Journal of the American College of Cardiology

2002 by the American College of Cardiology Foundation

Published by Elsevier Science Inc.

Vol. 40, No. 11, 2002

ISSN 0735-1097/02/$22.00
PII S0735-1097(02)02570-6

Delisting of Infants and Children

From the Heart Transplantation
Waiting List After Carvedilol Treatment
Estela Azeka, MD, PHD, Jose Antonio Franchini Ramires, MD, PHD, FACC, Constante Valler,
Edimar Alcides Bocchi, MD, PHD
Sao Paulo, Brazil
We performed a prospective, randomized, double-blind, placebo-controlled study of carvedilol effects in children with severe, chronic heart failure (HF), despite the use of conventional
therapy.
BACKGROUND Little is known about the effects of carvedilol in youngsters with chronic HF and severe left
ventricular (LV) dysfunction.
METHODS
We conducted a double-blind, placebo-controlled study of 22 consecutive children with
severe LV dysfunction. The children had chronic HF and left ventricular ejection fraction
(LVEF) 30%. Patients were randomly assigned to receive either placebo (8 patients) or the
beta-blocker carvedilol (14 patients) at 0.01 mg/kg/day titrated up to 0.2 mg/kg/day,
followed-up for six months.
RESULTS
During the follow-up and the up-titration period in the carvedilol group, four patients died
and one underwent heart transplantation. In patients receiving carvedilol evaluated after six
months, a significant increase occurred in LVEF, from 17.8% (95% confidence interval [CI],
14.1 to 21.4%) to 34.6% (95% CI, 25.2 to 44.0%); p 0.001. Modified New York Heart
Association (NYHA) functional class improved in nine patients taken off the transplant
waiting list. All nine patients were alive at follow-up. In the placebo group, during the
six-month follow-up, two patients died, and two underwent heart transplantation. Four
patients persisted with HF symptoms (NYHA functional class IV). No significant change
occurred in LVEF or fractional shortening.
CONCLUSIONS Carvedilol added to standard therapy may reduce HF progression and improve cardiac
function, allowing some youngsters to be removed from the heart transplantation waiting
list. (J Am Coll Cardiol 2002;40:2034 8) 2002 by the American College of Cardiology
Foundation
OBJECTIVES

In heart failure (HF) beta-adrenergic receptors associated

with the alpha-adrenergic system play important roles in
myocardial contractility and cellular remodeling (1,2). Betablocking agents have been shown to reduce the risk of
hospitalization and death in patients with mild-to-moderate
HF (3,4).
In clinical trials, carvedilol, a nonselective thirdgeneration beta-blocker, vasodilator secondary to alpha1adrenergic blockade with antioxidant activity and apoptosis
inhibition, has been demonstrated to favorably affect survival in
adult patients with severe chronic HF (510), but very little is
known about its effects in infants and children (11).
We conducted a prospective, randomized, double-blind,
placebo-controlled study of the effect of the beta-blocker
carvedilol in children with severe chronic HF, despite the
use of conventional therapy.

METHODS
Study patients. All patients included in this study had
advanced HF, despite at least two months of treatment with
From the Heart Institute (InCor), University of Sao Paulo Medical School, Sao
Paulo, Brazil. Constante Valler was supported by the Fundacao de Amparo a Pesquisa
do Estado de Sao Paulo (FAPESP), Sao Paulo, Brazil.
Manuscript received March 11, 2002; revised manuscript received August 5, 2002,
accepted August 26, 2002.

digoxin, diuretics (in sufficient doses to maintain patients

free of edema), angiotensin-converting enzyme (ACE) inhibitors (if tolerated), and a poor response to conventional
therapy. They had ejection fractions 30% and were referred for heart transplantation for treatment of idiopathic
dilated cardiomyopathy at the Heart Institute (InCor) of the
University of Sao Paulo Medical School. Patients were
excluded if they had active myocarditis (excluded by endomyocardial biopsy); sustained ventricular tachycardia or
heart block not controlled by antiarrhythmic intervention or
a pacemaker; systemic arterial hypertension; progressive
systemic diseases causing cardiomyopathy; clinically important hepatic or renal disease; were hemodynamically unstable and taking either alpha- or beta-adrenergic agonists or
antagonists, or were on ventilatory mechanical support, or
both.
The Ethics Committee of our hospital approved the
protocol, and written informed consent was obtained from
each legal guardian of all patients before the study.
Study procedures. After a baseline evaluation, all consecutive children included in this study were randomly
assigned to receive carvedilol or placebo. The allocation
ratio (of patients given carvedilol to patients given placebo)
was two-to-one. They underwent a double-blind up-titration
phase, in addition to their usual medications. Patients received

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JACC Vol. 40, No. 11, 2002

December 4, 2002:20348

Abbreviations and Acronyms

ANOVA repeated-measures analysis of variance
FS
fractional shortening
HF
heart failure
LV
left ventricular/ventricle
LVDI
left ventricular diastolic index
LVEF left ventricular ejection fraction
NYHA New York Heart Association

an initial dosage of 0.01 mg/kg/day [0.13 mg/day (95%

confidence interval [CI], 0.08 to 0.19 mg/day)] of carvedilol
[0.14 mg/day (95% CI, 0.05 to 0.24 mg/day)] or placebo
[0.12 mg/day (95% CI, 0.07 to 0.16 mg/day)] for one week,
which was then increased (the dosage was double) at one-week
intervals (if tolerated), first to 0.02 mg/kg/day [0.20 mg/day
(95% CI, 0.12 to 0.29 mg/day); carvedilol 0.23 mg/day (95%
CI, 0.15 to 0.33 mg/day); placebo 0.23 mg/day (95% CI, 0.14
to 0.32 mg/day)], then to 0.04 mg/kg/day [0.44 mg/day (95%
CI, 0.25 to 0.62 mg/day); carvedilol 0.39 mg/day (95% CI,
0.32 to 0.45 mg/day); placebo 0.51 mg/day (95% CI, 0.34 to
0.69 mg/day)], proceeding in weekly steps to 0.08 mg/kg/day
[0.85 mg/day (95% CI, 0.49 to 1.21 mg/day); carvedilol
0.77 mg/day (95% CI, 0.66 to 0.88 mg/day); placebo
0.97 mg/day (95% CI, 0.6 to 1.35 mg/day)], then to
0.16 mg/kg/day [1.8 mg/day (95% CI, 1.05 to 2.56 mg/day);
carvedilol 1.67 mg/day (95% CI, 1.47 to 1.88 mg/day);
placebo 1.96 mg/day (95% CI, 1.22 to 2.7 mg/day)], and
finally to a target dose of 0.2 mg/kg/day [2.31 mg/day (95%
CI, 1.34 to 3.28 mg/day); carvedilol 2.17 mg/day (95% CI,
1.89 to 2.4 mg/day); placebo 2.49 mg/day (95% CI, 1.54 to
3.44 mg/day)], twice daily, if tolerated. During the up-titration
dosage period, patients were evaluated weekly after which
double-blind therapy was maintained for at least an additional
six months. During this time, patients were on standard
therapy with digoxin, diuretics, and ACE inhibitors. Adjustment in the standard medical therapy was at the discretion of
the physicians.
Study parameters. After six months of follow-up, patients
were observed for the occurrence of death for cardiovascular
reasons, modified New York Heart Association (NYHA)
functional classification (11), decrease in the use of conven-

2035

tional medications, and removal from the waiting list for

heart transplantation. Radionuclide ventriculography and
echocardiography were used to measure left ventricular
(LV) function, with results being compared with the pretreatment values. Left ventricular diastolic index (LVDI)
(LV diastolic diameter per body surface) and LV systolic
index (LV systolic diameter per body surface area) were also
compared before and after carvedilol treatment.
Statistics. All data are reported as means and 95% confidence intervals (CI). Differences in baseline characteristics
of the two treatment groups were compared with the
Student t test and the Fisher exact test. When the protocol
was terminated, the statistical treatment was performed
whenever possible on patients who had completed the study
(more than six months of treatment). Comparison between
treatment profiles was performed with repeated-measures
analysis of variance (ANOVA). This analysis consisted of
evaluation for each variable if its mean profiles during the
study period were similar for the placebo and carvedilol
groups, in other words, if the mean profiles of each variable
for each group were parallel. If this hypothesis was not
rejected, the group effects (if the curves were coincident) and
the evaluation of condition effects (parallelism of the curves
in relation to the abscissa axis) were tested. Otherwise, the
analysis was carried out with multiple comparison of the
means. The measures were analyzed before and after treatment. The variables tested were LV ejection fraction
(LVEF), fraction shortening (FS), LVDI, LV systolic
index, systolic and diastolic arterial pressures, the dosage of
furosemide, and ACE inhibitors. A value of p 0.05 was
considered statistically significant.

RESULTS
We enrolled 22 consecutive children, age 3.2 months to 10
years, who had severe LV systolic dysfunction. Characteristics of the study population are listed in Table 1.
The carvedilol (14 patients) and placebo (8 patients)
groups were similar in all pretreatment characteristics with
respect to clinical, functional, and hemodynamic parameters, except for gender. After randomization and the adjustment of the carvedilol dosage to 0.2 mg/kg/day, the total

Table 1. Pretreatment Characteristics of Study Patients

Characteristic

Placebo Group
(n 8)
Mean (95% CI)

Carvedilol Group
(n 14)
Mean (95% CI)

Age (yrs)
Gender (M/F)
Weight (kg)
NYHA functional class IV
LV ejection fraction (%)
Fraction shortening (%)
LV diastolic diameter index (mm/m2)
LV systolic diameter index (mm/m2)
Titration period (days)

3.7 (1.16.2)
7/1
12.1 (7.316.8)
8 (100%)
19.4 (15.922.8)
14.1 (11.217.0)
121.3 (93.9148.6)
103.2 (79.1127.1)
61.7 (35.887.7)

2.1 (1.42.8)
4/10
9.2 (7.710.8)
14 (100%)
16.7 (14.219.2)
13.3 (11.315.2)
110.9 (97.2124.5)
97.3 (83.1111.3)
59.8 (37.482.2)

CI confidence interval; LV left ventricle/ventricular; NYHA New York Heart Association.

p Value
NS
0.02
NS
NS
NS
NS
NS
NS

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Azeka et al.
Heart Transplantation Waiting List Removal

results in the follow-up study period were similar in both

placebo and carvedilol groups.
Effects of carvedilol at follow-up. Compared with patients in the placebo group, those in the carvedilol group
had improved cardiac function as reflected by an increase in
LVEF measured with radionuclide ventriculography (Fig.
1) and FS measured with echocardiography (Fig. 2). In
addition, the carvedilol-group patients benefited clinically,
as shown by NYHA functional class improvement, with a
decrease in the dosage of furosemide (p 0.04) and no
change in the dosage of ACE inhibitors (p 0.09).
However, the functional class of patients in the placebo
group did not change, and a significant increase occurred in
the dosage of diuretics (p 0.01) used in this group.
During the six-month follow-up and the up-titration
period in the carvedilol group (mean follow-up 59.8 days
[95% CI 37.4 to 82.2 days]), four patients died ([three in
the up-titration period, mean dosage 0.04 mg/kg/day, one
after a mean period of 26 days [dosage 0.2 mg/kg/day]), and
one patient underwent heart transplantation [during the
up-titration period receiving a dosage of 0.09 mg/kg/day]).
In patients evaluated after six months (carvedilol dosage
0.2 mg/kg/day), treatment with the drug was associated
with no deaths. No significant change occurred in systemic
systolic arterial pressure 93 mm Hg (95% CI 83 to 104 mm
Hg) versus 98 mm Hg (95% CI 89 to 107 mm Hg), p
0.96 or diastolic pressure 63 mm Hg (95% CI 56 to 71 mm
Hg) versus 67 mm Hg (95% CI 59 to 75 mm Hg), p
0.41. The LVEF increased from 17.8% (95% CI 14.1 to
21.4%) to 34.6% (95% CI 25.2 to 44.0%) (p 0.001) (Fig.
1). The FS increased from 14.4% (95% CI 11.5 to 17.2%) to
21.3% (95% CI 16.0 to 26.4%) (p 0.001) (Fig. 2). No
significant change occurred in LVDI (p 0.08) (Fig. 3),
but systolic index decreased (p 0.001). The NYHA
functional class improved in nine patients. The clinical
status of nine patients who were removed from the transplantation waiting list was NYHA functional class I in eight
patients and NYHA class II in one patient. All patients

Figure 1. Left ventricular ejection fraction (LVEF) by radionuclide ventriculography in the carvedilol and placebo groups.

JACC Vol. 40, No. 11, 2002

December 4, 2002:20348

Figure 2. Fractional shortening (FS) by echocardiogram in the carvedilol

and placebo groups.

were alive at mean follow-up of 593 days (95% CI 514 to

644 days).
In addition, no significant changes occurred while patients were on ACE inhibitors (p 0.09) when compared
with baseline, but a decrease occurred in the dosage of
furosemide (p 0.04). In the placebo group, during the
six-month follow-up (mean follow-up 139 days [95% CI 99
to 179 days], dosage 0.2 mg/kg/day), two patients died, and
two others underwent heart transplantation. Four patients
evaluated after six months of treatment persisted with
symptoms and signs of HF (all patients were in NYHA
functional class IV), with a significant increase in the dosage
of furosemide (p 0.01) but no change in the ACE
inhibitor dosage (p 0.09). No significant change occurred
in systemic systolic arterial pressure 90 mm Hg (95% CI 82
to 98 mm Hg) versus 85 mm Hg (95% CI 79 to 90 mm Hg,
p 0.96) or diastolic pressure 60 mm Hg versus 62 mm Hg
(95% CI 57 to 67 mm Hg), p 0.41. No increase occurred
in LVEF 21.3% (95% CI 16.4 to 26.0%) versus 19.3% (95%
CI 14.3 to 24.1%), p 0.71 (Fig. 1) or in FS 15.5% (95%
CI 9.8 to 21.2%) versus 14.0% (95% CI 10.7 to 17.3%), p
0.54 (Fig. 2). The mean LVDI increased significantly when
compared with that at baseline (p 0.01) (Fig. 3), and no
change occurred in LV systolic index (p 0.9).

Figure 3. Left ventricular diastolic index (LVDI) by echocardiogram in the

carvedilol and placebo groups.

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Safety. The discontinuation of treatment was not observed

in either group (carvedilol and placebo).

DISCUSSION
Our study indicates that the addition of carvedilol to
conventional therapy in children with dilated cardiomyopathy and severe LV dysfunction is associated with a marked
improvement in ventricular function. Patients have been
removed from the transplantation waiting list because of
their favorable response to carvedilol. Previous studies
(1113) in children taking beta-blockers have reported
improvement in ventricular function; nevertheless, these
studies were not double-blinded or randomized, and they
did not recruit patients with severe congestive HF referred
for heart transplantation.
Our results demonstrate that significant decrease in the
final dosage required of the background medications (furosemide) was observed with the addition of carvedilol to our
armamentarium (14 16) in children with congestive HF.
Conversely, patients treated with placebo required an increase in the dosage of diuretics owing to the worsening of
congestive HF. These results corroborate the findings of
other investigators in adult populations, showing that carvedilol may delay the worsening of HF (3,9,17).
The action mechanisms of beta-blocking agents in HF
are not fully understood. One mechanism is to prevent and
reverse adrenergically mediated intrinsic myocardial dysfunction and remodeling (2). However, carvedilol has additional properties (e.g., alpha-adrenergic blockade, antioxidant activity, anti-endothelin effects) that may enhance its
ability to attenuate the adverse effects of the sympathetic
nervous system on circulation (6,18 25). These additional
actions may be particularly important in severe HF and may
determine the differences between the effects of carvedilol
and those of other beta-blocking agents (e.g., bucindolol)
(26). In addition, this study demonstrates that, despite some
differences in the pathophysiologic mechanisms of progressive cardiac dysfunction in children, particularly neonates,
compared with that in adults, which involve cellular mechanisms of calcium regulation and excitation-contraction
coupling and physiologic responses relating to betaadrenergic receptors (27), carvedilol improved symptoms
and LV function in pediatric patients with HF. Therefore,
it may have similar mechanisms of action as that of
beta-blockers in adult populations.
After six months of treatment with carvedilol, no change
was noted in LVDI compared with that at baseline, but a
decrease occurred in systolic index. However, in the placebo
group, an increase did occur in the LVDI. These results are
consistent with those of a recent study (28) that showed the
beneficial effect of carvedilol on LV remodeling.
Other issues that may have influenced our results are the
type of pediatric cardiomyopathy amenable to beta-blocker
therapy, the optimal timing of beta-blocker therapy, and the
preferable type of beta-blockers to be used in children. In

Azeka et al.
Heart Transplantation Waiting List Removal

2037

the current study, we recruited only hemodynamically stable

patients with severe dilated cardiomyopathy referred for
heart transplantation. Carvedilol was our drug of choice
because it is one of the new-generation beta-blockers with
both beta-1 and beta-2 blocking properties and vasodilating
properties that may enhance their effects on HF in adult
populations (9).
The initiation of therapy with carvedilol in our study
produced no side effects consistent with its antiadrenergic
actions, so discontinuation of double-blind treatment was
not required. Thus, patients were able to tolerate the target
doses of carvedilol used. It must be emphasized, however,
that carvedilol therapy was initiated in the study with
extreme caution by physicians experienced in managing
heart failure to ensure the safety of the patient, because our
study recruited patients with severe LV dysfunction. To
enhance patient safety, therapy with carvedilol was initiated
in small doses that were gradually increased over a period of
several weeks. This cautious approach has been followed in
studies of other beta-blockers and is designed to minimize
the adverse effects that may occur after abrupt withdrawal of
the homeostatic support provided by the sympathetic nervous system (2).
Heart transplantation has been the option for infants and
children with lethal cardiac disease. Although many efforts
have been made to decrease waiting-list mortality, including
breaching the barrier of ABO incompatibility (29,30),
effective strategies for managing severe HF in infants and
children with cardiomyopathy that could delay or even
eliminate the need for transplantation still remain the goal
of therapy in this group of patients. Therefore, our finding
that carvedilol improves ventricular function contributing to
the removal of children from the heart transplantation
waiting list supports the hypothesis that carvedilol can
favorably influence the course of disease in children with
severe LV dysfunction.
Study limitations. The baseline characteristics of treatment groups were similar except for gender; however, this
probably reflects the number of patients recruited. Otherwise, no evidence exists that gender is a predictor of
tolerability or an influence on the effects of carvedilol in
patients with chronic heart failure in the adult population
(31) or is an important determinant of prognosis in children
with idiopathic dilated cardiomyopathy (3236).
Acknowledgment
We are indebted to Ms. Ann Conti Morcos, MA, ELS, for
her assistance with the manuscript.

Reprint requests and correspondence: Dr. Estela Azeka, Rua

Araripina 95, Sa o Paulo, Sa o Paulo, Brazil 05603-030. E-mail:
estela_azeka9@hotmail.com.

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