FIG 65.7 Mortality rates from all causes in patients treated with either carvedilol or metoprolol in the COMET trial Mortality was significantly lower in the carvedilol group (34%) than the metoprolol group (40%) (From Poole-Wilson PA, Swedberg K, Cleland JG, et al Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial [COMET]: Randomised controlled trial Lancet 2003;362:7–13.) The initial reports of the use of β-blockers in children suggested possible benefit of metoprolol in some children with heart failure due to anthracycline toxicity, dilated cardiomyopathy, or congenital heart disease.92–94 After the US Food and Drug Administration (FDA) approved the use of carvedilol in adults, many small (mostly retrospective) studies reported its potential benefit in children with heart failure due to systemic ventricular dysfunction.95–100 However, the only multicenter, prospective, randomized, double-blind trial of carvedilol in children with HFrEF failed to detect a benefit of carvedilol over placebo in a composite end point of clinical outcomes.101 The half-life of carvedilol in children is shorter than that in adults.97 Thus higher doses may be needed in order to produce a benefit Carvedilol increases the levels of digoxin, so one must monitor its use and possibly decrease doses of digoxin in children started on carvedilol.102 It is likely that certain children with HFrEF may benefit from β-blocker therapy, but the indications and dosing must be better defined Angiotensin Receptor/Neprilysin Inhibitors The newest medication that has been shown to be efficacious in the treatment of HFrEF in adults is a combination drug that is an ARB―valsartan combined with the neprilysin inhibitor sacubritil ARBs have been discussed earlier The neprilysin inhibitor sacubritil is one of a new class of medications that have broad effects This medication blocks the degradation of many biologic compounds in the body, including natriuretic peptides, bradykinin, angiotensin, substance P, amyloid β (Aβ) peptide, and others.103 In the largest chronic HFrEF trial ever performed in adults, angiotensin receptor/neprilysin inhibitors LCZ696 (Entresto), showed a significant survival benefit over a 5-year period as compared with enalapril (Fig 65.8).104 Based on this study, there is currently a multicenter trial with HFrEF under way to study the pharmacokinetics and pharmacodynamics of this drug in children, to be followed by a prospective, randomized, placebo-controlled, double blind trial of LCZ696 compared with enalapril The primary outcome will be a global rank-order analysis of clinical outcomes FIG 65.8 Estimate of the probability of the primary composite end point (death from cardiovascular causes or first hospitalization for heart failure) (From McMurray JJ, Packer M, Desai AS, et al Angiotensin-neprilysin inhibition versus enalapril in heart failure N Engl J Med 2014;371:993– 1004.) Cardiac Resynchronization Therapy Patients with a left bundle branch block have delayed activation and contraction of the free wall of the left ventricle It has long been recognized that this may alter regional loading conditions, myocardial blood flow, and myocardial metabolism.105 There are regional alterations in gene expression and production of proteins involved with mechanical function and stress, which lead to derangements of both contractile and noncontractile elements, resulting in ventricular remodeling, dilation, and pump failure Early studies demonstrated that cardiac resynchronization therapy (CRT) results in improvements in functional class, quality of life, distances walked in 6 minutes, and ejection fraction.106 More recently, resynchronization therapy has been shown to improve survival in heart failure,107 thus making it a class 1 recommendation for the treatment of adults with left ventricular ejection fraction lower than 35%, sinus rhythm, QRS duration of at least 120 ms, and with moderate-to-severe heart failure on maximal heart failure medications.58 The knowledge base for CRT in children is small Some series have demonstrated its feasibility in children, with a resultant decrease in QRS duration and possible beneficial effects on ventricular reverse remodeling.108,109 In the largest report to date, Dubin and colleagues reviewed their experience with this form of treatment in 103 children with heart failure due to dilated cardiomyopathy, congenital heart disease, or complete heart block.110 The average change in left ventricular ejection fraction reported after treatment was about 13%, although there was no difference in this measurement between the three groups The only discernible characteristic predictive of response versus no response was a lower ejection fraction before treatment (24% vs 32%) However, the incidence of side effects was significant: 3% of patients died early and 2% later, whereas 5% had complications related to the coronary sinus electrode Thus, as with virtually all other treatments for heart failure in children, the indications for resynchronization therapy are unclear and their potential riskbenefit ratio is still to be determined A recent review of CRT in congenital heart disease emphasized the technical challenges associated with this treatment in addition to the unpredictable response of patients with heart failure and congenital heart disease.111 Clearly adult heart failure criteria cannot be easily applied to pediatric patients ... addition to the unpredictable response of patients with heart failure and congenital heart disease.111 Clearly adult heart failure criteria cannot be easily applied to pediatric patients