Carvedilol for children and adolescents with heart failure

A randomized controlled trial

Robert E. Shaddy, Mark M. Boucek, Daphne T. Hsu, Robert J. Boucek, Charles E. Canter, Lynn Mahony, Robert D. Ross, Elfriede Pahl, Elizabeth D. Blume, Debra A. Dodd, David N. Rosenthal, Jeri Burr, Bernie LaSalle, Richard Holubkov, Mary Ann Lukas, Lloyd Y. Tani

Research output: Contribution to journalArticle

331 Citations (Scopus)

Abstract

Context: Although β-blockers improve symptoms and survival in adults with heart failure, little is known about these medications in children and adolescents. Objective: To prospectively evaluate the effects of carvedilol in children and adolescents with symptomatic systemic ventricular systolic dysfunction. Design, Setting, and Participants: A multicenter, randomized, double-blind, placebo-controlled study of 161 children and adolescents with symptomatic systolic heart failure from 26 US centers. In addition to treatment with conventional heart failure medications, patients were assigned to receive placebo or carvedilol. Enrollment began in June 2000 and the last dose was given in May 2005 (each patient received medication for 8 months). Interventions: Patients were randomized in a 1:1:1 ratio to twice-daily dosing with placebo, low-dose carvedilol (0.2 mg/kg per dose if weight <62.5 kg or 12.5 mg per dose if weight ≥62.5 kg), or high-dose carvedilol (0.4 mg/kg per dose if weight <62.5 kg or 25 mg per dose if weight ≥62.5 kg) and were stratified according to whether each patient's systemic ventricle was a left ventricle or not. Main Outcome Measures: The primary outcome was a composite measure of heart failure outcomes in patients receiving carvedilol (low- and high-dose combined) vs placebo. Secondary efficacy variables included individual components of this composite, echocardiographic measures, and plasma b-type natriuretic peptide levels. Results: There was no statistically significant difference between groups for the composite end point based on the percentage of patients who improved, worsened, or were unchanged. Among 54 patients assigned to placebo, 30 improved (56%), 16 worsened (30%), and 8 were unchanged (15%); among 103 patients assigned to carvedilol, 58 improved (56%), 25 worsened (24%), and 20 were unchanged (19%). The rates of worsening were lower than expected. The odds ratio for worsened outcome for patients in the combined carvedilol group vs the placebo group was 0.79 (95% CI, 0.36-1.59; P=.47). A prespecified subgroup analysis noted significant interaction between treatment and ventricular morphology (P=.02), indicating a possible differential effect of treatment between patients with a systemic left ventricle (beneficial trend) and those whose systemic ventricle was not a left ventricle (nonbeneficial trend). Conclusions: These preliminary results suggest that carvedilol does not significantly improve clinical heart failure outcomes in children and adolescents with symptomatic systolic heart failure. However, given the lower than expected event rates, the trial may have been underpowered. There may be a differential effect of carvedilol in children and adolescents based on ventricular morphology. Trial Registration: clinicaltrials.gov Identifier: NCT00052026.

Original languageEnglish (US)
Pages (from-to)1171-1179
Number of pages9
JournalJournal of the American Medical Association
Volume298
Issue number10
DOIs
StatePublished - Sep 12 2007
Externally publishedYes

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Randomized Controlled Trials
Heart Failure
Placebos
Systolic Heart Failure
Heart Ventricles
Weights and Measures
carvedilol
Ventricular Dysfunction
Natriuretic Peptides
Therapeutics
Odds Ratio
Outcome Assessment (Health Care)
Survival

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Carvedilol for children and adolescents with heart failure : A randomized controlled trial. / Shaddy, Robert E.; Boucek, Mark M.; Hsu, Daphne T.; Boucek, Robert J.; Canter, Charles E.; Mahony, Lynn; Ross, Robert D.; Pahl, Elfriede; Blume, Elizabeth D.; Dodd, Debra A.; Rosenthal, David N.; Burr, Jeri; LaSalle, Bernie; Holubkov, Richard; Lukas, Mary Ann; Tani, Lloyd Y.

In: Journal of the American Medical Association, Vol. 298, No. 10, 12.09.2007, p. 1171-1179.

Research output: Contribution to journalArticle

Shaddy, RE, Boucek, MM, Hsu, DT, Boucek, RJ, Canter, CE, Mahony, L, Ross, RD, Pahl, E, Blume, ED, Dodd, DA, Rosenthal, DN, Burr, J, LaSalle, B, Holubkov, R, Lukas, MA & Tani, LY 2007, 'Carvedilol for children and adolescents with heart failure: A randomized controlled trial', Journal of the American Medical Association, vol. 298, no. 10, pp. 1171-1179. https://doi.org/10.1001/jama.298.10.1171
Shaddy, Robert E. ; Boucek, Mark M. ; Hsu, Daphne T. ; Boucek, Robert J. ; Canter, Charles E. ; Mahony, Lynn ; Ross, Robert D. ; Pahl, Elfriede ; Blume, Elizabeth D. ; Dodd, Debra A. ; Rosenthal, David N. ; Burr, Jeri ; LaSalle, Bernie ; Holubkov, Richard ; Lukas, Mary Ann ; Tani, Lloyd Y. / Carvedilol for children and adolescents with heart failure : A randomized controlled trial. In: Journal of the American Medical Association. 2007 ; Vol. 298, No. 10. pp. 1171-1179.
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T1 - Carvedilol for children and adolescents with heart failure

T2 - A randomized controlled trial

AU - Shaddy, Robert E.

AU - Boucek, Mark M.

AU - Hsu, Daphne T.

AU - Boucek, Robert J.

AU - Canter, Charles E.

AU - Mahony, Lynn

AU - Ross, Robert D.

AU - Pahl, Elfriede

AU - Blume, Elizabeth D.

AU - Dodd, Debra A.

AU - Rosenthal, David N.

AU - Burr, Jeri

AU - LaSalle, Bernie

AU - Holubkov, Richard

AU - Lukas, Mary Ann

AU - Tani, Lloyd Y.

PY - 2007/9/12

Y1 - 2007/9/12

N2 - Context: Although β-blockers improve symptoms and survival in adults with heart failure, little is known about these medications in children and adolescents. Objective: To prospectively evaluate the effects of carvedilol in children and adolescents with symptomatic systemic ventricular systolic dysfunction. Design, Setting, and Participants: A multicenter, randomized, double-blind, placebo-controlled study of 161 children and adolescents with symptomatic systolic heart failure from 26 US centers. In addition to treatment with conventional heart failure medications, patients were assigned to receive placebo or carvedilol. Enrollment began in June 2000 and the last dose was given in May 2005 (each patient received medication for 8 months). Interventions: Patients were randomized in a 1:1:1 ratio to twice-daily dosing with placebo, low-dose carvedilol (0.2 mg/kg per dose if weight <62.5 kg or 12.5 mg per dose if weight ≥62.5 kg), or high-dose carvedilol (0.4 mg/kg per dose if weight <62.5 kg or 25 mg per dose if weight ≥62.5 kg) and were stratified according to whether each patient's systemic ventricle was a left ventricle or not. Main Outcome Measures: The primary outcome was a composite measure of heart failure outcomes in patients receiving carvedilol (low- and high-dose combined) vs placebo. Secondary efficacy variables included individual components of this composite, echocardiographic measures, and plasma b-type natriuretic peptide levels. Results: There was no statistically significant difference between groups for the composite end point based on the percentage of patients who improved, worsened, or were unchanged. Among 54 patients assigned to placebo, 30 improved (56%), 16 worsened (30%), and 8 were unchanged (15%); among 103 patients assigned to carvedilol, 58 improved (56%), 25 worsened (24%), and 20 were unchanged (19%). The rates of worsening were lower than expected. The odds ratio for worsened outcome for patients in the combined carvedilol group vs the placebo group was 0.79 (95% CI, 0.36-1.59; P=.47). A prespecified subgroup analysis noted significant interaction between treatment and ventricular morphology (P=.02), indicating a possible differential effect of treatment between patients with a systemic left ventricle (beneficial trend) and those whose systemic ventricle was not a left ventricle (nonbeneficial trend). Conclusions: These preliminary results suggest that carvedilol does not significantly improve clinical heart failure outcomes in children and adolescents with symptomatic systolic heart failure. However, given the lower than expected event rates, the trial may have been underpowered. There may be a differential effect of carvedilol in children and adolescents based on ventricular morphology. Trial Registration: clinicaltrials.gov Identifier: NCT00052026.

AB - Context: Although β-blockers improve symptoms and survival in adults with heart failure, little is known about these medications in children and adolescents. Objective: To prospectively evaluate the effects of carvedilol in children and adolescents with symptomatic systemic ventricular systolic dysfunction. Design, Setting, and Participants: A multicenter, randomized, double-blind, placebo-controlled study of 161 children and adolescents with symptomatic systolic heart failure from 26 US centers. In addition to treatment with conventional heart failure medications, patients were assigned to receive placebo or carvedilol. Enrollment began in June 2000 and the last dose was given in May 2005 (each patient received medication for 8 months). Interventions: Patients were randomized in a 1:1:1 ratio to twice-daily dosing with placebo, low-dose carvedilol (0.2 mg/kg per dose if weight <62.5 kg or 12.5 mg per dose if weight ≥62.5 kg), or high-dose carvedilol (0.4 mg/kg per dose if weight <62.5 kg or 25 mg per dose if weight ≥62.5 kg) and were stratified according to whether each patient's systemic ventricle was a left ventricle or not. Main Outcome Measures: The primary outcome was a composite measure of heart failure outcomes in patients receiving carvedilol (low- and high-dose combined) vs placebo. Secondary efficacy variables included individual components of this composite, echocardiographic measures, and plasma b-type natriuretic peptide levels. Results: There was no statistically significant difference between groups for the composite end point based on the percentage of patients who improved, worsened, or were unchanged. Among 54 patients assigned to placebo, 30 improved (56%), 16 worsened (30%), and 8 were unchanged (15%); among 103 patients assigned to carvedilol, 58 improved (56%), 25 worsened (24%), and 20 were unchanged (19%). The rates of worsening were lower than expected. The odds ratio for worsened outcome for patients in the combined carvedilol group vs the placebo group was 0.79 (95% CI, 0.36-1.59; P=.47). A prespecified subgroup analysis noted significant interaction between treatment and ventricular morphology (P=.02), indicating a possible differential effect of treatment between patients with a systemic left ventricle (beneficial trend) and those whose systemic ventricle was not a left ventricle (nonbeneficial trend). Conclusions: These preliminary results suggest that carvedilol does not significantly improve clinical heart failure outcomes in children and adolescents with symptomatic systolic heart failure. However, given the lower than expected event rates, the trial may have been underpowered. There may be a differential effect of carvedilol in children and adolescents based on ventricular morphology. Trial Registration: clinicaltrials.gov Identifier: NCT00052026.

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