Heart failure (HF) is a common and serious sequela of many pediatric cardiovascular diseases. Overall, there are 15 to 18 HF-related hospital admissions per 100,000 children in the U.S., with approximately 14,000 admissions in 2006.¹ Most were in children with congenital heart disease (CHD), and 15-17% were due to cardiomyopathy and myocarditis. Pediatric heart failure morbidity and mortality are substantial. A child with HF admitted to the hospital has an over 20-fold increase in the risk of death compared to a child without HF, and children with cardiomyopathy hospitalized with HF have significantly increased morbidity, mortality, and resource utilization compared to adults.²

Medical therapy has led to dramatic improvements in adult HF survival. Medications blocking the maladaptive adrenergic and renin-angiotensin-aldosterone system with angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and beta-blockers have been found to be beneficial in adults. Use of these medications currently form the cornerstone of chronic HF management.³ There are also novel, promising agents, albeit not currently approved for use in the U.S., such as the angiotensin receptor blocker (neprilysin inhibitor [LCZ696]) and the I_f current inhibitor of the sinoatrial node (ivabradine) that may further reduce morbidity and mortality in this population.^4,5

An important question then arises: do these medications also confer a survival advantage for pediatric patients with HF? Not surprisingly, this is a challenging question to answer. In contradistinction to the adult population, there are few prospective studies and far fewer randomized controlled trials of HF medications in children.⁶ The Pediatric Carvedilol Study Group performed a multicenter, randomized, double blind, placebo-controlled trial of carvedilol that failed to show a benefit of this medication over placebo in patients with both CHD and cardiomyopathy.⁷ Though there was a trend toward improvement in single ventricle patients with a systemic left ventricle, this did not reach statistical significance. Possible explanations for the apparent disparate response to beta-blockers in pediatric versus adult studies include sample size considerations, and differences in patient comorbidity profile, pharmacokinetic/pharmacodynamic characteristics, and HF pathogenesis.⁶ However, it is also possible that beta-blockers are truly not as beneficial in children as they are in adults. Since similar pediatric studies on the use of ACEIs, ARBs, or MRAs do not exist, it becomes challenging to assess the magnitude of the benefit, if any, that these medications may confer. Despite this, however, these medications are commonly used in pediatric patients with HF and are even recommended by consensus guidelines.^8,9

All, however, is not bleak when it comes to the medical management of pediatric HF. Despite the absence of large-scale, randomized controlled trials with hard endpoints, there are accumulating data that these medications are beneficial, at least for some HF etiologies. For example, dilated cardiomyopathy in the setting of Duchenne muscular dystrophy seems to respond favorably to standard heart failure therapies.^10,11 Moreover, there are recent data that demonstrate an improvement in survival for both acute, and possibly chronic, HF exacerbations.^2,12 A study from the Pediatric Cardiomyopathy Registry demonstrated an improvement in transplant-free survival in patients diagnosed after the year 2000 compared to a cohort diagnosed in the 1990s. While not a prospective randomized trial of specific medications, these data suggest that there has been an improved response to HF medical therapy over time.¹²

So what have we learned in regards to medical therapy for pediatric HF in the last 10 years? We have certainly learned that there is a lot more to learn. Currently, there are numerous diseases that all lead to pediatric HF, and we have a limited ability to tailor therapy that is disease- and patient-specific. Fortunately, this is an exciting time of active investigation with novel medical therapies and mechanical circulatory support options that have the field poised for significant advances in the decade to come.

References

1. Rossano JW, Kim JJ, Decker JA, et al. Prevalence, morbidity, and mortality of heart failure-related hospitalizations in children in the United States: a population-based study. J Card Fail 2012;18:459-70.
2. Wittlieb-Weber CA, Lin KY, Zaoutis TE, et al. Pediatric versus adult cardiomyopathy and heart failure-related hospitalizations: a value-based analysis. J Card Fail 2015;21:76-82.
3. Braunwald E. Heart failure. JACC Heart Fail 2013;1:1-20.
4. McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
5. Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010;376:875-85.
6. Rossano JW, Shaddy RE. Update on pharmacological heart failure therapies in children: do adult medications work in children and if not, why not? Circulation 2014;129:607-12.
7. Shaddy RE, Boucek MM, Hsu DT, et al. Carvedilol for children and adolescents with heart failure: a randomized controlled trial. JAMA 2007;298:1171-9.
8. Kantor PF, Lougheed J, Dancea A, et al. Presentation, diagnosis, and medical management of heart failure in children: Canadian Cardiovascular Society guidelines. Can J Cardiol 2013;29:1535-52.
9. Kirk R, Dipchand AI, Rosenthal DN, et al. The International Society of Heart and Lung Transplantation guidelines for the management of pediatric heart failure: executive summary. J Heart Lung Transplant 2014;33:888-909.
10. Jefferies JL, Eidem BW, Belmont JW, et al. Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy. Circulation 2005;112:2799-804.
11. Raman SV, Hor KN, Mazur W et al. Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2015;14:153-61.
12. Singh RK, Canter C, Shi L, et al. Improved transplant-free survival of children with dilated cardiomyopathy: analysis of two decades from the pediatric cardiomyopathy registry (abstract). Circulation 2014;130:A16801.

Keywords: Adrenergic beta-Antagonists, Aldosterone, Aminobutyrates, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Benzazepines, Carbazoles, Cardiomyopathy, Dilated, Comorbidity, Double-Blind Method, Heart Defects, Congenital, Heart Failure, Heart Ventricles, Humans, Mineralocorticoid Receptor Antagonists, Muscular Dystrophy, Duchenne, Myocarditis, Neprilysin, Propanolamines, Prospective Studies, Receptors, Angiotensin, Registries, Renin-Angiotensin System, Sample Size, Sinoatrial Node, Tetrazoles, United States

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