Carvedilol for children and adolescents with heart failure: a randomized controlled trial.
BACKGROUND
Although beta-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.


METHODS
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).


METHODS
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 > or =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 > or =62.5 kg) and were stratified according to whether each patient's systemic ventricle was a left ventricle or not.


METHODS
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT00052026.
Shaddy
Robert E
RE
Department of Pediatrics, University of Utah School of Medicine and Primary Children's Medical Center, Salt Lake City, USA. shaddyr@email.chop.edu
Boucek
Mark M
MM
Hsu
Daphne T
DT
Boucek
Robert J
RJ
Canter
Charles E
CE
Mahony
Lynn
L
Ross
Robert D
RD
Pahl
Elfriede
E
Blume
Elizabeth D
ED
Dodd
Debra A
DA
Rosenthal
David N
DN
Burr
Jeri
J
LaSalle
Bernie
B
Holubkov
Richard
R
Lukas
Mary Ann
MA
Tani
Lloyd Y
LY
D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000097:blood / Q000627:therapeutic use*; D002227:Carbazoles / Q000097:blood / Q000627:therapeutic use*; D002303:Cardiac Output, Low / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D000077261:Carvedilol; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000097:blood; D011412:Propanolamines / Q000097:blood / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D011446:Prospective Studies; D013599:Systole; D018754:Ventricular Dysfunction / Q000150:complications*; D020257:Ventricular Remodeling / Q000187:drug effects
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D020097:Natriuretic Peptide, Brain