorbidities, including atrial fibrillation
(20%35%), diabetes mellitus (25%47%), and hypertension
(40%70%).4547 In contrast, these comorbidities are virtually nonexistent in pediatric nonischemic cardiomyopathies.
It is certainly possible, even likely, that the response to heart

Figure 1. The 10 most abundantly expressed microRNAs (miRs) in the right ventricle (RV) of sham and pulmonary arteryconstricted animals compared with the RV of sham and serum response factorinduced left ventricular (LV) hypertrophy (LVH) ventricles. RVH indicates
RV hypertrophy. Reproduced from Reddy etal58 with permission from the publisher. Copyright 2012 American Physiological Society.

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610CirculationFebruary 4, 2014
failure medications will be very different in a hypertensive,
diabetic adult with atrial fibrillation than in a child with idiopathic DCM, despite the fact that both patients have heart failure caused by systolic LV dysfunction.
In addition to systolic LV dysfunction as a cause of heart
failure in children, systolic dysfunction of a systemic ventricle that is not of LV morphology is becoming increasingly
common in pediatric patients. Now that a higher percentage
of patients are surviving surgery for CHD, many of whom
have a systemic right or single ventricle, systolic dysfunction is becoming increasingly common as they age.2 An early
prospective, randomized trial of enalapril compared with placebo in a group of patients after the Fontan operation failed
to show any benefit of enalapril over placebo with respect to
exercise capacity.48 However, more concerning was the finding that the mean percent change in cardiac index from rest to
maximal exercise was significantly decreased in the enalapril
group compared with the placebo group, suggesting potential
deleterious effects of angiotensin-converting enzyme inhibitors in patients with Fontan circulation. Other studies in adults
with a systemic right ventricle have failed to demonstrate
improvement in right ventricular ejection fraction with enalapril49 or to demonstrate improvement in exercise capacity or
N-terminal pro-brain natriuretic peptide levels with losartan (Table).15,50 Most recently, a double-blind, randomized,
placebo-controlled pilot study in a group of young adults with
a systemic right ventricle showed no benefit of valsartan over
placebo with regard to right ventricular ejection fraction, exercise capacity, or quality of life.17 Moreover, there are data to
suggest that the right ventricles and LVs may be different in
terms of gene expression, microRNA expression, and adaptation to fibrosis (Figure1).5860

Although it is possible that these studies were also underpowered to detect a difference between groups, they clearly
raise the question of whether the proven standard treatments
for heart failure in those with a systemic LV can be extrapolated to those with a systemic ventricle that is not an LV.
Similarly, there are no randomized trials demonstrating clear
benefit of -blockers in this subgroup of pediatric and young
adult patients with a systemic ventricle that is not an LV.

Different Substrate
In addition to potential differences in drug metabolism and differences in morphology, the underlying substrate of the systemic
ventricle may be very different between children and adults. In
the first pharmacogenetic analysis of angiotensin-converting
enzyme inhibition in children with CHD, Mital and colleagues61
showed that renin-angiotensin-aldosterone system upregulation genotypes are associated with unfavorable remodeling and
a deleterious effect of enalapril on growth. Using an explanted
human heart biorepository, Miyamoto and colleagues62 have
shown that the molecular characteristics of pediatric heart failure may be markedly different from those in adults (Figure2),
including downregulation of 1- and 2-adrenergic receptors
in children but no downregulation of 2-adrenergic receptors
in adults, upregulation of connexin 43 in children compared
with downregulation in adults, no differences in phosphatase
expression in children whereas upregulation occurs in adults,
and no decrease in phosphorylation of phospholamban in children with heart failure, a known characteristic of adult heart
failure. This difference in -adrenergic receptor expression
between adults and children may have important implications
for -receptor blockade therapy in heart failure. Data from
Bernstein and other investigators63 suggesting that there are

Figure 2. Differences in -adrenergic receptors (ARs) between pediatric and adult failing and nonfailing hearts. Reproduced from
Miyamoto etal62 with permission from the publisher. Copyright 2012 European Society of Cardiology.

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Rossano and Shaddy Heart Failure Therapies in Children 611

differential effects of cardiac 1-adrenergic receptors (as being
more cardiotoxic) and 2-adrenergic receptors (as being more
cardioprotective) imply that the response to -blockade may
depend at least partially on the ratio of each receptor type in
pediatric versus adult myocardium. Furthermore, Stauffer and
colleagues64 have recently shown differences in microRNA
and SMAD4 expression in pediatric failing human heart, suggesting changes unique to children. These studies suggest that
there may be important developmental differences between
pediatric and adult heart failure among cardiomyopathy
patients that may account for at least some of the differential
treatmenteffects.

Conclusions
Currently, it is difficult to conclude with any degree of certainty whether the medications that have been well established
to be beneficial for adult heart failure patients are also beneficial for children. An adequately powered study with a pediatric
population with sufficiently long follow-up for important clinical outcomes such as death is unlikely to happen in the current funding environment and would be difficult in any funding
environment. Thus, it will continue to be difficult to properly
interpret negative studies. However, there are important differences in the pediatric and adult heart failure populations
in terms of underlying diseases, pharmacokinetic/pharmacodynamic characteristics, and gene expression that provide a
plausible explanation of why these medications may not work
in children. Extrapolating evidence from adult patients to children with heart failure may have limited utility. This presents
a challenging dilemma for the practitioner having to deciding
to use or not use these medications for pediatric heart failure
patients without the guidance of evidence-based recommendations and highlights the need for ongoing research in the field.

Disclosures
None.

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Key Words:heart failure pediatrics pharmaceutical preparations

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Update on Pharmacological Heart Failure Therapies in Children: Do Adult Medications

Work in Children and if Not, Why Not?
Joseph W. Rossano and Robert E. Shaddy
Circulation. 2014;129:607-612
doi: 10.1161/CIRCULATIONAHA.113.003615
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