Children with pulmonary arterial hypertension and prostanoid therapy: Long-term hemodynamics

doi:10.1016/j.healun.2013.01.1055

The Journal of Heart and Lung Transplantation

Volume 32, Issue 5, May 2013, Pages 546-552

https://doi.org/10.1016/j.healun.2013.01.1055 Get rights and content

Background

Pediatric patients with severe pulmonary arterial hypertension (PAH) are treated with intravenous epoprostenol or intravenous or subcutaneous treprostinil. Little is known about longitudinal hemodynamics and outcomes of epoprostenol, treprostinil, and transitions from epoprostenol to treprostinil.

Methods

This was retrospective study of 77 pediatric patients (47 idiopathic PAH, 24 congenital heart disease-PAH) receiving epoprostenol or treprostinil from 1992 to 2010 at 2 centers. Outcomes were defined as living vs dead/transplant.

Results

Mean age at baseline was 7.7 ± 5.2 years, with follow-up of 4.3 ± 3.4 years. Thirty-seven patients were treated with epoprostenol, 20 with treprostinil, and 20 were transitioned from epoprostenol to treprostinil. Mean pulmonary-to-systemic vascular resistance ratio (Rp/Rs) for epoprostenol was 1.0 ± 0.4, 0.8 ± 0.4, 0.8 ± 0.4, 1.0 ± 0.4, and 1.2 ± 0.4, respectively, at baseline, 1, 2, 3, and 4 years. For treprostinil, Rp/Rs was 0.9 ± 0.3, 0.7 ± 0.3, 0.5 ± 0.2, (p < 0.01 vs baseline), and 1.1 ± 0.2, respectively, at baseline, 1, 2, and 3 to 4 years, respectively. There were similar changes in mean pulmonary artery pressure and pulmonary vascular resistance index. The Rp/Rs 1 year after epoprostenol to treprostinil transition increased from 0.6 to 0.8 (n = 7). Changes not statistically significant unless noted. Eight patients died or received a transplant within 2 years of baseline; compared with the rest of the cohort, mean baseline Rp/Rs, right atrial pressure, and pulmonary vascular resistance index were significantly worse in this group. Thirty-nine patients remain on prostanoids, 17 are off, 16 died, and 5 received heart-lung transplant. Kaplan-Meier 5-year transplant-free survival was 70% (95% confidence interval, 56%-80%).

Conclusion

There was improvement in Rp/Rs on both therapies at 1 to 2 years that was not sustained. The 5-year transplant-free survival was better than in similar adult studies.

Section snippets

Methods

This was a 2-center, retrospective, descriptive study. The study was approved by the Stanford University Administrative Panel on Human Subjects in Medical Research and by the University of Colorado, Colorado Multiple Institutional Review Board.

All patients who were treated for PAH or repaired CHD-PAH at Lucile Packard Children’s Hospital in conjunction with the Vera Moulton Wall Center for Pulmonary Vascular Diseases at Stanford University and Children’s Hospital Colorado were identified

Results

Between 1992 and 2010, 79 pediatric patients were treated with epoprostenol or treprostinil for PAH between the 2 institutions. The study excluded 2 patients with left heart obstructive lesions. Of the 77 patients eligible for inclusion in this study, 46 (61%) were girls. There were 47 patients with IPAH, 24 with repaired CHD-PAH, and 6 with other forms of World Health Organization Group 1 IPAH. Thirty-seven patients were treated with epoprostenol alone, 20 with treprostinil alone, and 20

Discussion

Before the availability of specific drugs for PAH, median survival in adults with IPAH was 2.8 years, with a 5-year survival of 34%.¹ Since the introduction of prostacyclin therapy, long-term outcomes and survival have improved in adults with PAH.12, 13, 14, 15 Sitbon et al¹⁵ reported hemodynamic improvement at 1 year in 156 patients with IPAH on epoprostenol with a 5-year survival of 55%. Similarly, several large adult studies consistently demonstrated a reduction in PVR on follow-up

Disclosure statement

This study was supported by the Jayden DeLuca Foundation, the Leah Bult Foundation, and UL1 RR025780 Colorado Clinical Translational Science Institute, National Center for Research Resources, and National Institutes of Health.

None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.

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Treprostinil Effectiveness in Higher-Risk Pediatric Patients With Idiopathic and Heritable Pulmonary Arterial Hypertension
2024, Canadian Journal of Cardiology
Little is known about the effectiveness of treprostinil in higher-risk paediatric patients with various pulmonary arterial hypertension genotypes. This study was designed to investigate the prognosis of higher-risk paediatric patients with idiopathic or heritable pulmonary arterial hypertension (IPAH/HPAH) after treprostinil therapy.
Children with IPAH/HPAH who were stratified as higher risk and treated with treprostinil in our centre were included as the study cohort. Those who received only oral medications were included as the reference cohort. All patients in the study cohort received PAH-related genotyping. Survival was defined as no death. Event-free survival was defined as no death, Potts shunt, or atrial septostomy.
Forty-nine children (median age 7.7 years [interquartile range (IQR) 4.2-11.5 years], 65% female) were included in the study cohort and 48 children were included in the reference cohort; 84% of the study cohort had genetic disorders after genetic testing with a dominance of BMPR2 and ACVRL1 mutations. After a median therapy duration of 5.56 months (IQR 2.66-11.12 months), all patients were alive with significant improvements in clinical characteristics. One-, 2-, and 3-year survival rates were 91%, 84%, and 69%, respectively with a median follow-up duration of 19.17 months (IQR 9.7-29.79 months), which was significantly superior to the reference cohort (P = 0.038). Multivariate Cox regression analysis identified World Health Organisation functional class after therapy as a predictor for survival. There was no significant difference in survival among patients with different genotypes.
Treprostinil can significantly improve the prognosis in children with IPAH/HPAH who are at higher risk, despite genetic backgrounds.
On en sait peu sur l’efficacité du treprostinil chez les enfants atteints d’hypertension artérielle pulmonaire de divers génotypes et présentant un risque élevé. Cette étude a été conçue pour étudier le pronostic chez des enfants à risque élevé atteints d’hypertension artérielle pulmonaire idiopathique ou héréditaire (HTAPI/HTAPH) après un traitement par le treprostinil.
Les enfants atteints d’HTAPI/HTAPH qui ont été stratifiés comme présentant un risque élevé et qui ont été traités par le treprostinil dans notre centre ont été inclus dans la cohorte de l’étude. Les patients qui ont reçu uniquement des médicaments par voie orale ont été inclus dans la cohorte témoin. Tous les patients de la cohorte de l’étude ont été soumis à un génotypage lié à l’hypertension artérielle pulmonaire. La survie a été définie comme l’absence de décès. La survie sans épisode a été définie comme l’absence de décès, d’anastomose de Potts ou de septostomie auriculaire.
Quarante-neuf enfants (âge médian 7,7 ans [écart interquartile 4,2-11,5 ans], 65 % de sexe féminin) ont été inclus dans la cohorte de l’étude et 48 enfants ont été inclus dans la cohorte témoin. Une analyse génétique a révélé que 84 % des enfants de la cohorte de l’étude affichaient des troubles génétiques avec une dominance des mutations des gènes BMPR2 et ACVRL1. Après un traitement d’une durée médiane de 5,56 mois (écart interquartile 2,66-11,12 mois), tous les patients étaient en vie et présentaient des améliorations marquées des caractéristiques cliniques. Les taux de survie à 1, à 2 et à 3 ans étaient respectivement de 91 %, de 84 % et de 69 % avec un suivi médian de 19,17 mois (écart interquartile 9,7-29,79 mois). Ces résultats sont significativement supérieurs à ceux observés dans la cohorte témoin (p = 0,038). Une analyse de régression de Cox multivariable a révélé que la classification fonctionnelle de l’Organisation mondiale de la Santé après le traitement était un facteur prédictif de la survie. Aucune différence notable quant à la survie n’a été observée entre les patients des différents génotypes.
Le treprostinil peut considérablement améliorer le pronostic chez les enfants atteints d’HTAPI/HTAPH à risque élevé, en dépit de leurs antécédents génétiques.
Treprostinil in Neonates with Congenital Diaphragmatic Hernia-Related Pulmonary Hypertension
2023, Journal of Pediatrics
To describe our experience with treprostinil, evaluate correlations with cardiac function, and assess for adverse effects in neonates with congenital diaphragmatic hernia-related pulmonary hypertension (CDH-PH).
A retrospective review of a single-center prospective registry at a quaternary care children's hospital. Patients included in the study had CDH-PH treated with treprostinil between April 2013 and September 2021. Assessed outcomes were brain-type natriuretic peptide levels and quantitative echocardiographic parameters collected at baseline, 1 week, 2 weeks, and 1 month after treprostinil initiation. Right ventricular (RV) function was assessed by tricuspid annular plane systolic excursion Z-score and speckle tracking echocardiography (global longitudinal and free wall strain). Septal position and left ventricular (LV) compression were assessed by eccentricity index and M-mode Z-scores.
Fifty-one patients were included, with an average expected/observed lung-to-head ratio of 28.4 ± 9.0%. Most patients required extra-corporeal membrane oxygenation (n = 45, 88%). Survival to hospital discharge was 31/49 (63%). Treprostinil was initiated at a median age of 19 days with a median effective dose of 34 ng/kg/minute. Median baseline brain-type natriuretic peptide level decreased from 416.9 pg/mL to 120.5 pg/mL after 1 month. Treprostinil was associated with improved tricuspid annular plane systolic excursion Z-score, RV global longitudinal strain, RV free wall strain, LV eccentricity index, and LV diastolic and systolic dimensions, reflecting less compression by the RV, regardless of ultimate patient survival. No serious adverse effects were recorded.
In neonates with CDH-PH, treprostinil administration is well tolerated and is associated with improved RV size and function.
Assessment of Quality of Life in Children With Pulmonary Hypertension Using Parent and Self-report Questionnaires
2022, Transplantation Proceedings
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevation of pulmonary vascular resistance and right ventricular failure. By using advanced therapies to reduce mortality, clinicians focus on improving functional status and quality of life (QOL). The aim of our study was to assess health-related QOL of pediatric patients with PAH. Parents of all children (aged 2-18 years) and patients aged 5-18 years with an appropriate level of intellectual development completed general and cardiac-specific validated surveys (Pediatric Quality of Life Inventory 4.0 and Pediatric Quality of Life Inventory 3.0, respectively). Demographic and clinical information was collected to grade disease severity.
Twenty-five children were enrolled, yielding 25 parent reports and 15 patient self-reports. The PAH group had significantly lower scores than healthy children in all domains. Patients with World Health Organization Functional Class I had significantly higher parent proxy scores in School Functioning (P = .029) and in Heart Problems and Symptoms domain (P = .014) Patients with tricuspid annular plane systolic excursion below −2 z score showed impairment in each parent proxy general domain and in the Cognitive Problems score of the Cardiac module (P = .006).
In conclusion the QOL of patients with PAH was impaired in every domain compared with healthy children. Patients with reduced right ventricle systolic function showed significantly lower QOL in all core domains. These results point to the need for psychosocial rehabilitation in addition to somatic care to improve the QOL in this severely ill population
Intravenous prostacyclin-analogue therapy in pulmonary arterial hypertension – A review of the past, present and future
2021, Respiratory Medicine
Citation Excerpt :
A double-blind randomized study of 44 therapy-naïve patients with PAH (42 with idiopathic or familial PAH) receiving intravenous treprostinil (n = 30) or placebo (n = 14) for 12 weeks showed a placebo-corrected improvement in 6-MWD of 93 ± 42 m [125]. Reports on intravenously applied treprostinil in children with PAH [126,127] and adult patients with portopulmonary hypertension [128] are also available. Of methodological interest, fast titration of intravenous treprostinil has been reported, with dosages of 20 ng/kg/min [129] or 42 ng/kg/min [130] being reached within 6 days.
Therapy with intravenous prostacyclin analogues in patients with pulmonary arterial hypertension (PAH) has been established for decades and is an integral component of the current guidelines for the treatment of pulmonary hypertension.
Initially, these drugs were infused by external pump systems via tunnelled right atrial catheters with the need for cooling and frequent exchange of drug reservoirs. Associated complications included, among others, catheter-related infections.
More recently, fully implantable pump systems have been developed with drug reservoirs that are filled transcutaneously, allowing intervals between refills of several weeks. This technique results in a low rate of infections.
Epoprostenol, iloprost and treprostinil have all been used intravenously in PAH, but titration, dosing and dose escalation in long-term therapy are not standardized.
Intravenous prostacyclin analogues are still under-used, despite available data suggesting that early and broad application of these therapies as part of risk-oriented, guideline-directed combination therapy for patients with PAH may lead to a survival benefit.
This review provides a detailed overview of the drugs, infusion systems and dosing strategies used for intravenous therapy in patients with PAH.
Pulmonary Hypertension in Children: A Global View
2021, Encyclopedia of Respiratory Medicine, Second Edition
Over a quarter of the World’s population are children. The last decade has witnessed great strides in our understanding of pediatric pulmonary hypertension (PH) driven in large part by the development of organized clinical networks, specialized centers and research registries. We have learned about the heterogeneous nature of PH in childhood dominated by congenital and developmental disorders and transient forms of the disease. This article focuses on areas of difference between adult and pediatric PH. These are also areas which promise to challenge prevailing paradigms and provide novel insights into disease mechanisms.
Pediatric Pulmonary Arterial Hypertension
2020, Pediatric Clinics of North America
Citation Excerpt :
Patients with severe PH also have decreased prostacyclin synthase expression at the level of their PAs.62 Early studies demonstrated that prostacyclins administered chronically, using intravenous epoprostenol, improved survival and quality of life in adults and children with idiopathic PAH.63–67 The Food and Drug Administration (FDA) approved the prostacyclin analog treprostinil for subcutaneous use in 2002, followed by intravenous administration in 2004, inhaled administration in 2009, and oral therapy in 2013.

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Children with pulmonary arterial hypertension and prostanoid therapy: Long-term hemodynamics

Background

Methods

Results

Conclusion

Section snippets

Methods

Results

Discussion

Disclosure statement

J Am Coll Cardiol

J Am Coll Cardiol

Am J Cardiol

J Am Coll Cardiol

J Pediatr

Am J Cardiol

Survival in patients with primary pulmonary hypertension. Results from a national prospective registry

Ann Intern Med

Severe paediatric pulmonary hypertension: new management strategies

Arch Dis Child

Pulmonary arterial hypertension in children

Pediatr Pulmonol

Effects of long-term sildenafil treatment for pulmonary hypertension in infants with chronic lung disease

J Pediatr

Beneficial effect of oral sildenafil therapy on childhood pulmonary arterial hypertension: twelve-month clinical trial of a single-drug, open-label, pilot study

Circulation

Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension

Clin Pharmacol Therapeut

Treatment and survival in children with pulmonary arterial hypertension: the UK Pulmonary Hypertension Service for Children 2001–2006

Heart