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. 2020 Oct;10(5):1675-1685.
doi: 10.21037/cdt.2020.04.01.

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

Sabrina Schweintzger  1   2 , Martin Koestenberger  1   2 , Axel Schlagenhauf  3 , Gernot Grangl  1 , Ante Burmas  1 , Stefan Kurath-Koller  1 , Mirjam Pocivalnik  4 , Hannes Sallmon  2   5 , Daniela Baumgartner  1 , Georg Hansmann  2   6 , Andreas Gamillscheg  1
Affiliations

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

Sabrina Schweintzger et al. Cardiovasc Diagn Ther. 2020 Oct.

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 treatment-naïve and started on a de novo macitentan therapy. The remaining 14/18 children were already on a PH-targeted 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.

Keywords: Bosentan; child; endothelin receptor antagonist (ERA); macitentan; pulmonary hypertension (PH).

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt.2020.04.01). The series “Right Ventricular Dysfunction” was commissioned by the editorial office without any funding or sponsorship. AG reports grants from JNJ during the conduct of the study. Actelion/Johnson&Johnson had no influence on this publication, has not seen the data or the manuscript and had no role in the production of this manuscript. The authors are solely responsible for the design and conduction of this study, all study analyses, the drafting and editing of the paper and its final contents. The authors have no other conflicts of interest to declare.

Figures

Figure 1
Figure 1
Treatment of pulmonary hypertension. PH, pulmonary hypertension; n, number.
Figure 2
Figure 2
Clinical assessment. (A) Distribution of the New York Heart Association (NYHA) Functional Classification (FC) of all children (n=18) pre and post macitentan (MAC) start. (B) Six-minute walking distance (6MWD) in meters (m) pre and post macitentan (MAC) start. Left: absolute values. The box and whisker plots (left) show the median, IQR and range. Right: percent change from baseline. The scatter plots (right) show the median with IQR.
Figure 3
Figure 3
Echocardiography. (A) Trend of pulmonary acceleration time (PAAT), estimated right ventricular systolic pressure gradient (RVSP) and tricuspid annular plane systolic excursion (TAPSE) pre and post macitentan (MAC) start. The box and whisker plots (left) show the median, IQR and range. (B) PAAT, RVSP and TAPSE shown as percent change from baseline (before macitentan therapy). The scatter plots (right) show the median with IQR. *, significant change P<0.05.
Figure 4
Figure 4
Invasive hemodynamics. (A) Left: the pulmonary vascular resistance index (PVRI) in Wood units (WU) × m2 Body surface area (BSA) before (per) and after (post) macitentan (MAC) initiation. The box and whisker plots (left) show the median, IQR and range. Right: percent change from baseline (before macitentan therapy). The scatter plots (right) show the median with IQR. (B) Left: ratio of mean pulmonary artery pressure/mean systemic artery pressure (mPAP/mSAP ratio) in percent (%) before (pre) and after (post) macitentan initiation. The box and whisker plots (left) show the median, IQR and range. Right: percent change from baseline (before macitentan therapy). The scatter plots (right) show the median with IQR. (C) Left: mean pulmonary artery pressure (mPAP) in millimeters of mercury (mmHg) before (pre) and after (post) macitentan initiation. The box and whisker plots (left) show the median, IQR and range. Right: percent change from baseline (before MAC therapy). The scatter plots (right) show the median with IQR. *, significant change P<0.05.
Figure 5
Figure 5
NT-proBNP. Left: absolute values of NT-proBNP. The box and whisker plots (left) show the median, IQR and range. Right: percent change from baseline (before macitentan therapy). The scatter plots (right) show the median with IQR. *, significant change P<0.05. NT-proBNP, N-terminal pro-brain natriuretic peptide.
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