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Preliminary Communication
September 12, 2007

Carvedilol for Children and Adolescents With Heart Failure: A Randomized Controlled Trial

Author Affiliations

Author Affiliations: Department of Pediatrics, University of Utah School of Medicine and Primary Children's Medical Center, Salt Lake City (Drs Shaddy, Holubkov, and Tani, Ms Burr, and Mr LaSalle); Department of Pediatrics, University of Colorado Health Sciences Center, Denver (Dr M. Boucek); College of Physicians and Surgeons, Columbia University, New York, New York (Dr Hsu); Department of Pediatrics, University of South Florida, St Petersburg (Dr R. Boucek); Department of Pediatrics, Washington University, St Louis, Missouri (Dr Canter); Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas (Dr Mahony); Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan (Dr Ross); Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois (Dr Pahl); Department of Pediatrics, Harvard Medical School, Boston, Massachusetts (Dr Blume); Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee (Dr Dodd); Department of Pediatrics, Stanford University Medical Center, Stanford, California (Dr Rosenthal); and GlaxoSmithKline Pharmaceuticals, Philadelphia, Pennsylvania (Dr Lukas). Dr M. Boucek is now with Department of Pediatrics, Joe DiMaggio Children's Hospital, Hollywood, Florida. Dr R. Boucek is now with the Department of Pediatrics, University of Washington, Seattle. Dr Shaddy is now with the Department of Pediatrics, The Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia.

JAMA. 2007;298(10):1171-1179. doi:10.1001/jama.298.10.1171

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