Author + information
- aDepartment of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan
- bChildren’s Hospital of Michigan, Detroit, Michigan
- ↵∗Address for correspondence:
Dr. Steven E. Lipshultz, Department of Pediatrics, Wayne State University School of Medicine, 3901 Beaubien Boulevard, Pediatric Administration, T121A, Detroit, Michigan 48201.
The paper by Bonnet et al. (1) in this issue of the Journal describes the results of a clinical trial of ivabradine, a drug that lowers heart rate by inhibiting the funny channel, a mechanism different from that of calcium-channel blockers or beta-blockers. This multisite, randomized, age-stratified, double-blind, placebo-controlled trial studied 116 children with dilated cardiomyopathy and chronic heart failure and followed them for 12 months (1). Most children were concomitantly receiving 1 or more heart failure drugs, including angiotensin-converting enzyme inhibitors, diuretics, beta-blockers, digitalis, and angiotensin II receptor antagonists. The proportion of children taking any of these drugs did not differ by treatment group. Briefly, the ivabradine group was substantially more likely to reach the primary endpoint of a 20% reduction in heart rate than was the placebo group at 12 months. The secondary, echocardiographic endpoints of left ventricular (LV) fractional shortening and LV end-systolic volume at 12 months also improved markedly in the ivabradine group. Another secondary endpoint, quality-of-life scores, improved slightly in the treatment group, but the improvement was not statistically significant. The quality-of-life metric is useful because patient-reported outcomes are increasingly considered to be as important as clinical responses (2). The trial design and analysis were robust, and the investigators appropriately interpreted the results. This study is a significant addition to the few clinical trials of drugs for treating heart failure in this population.
One of the only similar studies is a randomized, multicenter, multidose trial of carvedilol in 161 children with symptomatic heart failure and LV ejection fractions <40% (3). The primary efficacy endpoint was a composite of the following: death; hospitalization for heart failure; change in heart failure class; treatment failure; or administrative reasons, such as withdrawal of consent. Secondary endpoints included LV echocardiographic measurements and serum B-type natriuretic peptide plasma concentrations. The groups did not differ in the primary clinical composite endpoint, although LV fractional shortening improved somewhat in the treatment groups. Similarly, the adverse event profiles did not differ between groups. Both the ivabradine study and the carvedilol study have improved our knowledge of treating heart failure in children, but the fact that perhaps only 2 such trials have been completed in the past 11 years highlights the challenges of conducting such trials, including research complexity and funding.
One of the major challenges to conducting trials in children with dilated cardiomyopathy and heart failure is the number of eligible patients. The estimated incidence of dilated cardiomyopathy in children is 0.50 cases per 100,000 children per year, with approximately 70% of these children presenting with heart failure (4). Several reports estimate that, annually in the United States, between 12,000 and 35,000 children <19 years of age with congenital cardiovascular malformations or cardiomyopathy have heart failure. (5) In the current study, 116 children were enrolled at 47 pediatric heart centers in 16 countries. The enrollment data from the multisite carvedilol trial were similar. These sample sizes are about one-tenth of the size of those in trials of ivabradine or similar agents in adults (6,7), thus emphasizing the challenges of conducting robust trials and considering their external generalizability in a small population of children with a common phenotype but of multiple causes.
Another challenge to conducting trials in children with heart failure is selecting appropriate endpoints. Methods for selecting and interpreting study endpoints in the evaluation of policy and service interventions remain contested (8). In children with idiopathic or familial dilated cardiomyopathy, most of the important clinical events, death or heart transplantation, occur within 24 months after diagnosis (9). The time-to-event curves for events beyond 24 months are nearly flat. Therefore, in contrast to studies in adults, using such “hard” endpoints in trials of children with chronic heart failure will not likely detect improved efficacy, and so these endpoints are probably not appropriate for this population.
The third challenge to investigators conducting trials in these children is to identify validated surrogate endpoints. Many studies of these children have tested the utility of serum biomarkers, imaging studies, and disease severity as surrogate endpoints. Although such endpoints have been proven useful for risk stratification, none has been validated as a predictive proxy surrogate for “hard” clinical endpoints in this population (9,10). The 2 exceptions are elevated concentrations of N-terminal pro-brain natriuretic peptide (a marker of cardiomyopathy and heart failure) and cardiac troponin T (a marker of myocardial injury) in children with cancer who are receiving chemotherapy including anthracyclines. Both are validated surrogate endpoints for pathological cardiac changes for ≥5 years after the end of chemotherapy (11). We have also validated echocardiographic measurements of LV structure and function as predictive of subsequent clinical outcome in children with dilated cardiomyopathy who are infected with human immunodeficiency virus (12,13). These studies emphasize the need to validate surrogate endpoints in other populations of children with dilated cardiomyopathy and heart failure. However, extended sustained follow-up periods are needed to validate these endpoints and should be part of future trials.
In 2013, the National Heart, Blood, and Lung Institute (NHLBI) published a report titled, “New Targets for Pediatric Heart Failure” (14) that included 6 recommendations for research in this area: 1) create new paradigms for pediatric heart failure, including “avoiding hand-me-down dogma from adult research”; 2) focus research on molecular mechanisms of specific relevance to pediatric heart failure; 3) encourage collaboration among those studying and treating heart failure to augment existing resources, including developing a national pediatric heart failure registry; 4) expand existing phenotype registries and databases; 5) develop surrogate endpoints relevant to pediatric heart failure; and 6) create industry partnerships, including leveraging regulatory opportunities, such as the U.S. Food and Drug Administration’s Orphan Disease program and their pediatric exclusivity patent extension program. When implemented fully, these recommendations could address many of the challenges of conducting clinical trials of pediatric heart failure, as exemplified by the current ivabradine study.
A better framework for and a better approach to treating children with heart failure are needed, including a consensus on common diagnostic definitions and ensuring their widespread and consistent use by providers, regulators, insurers, and policy makers. The first step in implementing the “new paradigm” recommended in the NHLBI report noted earlier is for stakeholders to distinguish children with dilated cardiomyopathy and heart failure from adults with these conditions, given that the disease in each age group has distinct causes, clinical courses, outcomes, and research needs. Such a distinction would ensure that pediatric cardiomyopathy and heart failure meet the National Institutes of Health’s definition of rare “orphan” diseases (affecting <200,000 persons in the United States), which would open funding opportunities for industry sponsors, as well as promoting clinical trials of children with these conditions to test efficacy and safety of treatments (15). These conditions also affect families and communities, factors that should be included in developing trial-specific aims, methods, outcomes, and may enable a better understanding of their clinical implications (2).
In summary, this report highlights both the importance of clinical trials for studying heart failure in children and the challenges in doing so. In this randomized trial of children with heart failure by Bonnet et al. (1), ivabradine lowered heart rate to the desired level. Of course, the larger question remains unanswered: whether ivabradine, beyond heart rate reduction, is associated with sustained improved outcomes for children with dilated cardiomyopathy and heart failure.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the author and do not necessarily represent the views of JACC or the American College of Cardiology.
Drs. Lipshultz and Wilkinson have received funding from Amgen for a descriptive pediatric heart failure study not involving ivabradine or any other pharmaceutical agent. Dr. Barach has reported that he has no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation
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- for the Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection Study Group
- ↵Redington AN, Towbin JA, for the NHLBI Working Group. New Targets for Pediatric Heart Failure. Available at: https://www.nhlbi.nih.gov/research/reports/2013-pediatric-heart-failure. Accessed July 12, 2017.
- ↵Rare Diseases Clinical Research Network. Available at: https://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=126. Accessed July 12, 2017.