Safety and efficacy of the endothelin receptor antagonist macitentan in pediatric pulmonary hypertension

Abstract

Background: Macitentan, a dual endothelin receptor antagonist (ERA), was approved in 2014 for the treatment of adults with idiopathic pulmonary arterial hypertension (PAH). Once-per-day dosing and low potential hepatic toxicity make macitentan an appealing therapeutic option for children with PAH, but reports on its use in pediatric patients are still lacking.Methods: Prospective observational study of 18 children [10 male; median age: 8.5, minimum (min.): 0.6, maximum (max.): 16.8 years] with pulmonary hypertension (PH). Four of these 18 patients were treatmentnaïve and started on a de novo macitentan therapy. The remaining 14/18 children were already on a PHtargeted pharmacotherapy (sildenafil or bosentan as monotherapy or in combination). Nine children who were on bosentan were switched to macitentan. We analyzed the 6-minute walking distance (6MWD), NYHA functional class (FC)/modified ROSS score, invasive hemodynamics, echocardiographic variables and the biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP).Results: The median follow up was 6 months (min.: 0.5, max.: 30). Macitentan treatment was associated with improvement of invasive hemodynamics, e.g., the ratio of mean pulmonary arterial pressure/mean systemic arterial pressure decreased from a median of 62% (min.: 30%, max.: 87%) to 49% (min.: 30%, max.: 69%), P<0.05; pulmonary vascular resistance index (PVRi) decreased from a median of 7.6 (min.: 3.3, max.: 11.5) to 4.8 Wood units × m² body surface area (min.: 2.5, max.: 10), P<0.05. The tricuspid annular plane systolic excursion (TAPSE) increased from a median of 1.4 (min.: 0.8, max.: 2.8) to 1.9 (min.: 0.8, max.: 2.7) cm, (P<0.05). NT-proBNP values decreased from a median of 272 (min.: 27, max.: 2,010) to 229 (min.: 23, max.: 814) pg/mL under macitentan therapy (P<0.05). The 6MWD and NYHA FC/modified ROSS score did not change significantly.Conclusions: This is the first prospective study of macitentan pharmacotherapy in infants and children with PH <12 years of age. Except in one patient, macitentan treatment was well tolerated and was associated with improvements in invasive hemodynamics, longitudinal systolic RV function (TAPSE) and serum NT-proBNP values.

Pulmonary hypertension in bronchopulmonary dysplasia

“…However, longitudinal assessment of NT-proBNP in combination with echocardiography is very useful to assess disease progression and/or response to treatment. [41][42][43][44] Meanwhile, additional biomarkers are under consideration and may contribute to future PH management. 12,40 TREATMENT Supportive measures Supplemental oxygen should be supplied when target oxygen saturations are >93% for infants with suspected and >95% for infants with proven PH (Fig.…”

“…Macitentan has been studied in a small prospective pediatric study and was shown to be safe and efficacious as add-on therapy. 44 Off-label use of macitentan also has been reported in BPD-PH patients. 56 Of note, bosentan lowers circulating sildenafil levels, while the other two ERA, ambrisentan and macitentan, do not.…”

“…However, longitudinal assessment of NT-proBNP in combination with echocardiography is very useful to assess disease progression and/or response to treatment. 41 – 44 …”

Treatment of pulmonary arterial hypertension in children

“…After 24 weeks, there was no further increment in exercise capacity in this cohort of patients with different etiologies of PAH (62). Eighteen patients younger than 12 years were prospectively assessed after either switching from sildenafil and/or bosentan to macitentan or who were treatment-naïve (20). Schweintzger et al reported improvements in invasive hemodynamics, tricuspid annular plane systolic excursion (TAPSE) and NT-proBNP values after median 6 months (20).…”

Toward a standardized multidisciplinary team approach in preterm infants at-risk for pulmonary hypertension

“…The same holds true for endothelin receptor antagonists: Bosentan is approved for infants with pulmonary arterial hypertension above >1 year of age in Europe and >3 years of age in the U.S., but data on its safety and efficacy in young children with BPD-PH are sparse [ 2 , 3 ]. Recently, we published the first pediatric prospective observational study on the use of macitentan, including five infants with BPD-PH [ 4 ]. We believe that further research on new PH-targeted therapies and the role of early combination therapies might help reduce morbidity and mortality in BPD-PH.…”