Echocardiographic Changes and Long-Term Clinical Outcomes in Pediatric Patients With Pulmonary Arterial Hypertension Treated With Bosentan for 72 Weeks:A Post-hoc Analysis From the FUTURE 3 Study

FormUlation of bosenTan in pUlmonary arterial hypeRtEnsion (FUTURE) 3 was a 24-week open-label, prospective, and randomized phase 3 study that assessed the pharmacokinetics of bosentan 2 mg/kg b.i.d. or t.i.d. in children with pulmonary arterial hypertension (PAH). We report findings from a post-hoc analysis that explored the prognostic value of echocardiographic changes during FUTURE 3 in relation to clinical outcomes observed during the 24-week core study and 48-week extension. Patients aged ≥3 months to <12 years (n = 64) received oral doses of bosentan 2 mg/kg b.i.d. or t.i.d. (1:1) for 24 weeks, after which they were eligible to enter the extension with continued bosentan administration. Echocardiographic evaluations were performed at baseline, Week 12, and 24 of the core study via central reading, and analyzed post-hoc for correlation with clinical outcomes (time to PAH worsening, time to death, and vital status). Sixty-four patients were randomized in the core study [median (IQR) age 3.8 (1.7–7.8) years]; and 58 patients (90.6%) entered the 48-week extension. Most of the patients (68.8%) were receiving ≥1 PAH medication at baseline. Echocardiographic changes during the core study were small but with high variability. There were statistically significant associations at Week 24 between worsening of the parameters, systolic left ventricular eccentricity index (LVEIS) and E/A ratio mitral valve flow, and the outcomes of time to death and time to PAH worsening. Additional studies that utilize simple and reproducible echocardiographic assessments are needed to confirm these findings and subsequently identify potential treatment goals in pediatric PAH

Hemodynamic and prognostic impact of the diastolic pulmonary arterial pressure in children with pulmonary arterial hypertension-a registry-based analysis

BACKGROUND: Diastolic pulmonary arterial pressure (dPAP) is regarded to be less sensitive to flow metrics as compared to mean PAP (mPAP), and was therefore proposed for the assessment of a precapillary component in patients with postcapillary pulmonary hypertension (PH). To analyze the diagnostic and prognostic impact of dPAP in patients with pure precapillary PH, we purposed to compare the correlation between dPAP and mPAP, as well as hemodynamically-derived calculations [ratio of PAP to systemic arterial pressure (PAP/SAP), pulmonary vascular resistance index (PVRI), transpulmonary gradient (TPG)], using both dPAP and mPAP, at rest and during acute vasoreactivity testing (AVT) in children with idiopathic or heritable pulmonary arterial hypertension (IPAH/HPAH). Furthermore, we aimed to assess the association of these metrics (at baseline and changes after AVT) with transplant-free survival. METHODS: We conducted a retrospective analysis of the TOPP (Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension) registry including 246 IPAH/HPAH patients. Of these, 45 children (18.3%) died, and 13 (5.3%) received lung transplantation during the observation period. RESULTS: dPAP and mPAP-derived variables showed almost linear relationship. Higher mPAP/mSAP, and dPAP-/mPAP-derived PVRI at rest was associated with time to death/transplantation. At maximum AVT-response, the decrease of dPAP and mPAP, diastolic pulmonary gradient (DPG) and TPG, as well as dPAP/dSAP and mPAP/mSAP was associated with time to death/transplantation, showing higher significance than corresponding baseline values. Remarkably, no predictive value was found for PVRI-reduction during AVT, neither dPAP- nor mPAP-derived. CONCLUSIONS: There is a strong relationship between dPAP and mPAP-derived variables. According to our results, hemodynamics during AVT (irrespectively of dPAP- or mPAP-derived) may have more prognostic implications than resting hemodynamics in children with IPAH/HPAH, except for PVRI

Survival Differences in Pediatric Pulmonary Arterial Hypertension Clues to a Better Understanding of Outcome and Optimal Treatment Strategies

ObjectivesIn order to describe survival and treatment strategies in pediatric pulmonary arterial hypertension (PAH) in the current era of PAH-targeted drugs and to identify predictors of outcome, we studied uniformly defined contemporary patient cohorts at 3 major referral centers for pediatric PAH (New York [NY], Denver, and the Netherlands [NL]).BackgroundIn pediatric PAH, discrepancies exist in reported survival rates between North American and European patient cohorts, and robust data for long-term treatment effects are lacking.MethodsAccording to uniform inclusion criteria, 275 recently diagnosed consecutive pediatric PAH patients who visited the 3 referral centers between 2000 and 2010 were included.ResultsUnadjusted survival rates differed between the center cohorts (1-, 3-, and 5-year transplantation-free survival rates: 100%, 96%, and 90% for NY; 95%, 87%, and 78% for Denver; and 84%, 71%, and 62% for NL, respectively; p < 0.001). Based on World Health Organization (WHO) functional class and hemodynamic parameters, disease severity at diagnosis differed between the center cohorts. Adjustment for diagnosis, WHO functional class, indexed pulmonary vascular resistance, and pulmonary-to-systemic arterial pressure ratio resolved the observed survival differences. Treatment with PAH-targeted dual and triple therapy during the study period was associated with better survival than treatment with PAH-targeted monotherapy.ConclusionsSurvival rates of pediatric PAH patients differed between 3 major referral centers. This could be explained by differences between the center cohorts in patients’ diagnoses and measures of disease severity, which were identified as important predictors of outcome. In this study, treatment with PAH-targeted combination therapy during the study period was independently associated with improved survival

Parenteral Prostanoids in Pediatric Pulmonary Arterial Hypertension:Start Early, Dose High, Combine

RATIONALE: There are currently no data supporting specific dosing and weaning strategies for parenteral prostanoid therapy in children with pulmonary arterial hypertension (PAH). OBJECTIVES: To describe the clinical practice of intravenous (IV) or subcutaneous (SC) prostanoid therapy in pediatric PAH and identify dosing strategies associated with favorable outcome. METHODS: From an international multicenter cohort of 275 children with PAH, 98 patients who received IV/SC prostanoid therapy were retrospectively analyzed. RESULTS: IV/SC prostanoids were given as monotherapy (20%) or combined with other PAH-targeted drugs as dual (46%) or triple therapy (34%). The median time-averaged dose was 37 ng/kg/min, ranging 2–136 ng/kg/min. During follow-up, IV/SC prostanoids were discontinued and transitioned to oral or inhaled PAH-targeted therapies in 29 patients. Time-dependent receiver operating characteristic analyses showed specific hemodynamic criteria at discontinuation of IV/SC prostanoids (mean pulmonary arterial pressure 25 ng/kg/min), early start after diagnosis, and combination with other PAH-targeted drugs were associated with better transplant-free survival. CONCLUSIONS: Early initiation of IV/SC prostanoids, higher doses of IV/SC prostanoids, and combination with additional PAH-targeted therapy were associated with favorable outcome. Transition from IV/SC prostanoid therapy to oral or inhaled therapies is safe in the long term in selected children, identified by reaching hemodynamic criteria for durable IV/SC prostanoid discontinuation while on IV/SC prostanoid therapy

Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study

center dot Exposure to bosentan was lower in paediatric pulmonary arterial hypertension (PAH) patients treated with the marketed adult formulation at a dose of about 2 mg kg-1 when compared with adult PAH patients. center dot In healthy adult subjects, bosentan pharmacokinetics are less than dose-proportional at doses of >= 500 mg. WHAT THIS STUDY ADDS center dot The pharmacokinetics of a new paediatric bosentan formulation were characterized in paediatric PAH patients. center dot The level of exposure to bosentan as observed in adult PAH patients cannot be reached in paediatric patients with b.i.d. dosing. center dot In paediatric PAH patients, nondose-proportional pharmacokinetics of bosentan occur at lower doses when compared with healthy adult subjects. AIM To show equivalent bosentan exposure in paediatric patients with pulmonary arterial hypertension (PAH) when compared with a cohort of historical controls of adult PAH patients using a newly developed paediatric formulation. METHODS Thirty-six paediatric PAH patients were enrolled in this multicentre, prospective, open-label, noncontrolled study and treated for 4 weeks with bosentan 2 mg kg-1 b.i.d. and then for 8 weeks with 4 mg kg-1 b.i.d. Blood samples were taken for pharmacokinetic purposes. Exploratory efficacy measurements included World Health Organization (WHO) functional class and parent's and clinician's Global Clinical Impression scales. RESULTS Comparing children with a historical group of adults, the geometric mean ratio (90% confidence interval) of the area under the plasma concentration-time curve was 0.54 (0.37, 0.78), i.e. children had lower exposure to bosentan than adults. Bosentan concentrations following doses of 2 and 4 mg kg-1 were similar. Improvements in WHO functional class and the Global Clinical Impression scales occurred mainly in bosentan-naive patients, whereas the rare worsenings occurred in patients already on bosentan prior to study initiation. The paediatric formulation was well accepted and bosentan well tolerated in this study. No cases of elevated liver enzymes or anaemia were reported. CONCLUSIONS Exposure to bosentan, as shown comparing the results from this study with those from a study in adults, was different in paediatric and adult PAH patients. Since FUTURE-1 and past studies suggest a favourable benefit-risk profile for bosentan at 2 mg kg-1 b.i.d., this dose is recommended for children with PAH. The new paediatric formulation was well tolerate

Pulmonary-to-Systemic Arterial Shunt to Treat Children With Severe Pulmonary Hypertension

BACKGROUND: The placement of a pulmonary-to-systemic arterial shunt in children with severe pulmonary hypertension (PH) has been demonstrated, in relatively small studies, to be an effective palliation for their disease. OBJECTIVES: The aim of this study was to expand upon these earlier findings using an international registry for children with PH who have undergone a shunt procedure. METHODS: Retrospective data were obtained from 110 children with PH who underwent a shunt procedure collected from 13 institutions in Europe and the United States. RESULTS: Seventeen children died in-hospital postprocedure (15%). Of the 93 children successfully discharged home, 18 subsequently died or underwent lung transplantation (20%); the mean follow-up was 3.1 years (range: 25 days to 17 years). The overall 1- and 5-year freedom from death or transplant rates were 77% and 58%, respectively, and 92% and 68% for those discharged home, respectively. Children discharged home had significantly improved World Health Organization functional class (P < 0.001), 6-minute walk distances (P = 0.047) and lower brain natriuretic peptide levels (P < 0.001). Postprocedure, 59% of children were weaned completely from their prostacyclin infusion (P < 0.001). Preprocedural risk factors for dying in-hospital postprocedure included intensive care unit admission (hazard ratio [HR]: 3.2; P = 0.02), mechanical ventilation (HR: 8.3; P < 0.001) and extracorporeal membrane oxygenation (HR: 10.7; P < 0.001). CONCLUSIONS: A pulmonary-to-systemic arterial shunt can provide a child with severe PH significant clinical improvement that is both durable and potentially free from continuous prostacyclin infusion. Five-year survival is comparable to children undergoing lung transplantation for PH. Children with severely decompensated disease requiring aggressive intensive care are not good candidates for the shunt procedure

Clinical classification in pediatric pulmonary arterial hypertension associated with congenital heart disease

Abstract. Congenital heart disease (CHD) is a frequent cause of pediatric pulmonary arterial hypertension (PAH), with diverse etiology and outcome. We aimed to describe phenotypic heterogeneity in pediatric PAH associated with CHD (PAH-CHD), assess the applicability of the Nice CHD classification, and explore whether this classification accurately reflects patient/disease characteristics and survival. All children with CHD from a contemporary cohort of consecutive pediatric PAH patients followed in three major referral centers (Denver, New York, the Netherlands) were characterized and classified on the basis of the latest proposed clinical classification for PAH-CHD (World Symposium on Pulmonary Hypertension, Nice, 2013). According to this classification, 24% of 134 children were classified into group 1, 14% into group 2, 19% into group 3, and 30% into group 4; 11% could not be classified. Types of CHD and hemodynamic profile differed between groups, with the highest right atrial pressure in group 4 (P < 0.040). Group 3 children had Down syndrome less frequently (P = 0.011) but other (un)defined syndromes most frequently (P = 0.063) and received most intense PAH-targeted therapy (P = 0.003). With 15 deaths and one lung transplant (12%; median follow-up: 4.3 years), survival differences could not be demonstrated between the groups in the Nice CHD classification. Pediatric PAH-CHD is a heterogeneous condition frequently associated with extracardiac, developmental factors that are believed to affect disease development. The Nice CHD classification identifies groups with specific patient/disease characteristics. However, a substantial proportion of children could not be classified. Group 3 forms a distinct disease entity. Its prognostic value could not be determined because of the low number of events. The Nice CHD classification supports clinical characterization of PAH-CHD; however, further refinement is needed to classify all children with PAH-CHD

Hypoplastic Left Heart Syndrome Current Considerations and Expectations

In the recent era, no congenital heart defect has undergone a more dramatic change in diagnostic approach, management, and outcomes than hypoplastic left heart syndrome (HLHS). During this time, survival to the age of 5 years (including Fontan) has ranged from 50% to 69%, but current expectations are that 70% of newborns born today with HLHS may reach adulthood. Although the 3-stage treatment approach to HLHS is now well founded, there is significant variation among centers. In this white paper, we present the current state of the art in our understanding and treatment of HLHS during the stages of care: 1) pre-Stage I: fetal and neonatal assessment and management; 2) Stage I: perioperative care, interstage monitoring, and management strategies; 3) Stage II: surgeries; 4) Stage III: Fontan surgery; and 5) long-term follow-up. Issues surrounding the genetics of HLHS, developmental outcomes, and quality of life are addressed in addition to the many other considerations for caring for this group of complex patients