PHILADELPHIA -- The beta-blocker carvedilol (Coreg) does not appear to benefit children or adolescents with symptomatic systolic heart failure, suggest preliminary trial results.
PHILADELPHIA, Sept. 11 -- The beta-blocker carvedilol (Coreg) does not appear to benefit children or adolescents with symptomatic systolic heart failure, suggested preliminary trial results.
In a study of 161 children with symptomatic systemic ventricular systolic dysfunction, neither low-dose nor high-dose carvedilol given over eight months was superior to placebo at reducing an endpoint of combined heart failure outcomes, reported Robert E. Shaddy, M.D., of the Children's Hospital of Philadelphia, and colleagues in the Pediatric Carvedilol Study Group.
The study may have been underpowered, however, and the results should be considered preliminary until either confirmed or disproved in additional studies, the authors cautioned in the Sept. 12 issue of the Journal of the American Medical Association.
"It is possible that children and adolescents with heart failure do not receive benefit from carvedilol; this would represent the first heart failure population not to show benefit with b-blockade and is inconsistent with the many small studies supporting the benefit of b-blockade in this patient population to date," they wrote.
Possible reasons for their discordant findings include differences between children and adults in the etiology of heart failure, or factors related to study design, such as the choice of a composite endpoint or small patient sample, the investigators noted.
"The inherent heterogeneity of pediatric patients with heart failure and their high rate of spontaneous improvement make the definition of suitable clinical end points with a feasible sample size and sufficient statistical power a challenge for future treatment trials in this population," they wrote.
But despite the disappointing results, the study demonstrated the value of randomized clinical trials in a pediatric population, noted Samuel S. Giddings, M.D., of the Nemours Cardiac Center in Wilmington, Del., in an accompanying editorial.
"Adult cardiac trials, whether related to heart failure or prevention of recurrent myocardial infarction, are considered successful when the inevitable is delayed, he wrote. "For most adults, the inevitable still occurs. For children with heart disease, the goals are different: to treat pediatric patients effectively so that they can experience decades of as normal a quality of life as possible."
The multicenter randomized study involved 161 children and adolescents with symptomatic systolic heart failure from 26 U.S. centers. The patients were maintained on conventional heart failure drugs, and were randomly assigned in equal numbers to one of three treatments given twice daily. The treatments were:
The median age of the 55 children in the placebo group was 22 months (range 19-73). The median ages in the carvedilol groups (53 children each) were 43 months (range 14 to 154) for the low dose group, and 33 months (range 13-122) in the high dose group.
The primary study goal was to compare the efficacy of carvedilol with placebo, with patients rated as having worsened, improved, or unchanged condition.
Criteria for worsened condition included death, hospitalization for more than 24 hours for worsening heart failure requiring intravenous heart failure medication, permanent discontinuation of double-blind treatment due to worsening heart failure, treatment failure, lack of or insufficient therapeutic response, withdrawal of consent, or other administrative reason with worsening heart failure at the time of discontinuation, demonstrated worsening in heart failure class at the last observation carried forward, or moderate-marked worsening of global assessment score at the last observation carried forward.
The patients were stratified according to whether, in the investigator's judgment, the anatomic substrate of each patient's systolic was a left ventricle.
The authors found that there were no statistically significant differences between groups for the composite endpoint, with 56% of patients on placebo and the same percentage of those on carvedilol (combined doses) improving, 30% of patients on placebo worsening compared with 24% of those on carvedilol, and 15% of those on placebo having no change, compared with 19% of those on the active drug.
"The rates of worsening were lower than expected," the authors wrote. The odds ratio for worsened outcomes for patients on carvedilol versus placebo was 0.79 (95% confidence interval, 0.36 to 1.59; P=0.47).
They found that in a pre-specified subgroup analysis, there was a significant interaction between treatment and ventricular morphology, suggesting a possible benefit for patients with left ventricular involvement, but not others
"Our power calculations, based on adult data, greatly underestimated the number of placebo-treated patients that would improve during the eight months of the study," the authors wrote.
"This study suggests that more than 50% of children and adolescents with heart failure will demonstrate improvement in symptoms if treated with angiotensin-converting enzyme inhibitors, digoxin, and diuretics alone. This is a higher placebo improvement rate than is seen in adult heart failure trials."
They noted that their study focused more on positive endpoints (improvement) than do most adult heart failure studies, and that young children with dilated cardiomyopathy may be more likely to have spontaneous recovery than older children with the condition.
"There may be a differential effect of carvedilol in children and adolescents with a systemic ventricle of left ventricle morphology compared with those with a systemic ventricle that is not of left ventricle morphology but further study is needed to prove this," they wrote. "Furthermore, the high proportion of infants and toddlers enrolled and the higher placebo improvement rate than anticipated are factors that may have influenced the results."
In his editorial. Dr. Giddings noted that the study showed that children with heart failure, particularly young children, have different outcomes from adults, and that the origin of ventricular dysfunction (left versus right) makes a significant difference. The study also showed that carvedilol is metabolized more rapidly in children than in adults, suggesting that pediatric dosing may need to be different, he wrote.
He also noted that "in the absence of consensus criteria for the diagnosis of congestive heart failure in infants and children, Shaddy et al were forced to rely on a composite subjective end point related to assessment of clinical improvement by parents and clinicians," and that "an important reassuring finding is that carvedilol did not appear to cause harm, paving the way for more ambitious future trials."
The FDA approved the first generic versions of carvedilol on Sept. 5.