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• W1893841713 abstract "Improving long-term outcomes in pediatric pulmonary hypertension (PH) remains limited by the lack of proven clinical or study end points that can readily be applied to infants and young children. In adult clinical trials for pulmonary arterial hypertension (PAH), the 6-min walk distance has been the most commonly used primary end point to assess clinical course and response to therapeutic interventions.1Rubin LJ Badesch DB Barst RJ et al.Bosentan therapy for pulmonary arterial hypertension.N Engl J Med. 2002; 346: 896-903Crossref PubMed Scopus (2455) Google Scholar, 2Ghofrani HA Galiè N Grimminger F PATENT-1 Study Group et al.Riociguat for the treatment of pulmonary arterial hypertension.N Engl J Med. 2013; 369: 330-340Crossref PubMed Scopus (936) Google Scholar Event-driven trials that use combined end points have gained favor in adult studies because this approach better captures the key features of the disease course and includes more clinically relevant end points. In the Study With an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) trial, end points included time to first morbidity or mortality event, including all-cause mortality, atrial septostomy, lung transplantation, the initiation of IV or subcutaneous prostanoids, or other signs of worsening PAH.3Pulido T Adzerikho I Channick RN SERAPHIN Investigators et al.Macitentan and morbidity and mortality in pulmonary arterial hypertension.NEngl JMed. 2013; 369: 809-818Crossref PubMed Scopus (959) Google Scholar Whether such an approach would also be of value in children with PAH has not been previously studied, and a clear and critical need exists to develop relevant treatment goals that relate to long-term outcomes in children. In this issue of CHEST (see page 655), Ploegstra and colleagues4Ploegstra M-J Arjaans S Zijlstra WMH et al.Clinical worsening as composite study end point in pediatric pulmonary arterial hypertension.Chest. 2015; 148: 666Abstract Full Text Full Text PDF Scopus (23) Google Scholar report on clinical worsening of PH in pediatric patients enrolled in a Dutch national registry. As in the SERAPHIN trial, events including death, lung transplantation, PAH-related hospitalization, initiation of IV prostanoids, and functional deterioration (World Health Organization functional class deterioration, a > 15% decrease in 6-min walk distance, or both) were evaluated. In this series of pediatric subjects, the most common event of clinical worsening was functional deterioration. The occurrences of either hospitalization, initiation of IV prostanoids, or functional deterioration were predictive of death or lung transplantation. The authors suggest that clinical worsening may be useful as a study end point in future clinical PAH trials in children. The study by Ploegstra and colleagues4Ploegstra M-J Arjaans S Zijlstra WMH et al.Clinical worsening as composite study end point in pediatric pulmonary arterial hypertension.Chest. 2015; 148: 666Abstract Full Text Full Text PDF Scopus (23) Google Scholar represents an important advance in our understanding of events reflecting clinical deterioration that commonly occur during the management of children with PH. Understanding the frequency and timing of these events may prove to be important in models that predict and prevent progressive deterioration in pediatric PH, which until this study has been limited. Interventional studies and managing children with PH have been hindered by a lack of adequate end points for rigorous evaluation of outcomes during clinical trials and of treatment goals. Although there are no validated end points in pediatric PH, Ploegstra and colleagues4Ploegstra M-J Arjaans S Zijlstra WMH et al.Clinical worsening as composite study end point in pediatric pulmonary arterial hypertension.Chest. 2015; 148: 666Abstract Full Text Full Text PDF Scopus (23) Google Scholar provide an important step toward improving our understanding of the potential for such events of clinical worsening when developing clinical trials. As pointed out by Fleming and DeMets,5Fleming TR DeMets DL Surrogate end points in clinical trials: are we being misled?.Ann Intern Med. 1996; 125: 605-613Crossref PubMed Scopus (1352) Google Scholar “a correlate does not a surrogate make.” This statement is particularly relevant to Ploegstra and colleagues4Ploegstra M-J Arjaans S Zijlstra WMH et al.Clinical worsening as composite study end point in pediatric pulmonary arterial hypertension.Chest. 2015; 148: 666Abstract Full Text Full Text PDF Scopus (23) Google Scholar in that none of these end points have been validated. However, to move forward in pediatric PH trials, it is imperative that studies begin to look at potential end points for clinical trials. Over the past two decades, attempts to design clinical trials for children have faced many obstacles. These have included the lack of an end point that could be applied to all children with PH regardless of age and developmental status and end points that accurately reflect how children feel, function, and survive. Many studies have evaluated correlations between hemodynamic, echocardiographic, and protein biomarkers and events in pediatric PH.6Jone PN Hinzman J Wagner BD Ivy DD Younoszai A Right ventricular to left ventricular diameter ratio at end-systole in evaluating outcomes in children with pulmonary hypertension.J Am Soc Echocardiogr. 2014; 27: 172-178Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar Importantly, none of these have been validated, and these currently remain unacceptable as end points for clinical trials. In the Sildenafil in Treatment-Naive Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension (STARTS-1) trial, cardiac catheterization was performed in all study children.7Barst RJ Ivy DD Gaitan G et al.A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension.Circulation. 2012; 125: 324-334Crossref PubMed Scopus (280) Google Scholar Mean pulmonary artery pressure and pulmonary vascular resistance improved after 16 weeks of high-dose sildenafil, but mortality increased after 3 years of high-dose sildenafil.8Barst RJ Beghetti M Pulido T STARTS-2 Investigators et al.STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension.Circulation. 2014; 129: 1914-1923Crossref PubMed Scopus (145) Google Scholar Subsequently, because of the increased risk of complications with cardiac catheterization in children compared with adults, the US Food and Drug Administration deemed hemodynamics by cardiac catheterization an unacceptable end point in a clinical trial. However, this risk is low,9Beghetti M Berger RM Schulze-Neick I TOPP Registry Investigators et al.Diagnostic evaluation of paediatric pulmonary hypertension in current clinical practice.Eur Respir J. 2013; 42: 689-700Crossref PubMed Scopus (86) Google Scholar and catheterization in a subset of patients would provide meaningful data. As pointed out in the STARTS-1 trial, adverse events, which may not be seen in the first several months during and shortly after the intervention, may become notable during long-term treatment and follow-up.8Barst RJ Beghetti M Pulido T STARTS-2 Investigators et al.STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension.Circulation. 2014; 129: 1914-1923Crossref PubMed Scopus (145) Google Scholar Perhaps the weakest link in the end points proposed in Ploegstra and colleagues4Ploegstra M-J Arjaans S Zijlstra WMH et al.Clinical worsening as composite study end point in pediatric pulmonary arterial hypertension.Chest. 2015; 148: 666Abstract Full Text Full Text PDF Scopus (23) Google Scholar is the determination of functional class in children. Functional deterioration as an end point in a trial is problematic in children because functional status is a soft and subjective end point, and its applicability in infants and young children remains unproven.10Lammers AE Adatia I Cerro MJ et al.Functional classification of pulmonary hypertension in children: report from the PVRI Pediatric Taskforce, Panama 2011.Pulm Circ. 2011; 1: 280-285Crossref PubMed Scopus (88) Google Scholar Nonetheless, functional class has been found to correlate with survival in several registries.11Moledina S Hislop AA Foster H Schulze-Neick I Haworth SG Childhood idiopathic pulmonary arterial hypertension: a national cohort study.Heart. 2010; 96: 1401-1406Crossref PubMed Scopus (173) Google Scholar, 12Barst RJ McGoon MD Elliott CG Foreman AJ Miller DP Ivy DD Survival in childhood pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management.Circulation. 2012; 125: 113-122Crossref PubMed Scopus (267) Google Scholar, 13van Loon RL Roofthooft MT Delhaas T et al.Outcome of pediatric patients with pulmonary arterial hypertension in the era of new medical therapies.Am J Cardiol. 2010; 106: 117-124Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar Use of clinical worsening in a trial of children with PAH would likely require several years to complete for most diseases associated with PH. Such a lengthy trial would have advantages and disadvantages. Certainly, the use of clinical worsening as a combination end point would incorporate events that occur over several years. However, a disadvantage may be that a clinical trial in children may take many years to capture enough events to show significance between a control arm and a treatment arm. Although prospective evaluation of the end points is needed, the leap toward a meaningful clinical trial to obtain agency approval is necessary. Overall, Ploegstra and colleagues4Ploegstra M-J Arjaans S Zijlstra WMH et al.Clinical worsening as composite study end point in pediatric pulmonary arterial hypertension.Chest. 2015; 148: 666Abstract Full Text Full Text PDF Scopus (23) Google Scholar provide much-needed data to guide our thinking toward developing more rigorous and accurate assessments of meaningful outcomes in children with PH. Future work to link other end points or novel surrogate end points that are strongly associated with these outcomes may further advance our ability to study and care for children with PH." @default.
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• W1893841713 title "Beyond the 6-Minute Walk Test for Assessing Pediatric Pulmonary Hypertension" @default.
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