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Beyond the 6-Minute Walk Test for Assessing Pediatric Pulmonary HypertensionAssessing Pediatric Pulmonary Hypertension: Making Strides Through Combination End Points FREE TO VIEW

D. Dunbar Ivy, MD; Steven Abman, MD
Author and Funding Information

From the Department of Pediatrics, University of Colorado School of Medicine.

CORRESPONDENCE TO: D. Dunbar Ivy, MD, Section of Cardiology, Children’s Hospital Colorado, University of Colorado School of Medicine, 13123 E 16th Ave, Aurora, CO 80045; e-mail: dunbar.ivy@childrenscolorado.org


FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following conflicts of interest: The University of Colorado contracts with Actelion Pharmaceuticals Ltd, Bayer AG, Gilead, Eli Lilly and Company, and United Therapeutics Corporation for Dr Ivy to be a consultant. Dr Abman has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(3):576-577. doi:10.1378/chest.15-0779
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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.1,2 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.3 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 colleagues4 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 colleagues4 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 colleagues4 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,5 “a correlate does not a surrogate make.” This statement is particularly relevant to Ploegstra and colleagues4 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.6 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.7 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.8 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,9 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.8

Perhaps the weakest link in the end points proposed in Ploegstra and colleagues4 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.10 Nonetheless, functional class has been found to correlate with survival in several registries.11-13 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 colleagues4 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.

References

Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346(12):896-903. [CrossRef] [PubMed]
 
Ghofrani HA, Galiè N, Grimminger F, et al; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330-340. [CrossRef] [PubMed]
 
Pulido T, Adzerikho I, Channick RN, et al; SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809-818. [CrossRef] [PubMed]
 
Ploegstra M-J, Arjaans S, Zijlstra WMH, et al. Clinical worsening as composite study end point in pediatric pulmonary arterial hypertension. Chest. 2015:148(3):655-666.
 
Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996;125(7):605-613. [CrossRef] [PubMed]
 
Jone 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(2):172-178. [CrossRef] [PubMed]
 
Barst 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(2):324-334. [CrossRef] [PubMed]
 
Barst RJ, Beghetti M, Pulido T, et al; STARTS-2 Investigators. STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension. Circulation. 2014;129(19):1914-1923. [CrossRef] [PubMed]
 
Beghetti M, Berger RM, Schulze-Neick I, et al; TOPP Registry Investigators. Diagnostic evaluation of paediatric pulmonary hypertension in current clinical practice. Eur Respir J. 2013;42(3):689-700. [CrossRef] [PubMed]
 
Lammers 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(2):280-285. [CrossRef] [PubMed]
 
Moledina S, Hislop AA, Foster H, Schulze-Neick I, Haworth SG. Childhood idiopathic pulmonary arterial hypertension: a national cohort study. Heart. 2010;96(17):1401-1406. [CrossRef] [PubMed]
 
Barst 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(1):113-122. [CrossRef] [PubMed]
 
van 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(1):117-124. [CrossRef] [PubMed]
 

Figures

Tables

References

Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346(12):896-903. [CrossRef] [PubMed]
 
Ghofrani HA, Galiè N, Grimminger F, et al; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330-340. [CrossRef] [PubMed]
 
Pulido T, Adzerikho I, Channick RN, et al; SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369(9):809-818. [CrossRef] [PubMed]
 
Ploegstra M-J, Arjaans S, Zijlstra WMH, et al. Clinical worsening as composite study end point in pediatric pulmonary arterial hypertension. Chest. 2015:148(3):655-666.
 
Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996;125(7):605-613. [CrossRef] [PubMed]
 
Jone 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(2):172-178. [CrossRef] [PubMed]
 
Barst 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(2):324-334. [CrossRef] [PubMed]
 
Barst RJ, Beghetti M, Pulido T, et al; STARTS-2 Investigators. STARTS-2: long-term survival with oral sildenafil monotherapy in treatment-naive pediatric pulmonary arterial hypertension. Circulation. 2014;129(19):1914-1923. [CrossRef] [PubMed]
 
Beghetti M, Berger RM, Schulze-Neick I, et al; TOPP Registry Investigators. Diagnostic evaluation of paediatric pulmonary hypertension in current clinical practice. Eur Respir J. 2013;42(3):689-700. [CrossRef] [PubMed]
 
Lammers 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(2):280-285. [CrossRef] [PubMed]
 
Moledina S, Hislop AA, Foster H, Schulze-Neick I, Haworth SG. Childhood idiopathic pulmonary arterial hypertension: a national cohort study. Heart. 2010;96(17):1401-1406. [CrossRef] [PubMed]
 
Barst 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(1):113-122. [CrossRef] [PubMed]
 
van 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(1):117-124. [CrossRef] [PubMed]
 
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