Ivabradine in Pediatric Heart Failure
What is the dose-response relationship of ivabradine in children with dilated cardiomyopathy (DCM) and symptomatic chronic heart failure (HF)?
An international, multicenter, randomized, double-blind, placebo-controlled trial was performed. Children aged 6 months to 18 years on stable HF therapy were randomized to either ivabradine or placebo in a 2:1 ratio. After an initial titration period, the dose was adjusted to attain the primary endpoint of a ≥20% reduction in heart rate from baseline. Left ventricular (LV) function, clinical status, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and quality of life (QOL) were assessed.
A total of 116 patients were randomized. The etiology of HF was idiopathic in 56%, post-viral myocarditis in 22%, LV noncompaction in 19%, ischemia in 2%, and post-anthracycline treatment in 2%. Baseline medical therapy included angiotensin-converting enzyme inhibitors in 94%, beta-blockers in 76%, and digoxin in 50% of patients. The primary endpoint was reached by 51 of 73 children on ivabradine (70%) as compared with 5 of 41 on placebo (12%) at varying doses (odds ratio, 17.24; p < 0.0001). Both groups showed improvement in LV ejection fraction (LVEF) with a greater increase in LVEF in those patients on ivabradine as compared with those on placebo (13.5% increase vs. 6.9%; p = 0.024). There were trends in improvement in New York Heart Association (NYHA)/Ross Class (38% vs. 25%, p = 0.24) and QOL (p = 0.053). NT-proBNP levels decreased similarly in both groups. Adverse events were reported at similar rates for the study drug and placebo.
The authors concluded that ivabradine safely reduced the resting heart rate of children with chronic HF and dilated cardiomyopathy. The effect of ivabradine on heart rate was variable, demonstrating the importance of dose titration in pediatric patients.
Studies of potential therapies in pediatric HF have historically been a challenge because of small sample size, heterogeneity of disease, and often low event rates. Therefore, clinical practice is in large part informed by adult studies and guidelines. This study describes the dose-response relationship of ivabradine in pediatric HF. The drug was effective in lowering heart rate. A benefit was seen in LVEF, and there was suggestion of benefit in functional status and QOL. This study suggests a role for ivabradine in the management of pediatric HF. Further studies will be required to identify the patients most likely to benefit, as well as better understand the long-term impact of the drug on the natural history of pediatric HF.
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