Perspective:

The following are 10 points to remember regarding this review of heart failure therapies in children:

1. Pediatric heart failure is associated with significant morbidity and mortality, with no significant improvement in patient survival over the last several decades.

2. While agents such as beta-blockers, angiotensin-converting enzyme inhibitors, and aldosterone antagonists confer a survival advantage in adults with heart failure due to acquired disease, many drugs have not been shown to be effective in children.

3. Rarity of disease contributing to type II error (failure to demonstrate a difference that is truly present) may be a factor leading to the lack of strong data for the use of these agents in children, although additional factors likely contribute.

4. Patient heterogeneity contributes to the challenges of studies in pediatric heart failure. Trials often include patients with congenital heart disease as well as those with primary cardiomyopathies. Additionally, patients with single-ventricle anatomy and/or those with systemic right ventricles may not respond to therapies in the same way as those with systemic left ventricles (LVs) and two-chambered hearts.

5. Given the rarity of many congenital heart lesions, randomized controlled trials may have a limited role in determining optimal therapies. Comparative effectiveness research using registries and large databases will likely contribute significantly to the knowledge of optimal therapies for these rare diseases.

6. The pediatric carvedilol trial enrolled 161 children (mostly with New York Heart Association class II symptoms) from 26 centers over a 5-year period. Approximately 60% had dilated cardiomyopathy, whereas the remainder had varying types of congenital heart disease. No difference was seen in the primary endpoint, a composite measure of clinical heart failure, between carvedilol- and placebo-treated patients. In subanalysis, 64% of patients with a systemic LV showed an improved outcome as compared with 35% of those without a systemic LV, suggesting a differential response to carvedilol dependent on ventricular morphology.

7. A prospective, randomized trial of enalapril to placebo in patients after the Fontan operation not only failed to show improvement in exercise capacity, but demonstrated a lower change in cardiac index from rest to maximal exercise in the enalapril group, suggesting potentially harmful effects in patients after Fontan operations.

8. A recent randomized trial of the angiotensin-receptor blocker valsartan showed no improvement in right ventricular ejection fraction, exercise capacity, or quality of life in young adults with systemic right ventricles.

9. There is some evidence that children may show different beta-adrenergic receptor expression as compared with adults. This may account for differential treatment effects of beta-blocker therapy in adults as compared with children.

10. Determination of the optimal therapy for children with heart failure will likely remain a challenge moving forward. It is extremely unlikely that there will be sufficiently powered studies to convincingly demonstrate efficacy of various therapies in children. Differences in response to medications, underlying disease processes, and patient substrate limit the ability to extrapolate evidence from adult patients to children.