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J Am Coll Cardiol, 2002; 40:2034-2038
© 2002 by the American College of Cardiology Foundation
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CLINICAL STUDY

Delisting of infants and children from the heart transplantation waiting list after carvedilol treatment

Estela Azeka, MD, PhDa,*, José Antonio Franchini Ramires, MD, PhD, FACCa, Constante Vallera and Edimar Alcides Bocchi, MD, PhDa

a Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil

Manuscript received March 11, 2002; revised manuscript received August 5, 2002, accepted August 26, 2002.

* Reprint requests and correspondence: Dr. Estela Azeka, Rua Araripina 95, São Paulo, São Paulo, Brazil 05603-030.
estela_azeka9{at}hotmail.com


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: 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.

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

In heart failure (HF) beta-adrenergic receptors associated with the alpha-adrenergic system play important roles in myocardial contractility and cellular remodeling (1,2). Beta-blocking 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 third-generation beta-blocker, vasodilator secondary to alpha1-adrenergic blockade with antioxidant activity and apoptosis inhibition, has been demonstrated to favorably affect survival in adult patients with severe chronic HF (5–10), 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
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 Abstract
 Methods
Results
 Discussion
 References
 
Study patients.   All patients included in this study had advanced HF, despite at least two months of treatment with 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 São 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 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 conventional 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
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 Methods
 Results
Discussion
 References
 
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.


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  		Table 1 Pretreatment Characteristics of Study Patients

 
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 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.



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

 


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

 
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 were alive at mean follow-up of 593 days (95% CI 514 to 644 days).



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  		Figure 3 Left ventricular diastolic index (LVDI) by echocardiogram in the carvedilol and placebo groups.

 
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).

Safety.   The discontinuation of treatment was not observed in either group (carvedilol and placebo).


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
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 (11–13) 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 beta-adrenergic 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 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 (32–36).


   Acknowledgments
 
We are indebted to Ms. Ann Conti Morcos, MA, ELS, for her assistance with the manuscript.


   Footnotes
 
Constante Valler was supported by the Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP), São Paulo, Brazil.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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