While the treatment of children with heart failure includes the use of ACE inhibitors, aldosterone antagonist, and betablockers, studies have failed to demonstrate the robust morbidity and mortality benefit that was seen in adults. There have been some small studies in children that support the use of beta blockers and ACE inhibitors in pediatric patients with ventricular dysfunction.
However, the findings from these limited studies were not observed in larger trials. In 2007, a randomized double-blind control trial of the use of carvedilol in pediatric and adolescents with symptomatic heart failure did not demonstrate improved clinical outcomes.
Additionally, in 2010, a multi-center randomized trial evaluating the use of enalapril in the single ventricle population also demonstrated no benefit to growth, ventricular function, or heart failure severity when compared with placebo.
Furthermore, a retrospective evaluation of the impact of the introduction of ACE inhibition and beta blockade on patients with dilated cardiomyopathy did not demonstrate a long-term survival benefit.
Here are the Novel Therapeutic Options in Pediatric Heart Failure
Some of the pathologic fluid overload seen in heart failure is thought to occur secondary to the body’s inability to naturally increase natriuretic peptides to the degree that is needed to maintain a normal fluid status. The importance of the natriuretic system has been emphasized by the observation that those with genetic variants of the ANP and BNP genes which “increase circulating levels” are protected “against hypertension, structural remodeling of the heart, and metabolic disease”. As such, attempts to increase the amount of circulating natriuretic peptides in the body has been an attempted treatment strategy through a variety of mechanisms, with the intention of promoting natriuresis, vasodilatation, suppression of hypertrophy and fibrosis, and inhibition of RAAS.
In the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial, intravenous nesiritide was compared to intravenous nitroglycerin and placebo in patients with acute congestive heart failure. Initial results showed promise, with the alleviation of dyspnea within 3 h of administration and lower pulmonary capillary wedge pressures. There were, however, significant issues with hypotension, and the subsequent Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND) trial was unable to show a reduction in death or heart failure related hospitalization at 30 days.
Relaxin is a naturally occurring peptide hormone that is present in all people but is up-regulated in pregnant women to help govern the hemodynamic changes that take place in a women’s body during pregnancy. In particular, it is thought to increase cardiac output, decrease systemic vascular resistance, and improve blood flow to the kidneys. Given that all those effects would be potentially helpful in a patient with a heart failure, there have been recent studies which focused on the administration of a recombinant version of relaxin- 2 (Serelaxin) to patients with heart failure.
The RELAX-AHF was an international, multi-center, double blinded study, which compared the administration of Serelaxin to placebo in patients admitted to the hospital with acute heart failure. The study did demonstrate a reduction in both cardiovascular and all-cause mortality, in addition to acute improvement in worsening heart failure and concurrent reduction of dyspnea.
Given the impressive study results, the medication was granted breakthrough. However, the followup study with a much larger enrollment population, RELAX-AHF-2, did not show a difference in cardiovascular mortality at 180 days, nor was the reduction of worsening heart failure at day 5 statistically significant. Given those somewhat disappointing results, a trial in the pediatric population was discontinued.
Vasopressin receptor antagonists
Volume overload is a major cause of hospitalization and morbidity among patients hospitalized with acute heart failure, as elevated levels of circulating vasopressin lead to water retention and the resultant congestive symptoms. The abnormal hormone levels also cause electrolyte disturbances, and hyponatremia is present in 20% of heart failure patients on presentation.
The use of diuretics to relieve congestive symptoms is a mainstay of treatment but can be complicated by renal injury and electrolyte derangement. The availability of vasopressin receptor blockers has offered new possible treatment options.
Tolvaptan is a vasopressin receptor (V2) antagonist that promotes the secretion of free water and theoretically could restore a normal fluid balance without injuring the kidney or further altering electrolytes. It is also thought that the V2 receptor is associated with abnormal and pathologic hormonal pathways, and so antagonism of that receptor is hypothesized to not only improve symptoms but potentially to prevent progression of the disease.
The use of Tolvaptan was studied in the 2007 EVEREST trials that randomized about 4000 patients admitted with acute heart failure to tolvaptan or placebo for 60 days. At 10 months, there was no difference in all-cause mortality, cardiovascular mortality, or heart failure rehospitalization.
There was shown to be some benefits with respect to short term heart failure symptoms, raising the possibility that vasopressin antagonism may have a role in the symptomatic treatment of acute heart failure.
McKie PM, Burnett JC. NT-proBNP: the gold standard biomarker in heart failure. J Am Coll Cardiol 2016;68:2437–9. http://dx.doi.org/10.1016/j.jacc.2016.10.001.
Dschietzig T. Relaxin, a pregnancy hormone, is a functional Endothelin-1 antagonist: attenuation of endothelin-1-mediated vasoconstriction by stimulation of endothelin type-B receptor expression via ERK-1/2 and nuclear factor-kappaB. Circ Res 2003;92:32–40. http://dx.doi.org/10.1161/01.RES.0000051884.27117.7E.
Teerlink JR, Cotter G, Davison BA, Felker GM, Filippatos G, Greenberg BH, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet (London, England) 2013;381:29–39. http://dx.doi.org/10.1016/S0140-6736(12)61855-8.
Tietjens J, Teerlink JR. Serelaxin and acute heart failure. Heart 2016;102:95–9. http://dx.doi.org/10.1136/heartjnl-2014-306786. Serelaxin fails to meet primary endpoints in phase 3 RELAX-AHF-2 Trial 2017.
Verbrugge FH, Steels P, Grieten L, Nijst P, Tang WHW, Mullens W. Hyponatremia in acute decompensated heart failure: depletion versus dilution. J Am Coll Cardiol 2015;65:480–92. http://dx.doi.org/10.1016/j.jacc.2014.12.010.