Lessons learned from a pediatric clinical trial: The Pediatric Heart Network Angiotensin-Converting Enzyme Inhibition in Mitral Regurgitation Study

Li, Jennifer S.; Colan, Steven D.; Sleeper, Lynn A.; Newburger, Jane W.; Pemberton, Victoria L.; Atz, Andrew M.; Cohen, Meryl S.; Golding, Fraser; Klein, Gloria L.; Lacro, Ronald V.; Radojewski, Elizabeth; Richmond, Marc E.; Minich, L. LuAnn

doi:10.1016/j.ahj.2010.10.030

Cited by 27 publications

(29 citation statements)

References 23 publications

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“…However, as the SAMIS trial demonstrates, there are inherent difficulties in conducting randomized controlled trials in infants. These difficulties have been well documented, particularly when investigating cardiovascular drugs (15,16). Relative rarity of disease and difficulties enrolling vulnerable infants in clinical trials are often-cited causes, and these obstacles are not easily overcome (6,16).…”

Section: Discussionmentioning

confidence: 99%

Comparative Effectiveness of Digoxin and Propranolol for Supraventricular Tachycardia in Infants*

Hornik

Chu

et al. 2014

Pediatric Critical Care Medicine

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Objective Supraventricular tachycardia (SVT) is the most common arrhythmia in infants, and antiarrhythmic medications are frequently used for prophylaxis. The optimal prophylactic antiarrhythmic medication is unknown, and prior randomized trials have been underpowered. We used data from a large clinical registry to compare efficacy and safety of digoxin and propranolol for infant SVT prophylaxis. We hypothesized that SVT recurrence is less common on digoxin compared with propranolol. Design Retrospective cohort study. Setting Pediatrix Medical Group neonatal intensive care units. Patients Infants discharged from 1998–2012 with SVT treated with digoxin or propranolol. We excluded infants discharged prior to completing 2 days of therapy, those with Wolff-Parkinson-White syndrome, structural heart defects (except atrial/ventricular septal defects and patent ductus arteriosus), and those started on multi-drug therapy. Measurements We used Cox proportional hazards to evaluate SVT recurrence, defined as need for adenosine or electrical cardioversion while exposed to digoxin vs. propranolol, controlling for infant characteristics, inotropic support, supplemental oxygen, and presence of a central line. Results We identified 342 infants exposed to digoxin and 142 infants exposed to propranolol. The incidence rate of treatment failure was 6.7/1000 infant-days of exposure to digoxin and 15.4/1000 infant-days of exposure to propranolol. On multivariable analysis, treatment failure was higher on propranolol compared with digoxin (hazard ratio=1.97 [95% confidence interval: 1.05, 3.71]). Hypotension was more frequent during exposure to digoxin versus propranolol (39.4 versus 11.1/1000 infant-days, p<0.001). There was no difference in frequency of other clinical adverse events. Conclusions Digoxin was associated with fewer episodes of SVT recurrence but more frequent hypotension in hospitalized infants relative to propranolol.

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Section: Discussionmentioning

confidence: 99%

Comparative Effectiveness of Digoxin and Propranolol for Supraventricular Tachycardia in Infants*

Hornik

Chu

et al. 2014

Pediatric Critical Care Medicine

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“…This again highlighted the need for better longitudinal data on clinical course after repair of congenital heart defects, use of the actual trial criteria in the feasibility study, and pediatric‐specific, validated endpoints. Finally, clinical equipoise was lost among clinicians, and there was an absence of adequate data to appropriately estimate study power 45. In contrast, the more recent PHN Marfan trial comparing atenolol versus losartan on aortic root Z‐score in children and young adults with Marfan syndrome successfully randomized 608 patients out of 1367 screened (NCT00429364) 46.…”

Section: Approaches To Improving Clinical Trials In Children With Carmentioning

confidence: 99%

Recommendations to Enhance Pediatric Cardiovascular Drug Development: Report of a Multi‐Stakeholder Think Tank

Török

Kannankeril

et al. 2018

JAHA

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“…A recent failure of the Pediatric Heart Network’s Angiotensin Converting Enzyme (ACE) Inhibition in Mitral Regurgitation Study highlights the importance of clinical equipoise in pediatric trials (25). The study investigators sought to evaluate the efficacy of the drug enalapril versus placebo in reducing left ventricular volume overload in children with at least moderate mitral valve regurgitation following surgical repair of atrioventricular septal defect.…”

Section: Clinical Equipoisementioning

confidence: 99%

Pediatric Cardiovascular Drug Trials, Lessons Learned

Cohen‐Wolkowiez

Pasquali

2011

Journal of Cardiovascular Pharmacology

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Few drugs have been labeled for pediatric cardiovascular indications and many children with cardiac disease are prescribed drugs off-label. Recent initiatives have narrowed this gap and as a result there are an increasing number of cardiology trials in the pediatric population. Many studies, however, have either failed to show a dose response in children or have not shown efficacy in children when they have established efficacy in adults. Clinical trials are challenging in children; many factors such as lack of development of a liquid formulation, failure to fully incorporate pharmacokinetic information into trial design, poor dose selection, the lack of clinical equipoise, and the use of difficult surrogate and composite primary endpoints have led to the difficulties and failures observed in several pediatric cardiovascular trials. These lessons learned may help to inform future pediatric clinical trial development.Randomized clinical trials have resulted in remarkable advances in cardiovascular care. During the 1990s, results from more cardiovascular clinical trials were published than in the previous three decades combined, ushering in the current era of evidence-based cardiovascular medicine. (1) Cardiovascular trials have established novel treatments resulting in major improvements in patient outcomes and have also enhanced our understanding of heart disease and the impact of risk factors and adverse events. Certain populations, however, have been underrepresented in cardiovascular clinical trials, including women, the elderly, minority populations, and children (1-3).Many barriers impede the design and conduct of randomized clinical trials in children, including the relative rarity of specific diseases, disease heterogeneity, incompletely defined natural history, lack of research infrastructure, ethical issues in pediatric research, and difficulty in identifying valid clinical endpoints. Systematic controlled studies of medications in children with congenital heart disease have thus been limited and most medications are not labeled for pediatric use. Therefore, treatment decisions in this population are often based on clinical experience, small observational studies, and extrapolation from adult data, rather than clinical trial evidence. Fewer than 25% of approved drugs marketed in the USA have sufficient pediatric data to support approval for labeling for dosing, safety, and efficacy in children. Inadequate dosing and safety information places children at risk for adverse events and denies them potential therapeutic benefits. Pediatricians must therefore prescribe drugs to children for whom the dose, efficacy, and safety have not been studied. This practice known as "off label use" may result in benefit, no effect, or harm. This lack of information has had a negative impact on pediatric therapeutics, including reliance on anecdotal practice patterns, adaptation of data from adult trials that may not be applicable to children, and the use of extemporaneous formulations that may be inconsistently bi...

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Lessons learned from a pediatric clinical trial: The Pediatric Heart Network Angiotensin-Converting Enzyme Inhibition in Mitral Regurgitation Study

Cited by 27 publications

References 23 publications

Comparative Effectiveness of Digoxin and Propranolol for Supraventricular Tachycardia in Infants*

Comparative Effectiveness of Digoxin and Propranolol for Supraventricular Tachycardia in Infants*

Recommendations to Enhance Pediatric Cardiovascular Drug Development: Report of a Multi‐Stakeholder Think Tank

Pediatric Cardiovascular Drug Trials, Lessons Learned

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