Investigation of the Effects of Switching from Bosentan to Macitentan in Pediatric Pulmonary Hypertension Patients

Abstract

Objectives

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary vascular resistance and reduced exercise capacity. Bosentan, an endothelin receptor antagonist, is commonly used in pediatric PAH, but standardized guidelines for its use are lacking. Macitentan, another endothelin receptor antagonist, offers advantages such as a longer duration of action, greater tissue penetration, and lower hepatotoxicity.

Methods

This retrospective study evaluated 21 pediatric patients (≥12 years) who transitioned from bosentan to macitentan due to worsening functional class and increased pulmonary artery pressure. Patients received 10 mg of macitentan daily after obtaining regulatory approval. Clinical assessments, including WHO functional class, NT-proBNP levels, transthoracic echocardiographic systolic pulmonary artery pressure (sPAP), and six-minute walk test (6MWT) distances, were conducted before and 6 months after the switch.

Results

At follow-up, the prevalence of WHO functional class III decreased from 66% to 19% (p=0.001). Median NT-proBNP levels significantly decreased from 1361.01 pg/mL to 906.06 pg/mL (p=0.009). Median sPAP also showed a statistically significant reduction (p=0.001). Additionally, 6MWT distances improved significantly (p=0.002). No adverse events, hospitalizations, or significant changes in liver function tests were observed.

Conclusion

Macitentan demonstrated favorable efficacy and safety in pediatric patients with PAH, particularly those with idiopathic PAH. Its once-daily regimen may improve adherence and clinical outcomes. These findings are consistent with adult studies and highlight macitentan as a promising treatment option for pediatric PAH. Larger-scale studies are needed to establish its role in clinical guidelines.

Pulmonary arterial hypertension is a progressive and fatal disease associated with increased pulmonary vascular resistance and reduced exercise capacity due to primary causes, congenital heart disease, or various other etiologies.^[1] Patients with pulmonary hypertension use different drug groups that target specific pathways, thereby improving symptoms and prognosis.^[2,3] Endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins are widely accepted medications for the treatment of pulmonary hypertension.^[4]

Bosentan is a pulmonary vasodilator agent frequently used in the treatment of pediatric pulmonary hypertension, improving quality of life and exercise capacity.^[5] Unfortunately, there is no established gold-standard guideline for the treatment of pediatric pulmonary hypertension. Treatments recommended for adults are also suggested for children, but the number of studies in this population is very limited.^[6] The European Society of Cardiology (ESC) periodically publishes guidelines for the treatment of pulmonary hypertension, which serve as a reference for the management of pediatric pulmonary hypertension.

New pharmacological agents are being developed and integrated into the medical treatment of pulmonary arterial hypertension. One such agent is macitentan.^[7] Like bosentan, macitentan belongs to the endothelin receptor antagonist drug class. However, it differs from bosentan in having a longer duration of action, higher tissue penetration, greater selectivity for endothelin A receptors, and lower hepatotoxicity.^[8] In the current ESC guideline, it is classified as a Class Ia treatment.

Macitentan is administered orally and has demonstrated both safety and efficacy.^[9] It has been approved for use in pediatric patients aged 12 years and older, although studies evaluating its effectiveness in younger patients are limited. In our study, we aimed to observe clinical changes in patients aged 12 years and older who transitioned from bosentan to macitentan treatment.

Methods

This study was conducted retrospectively. Patients aged 12 years and older who were followed up with a diagnosis of pulmonary hypertension due to various etiologies and were receiving bosentan treatment in the pediatric cardiology clinic were included in the study.

Patients aged 12 years or older who experienced worsening functional classification while receiving bosentan treatment and showed an increase in pulmonary artery pressure measured by transthoracic echocardiography were included in the study. Median systolic pulmonary artery pressure (sPAP) values were estimated primarily using tricuspid regurgitation jet velocity when measurable. In patients with intracardiac shunts, pressure gradients across defects were also considered together with the overall echocardiographic assessment. Patients with significant right ventricular outflow tract obstruction or peripheral pulmonary stenosis that could independently increase right ventricular systolic pressure were evaluated carefully, and these anatomical factors were considered when interpreting echocardiographic sPAP values. Patients whose functional classification did not deteriorate with bosentan treatment and who did not show an increase in pulmonary artery pressure on transthoracic echocardiographic measurements were excluded. Because of the retrospective design of the study, detailed right ventricular functional parameters such as RV fractional area change (RV FAC), TAPSE, and tissue Doppler-derived RV s' could not be obtained consistently for all patients. Therefore, changes in sPAP were interpreted together with clinical status, WHO functional class, NT-proBNP levels, oxygen saturation, and six-minute walk test results rather than as an isolated marker of treatment response.

All patients were evaluated during clinically stable periods. Patients with acute infectious episodes or transient clinical deterioration related to infection at the time of assessment were not included in the comparative evaluation.

In our country, the use of macitentan in patients younger than 18 years is only possible with approval from the Ministry of Health. Therefore, in accordance with the Ministry’s regulations, informed consent forms for off-label drug use were obtained from the families of patients transitioning to macitentan treatment. Following official approval from the Ministry, macitentan therapy was initiated in the approved patients. The study was conducted in accordance with the Declaration of Helsinki.

The initial dose of macitentan was administered at least 24 hours after the last dose of bosentan. Patients who had been receiving bosentan twice daily at a weight-appropriate dose were switched to a once-daily oral dose of 10 mg of macitentan.

The study recorded sex, age, primary or secondary pulmonary hypertension diagnosis, and underlying congenital heart diseases in patients with secondary pulmonary hypertension. Functional classification, NT-proBNP levels, systolic pulmonary artery pressure measured by transthoracic echocardiography, six-minute walk test distance, hemoglobin (Hb), ALT, AST levels, and oxygen saturation were evaluated during bosentan treatment and at the 6th month after switching to macitentan. Concomitant medications used during the study period were reviewed from patient records, and no major medication changes that could independently explain the observed clinical improvement were identified during the 6-month follow-up period.

Transthoracic echocardiography and the six-minute walk test were performed by the same physician to ensure consistency in measurements. Ethical approval was obtained from the University of Health Sciences, Dr. Behçet Uz Pediatric Diseases and Surgery Training and Research Hospital (Decision No: 2024/04-03; Date: March 28, 2024).

Statistical Analysis

Data distribution was assessed using mean±standard deviation (SD) or median, as appropriate. For comparisons of normally distributed numerical data, Student’s t-test was used for both dependent and independent groups. For numerical data that did not follow a normal distribution, the Wilcoxon or Mann–Whitney U test was applied, as appropriate. Categorical data were analyzed using the chi-square test. A p-value<0.05 was considered statistically significant.

Results

A total of 21 patients who met the inclusion criteria were included in the study. Of these, 10 were male (47.6%) and 11 were female (52.4%). The median age of the patients was 15.52 years (range: 12–23).

Among the participants, one patient was receiving combination therapy with bosentan and sildenafil, while another was receiving bosentan and iloprost. The remaining 19 patients were receiving bosentan monotherapy. Concomitant sildenafil and iloprost therapies were continued without dose modification after switching from bosentan to macitentan. The median NT-proBNP level before switching to macitentan was 1361.01 pg/mL (range: 25–5521).

At the 6-month follow-up after initiating macitentan therapy, the median NT-proBNP level had decreased to 906.06 pg/mL (upper limit: 125), and sPAP measured by transthoracic echocardiography was 53.80 mmHg.

The proportion of patients classified as World Health Organization (WHO) functional class III was initially 66% and decreased to 19% after transitioning to macitentan therapy. When the two periods were compared, the improvement in WHO functional classification after switching to macitentan was statistically significant (p=0.001).

Additionally, NT-proBNP levels showed a statistically significant reduction after macitentan treatment compared with the period when patients were receiving bosentan (p=0.009).

The median baseline mean pulmonary artery pressure measured by transcatheter angiography was 62.95 mmHg (range: 25–104). The median sPAP measured by transthoracic echocardiography at the initiation of macitentan therapy was 64.47 mmHg.

Six patients (28.5%) were diagnosed with idiopathic pulmonary hypertension, one of whom had accompanying Kartagener syndrome. Six patients (28.5%) had a ventricular septal defect (VSD), one of whom also had an associated patent ductus arteriosus (PDA).

Other congenital heart defects observed in the study population included:

• Double-outlet right ventricle in one patient (4.7%)

• Mitral atresia in two patients (9.5%)

• Complete atrioventricular septal defect in two patients (9.5%)

• Truncus arteriosus in two patients (9.5%)

• Tetralogy of Fallot in one patient (4.7%)

• Tricuspid atresia in one patient (4.7%)

At the 6-month follow-up after switching to macitentan, the six-minute walk test (6MWT) showed a statistically significant improvement compared with the period when patients were receiving bosentan (p=0.002).

When transthoracic echocardiographic sPAP values were compared between the two periods, a statistically significant reduction in pulmonary artery pressure was observed after transitioning to macitentan therapy (p=0.001).

Demographic, clinical, and medical treatment data of the patients are presented in Table 1.

Table 1.

Demographic and Clinical Characteristics of the Patients

Patient Number	Gender	Age	Congenital Heart Disease	Initial Medical Treatment	NT-Pro-BNP Baseline (pg/mL)	NT-Pro-BNP Sixth Month (pg/mL)	Six-Minute Walking Distance Baseline (meters)	Six-Minute Walking Distance at Sixth Month (meters)	WHO FC Initial	WHO FC Sixth Month	sPAP Initial(mmHg)	sPAP Sixth Month mmHg)
1	F	16	VSD	Bosentan	5160	4153	430	420	3	3	48	42
2	F	16	Mitral Atresia	Bosentan	1500	968	440	400	3	2	68	63
3	M	17	DORV	Bosentan	1290	1131	480	500	3	3	66	45
4	M	17	VSD	Bosentan	25	21	500	520	2	1	28	24
5	M	16	AVSD	Bosentan	587	190	450	520	2	2	27	25
6	F	17	AVSD	Bosentan	90	64	275	365	2	2	72	65
7	M	16	VSD	Bosentan	114	72	480	498	2	1	49	40
8	M	16	VSD	Bosentan	73	46	450	545	2	2	43	40
9	F	23	PDA+VSD	Bosentan	406	319	490	495	2	2	81	64
10	F	19	Truncus Arteriosus	Bosentan	1300	983	430	500	3	2	70	68
11	F	15	Fallot Tetralogy	Bosentan	430	426	480	490	2	2	41	40
12	F	13	Mitral Atresia	Sildenafil+bosentan	764	549	350	400	3	2	56	40
13	M	13	None(IPAH)	İloprost+bosentan	5521	5067	420	440	3	2	81	73
14	F	16	None (IPAH)	Bosentan	4774	1601	365	435	3	2	56	42
15	M	14	VSD	Bosentan	343	198	450	480	3	2	67	66
16	M	13	None (IPAH)	Bosentan	2094	1800	450	550	3	3	108	100
17	F	15	Truncus Arteriosus	Bosentan	64	46	450	440	3	2	70	68
18	F	17	None(IPAH)	Bosentan	1394	20,4	150	250	3	1	92	42
19	M	13	None(IPAH)( Kartagener Syndrome	Bosentan	128,3	62	340	400	3	1	72	34
20	M	14	Tricuspid Atresia	Bosentan	499	191	380	440	3	3	65	57
21	F	12	None(IPAH)	Bosentan	2025	1120	320	450	3	2	94	90

NT-Pro-BNP: N-terminal pro-B-type natriuretic peptide; WHO FC: The World Health Organization Functional Class; sPAP: Transthoracic echocardiographic systolic pulmonary artery pressure; F: Female; M: Male; VSD: Ventricular septal defect; DORV: Double outlet right ventricle; AVSD: Atrioventricular septal defect; PDA: Patent ductus arteriosus; IPAH: Idiopathic pulmonary arterial hypertension

None of the patients who switched to macitentan experienced clinical deterioration requiring hospitalization or adverse events necessitating drug discontinuation. Additionally, no significant changes were observed in liver function tests or hemoglobin levels after the treatment switch (p>0.05).

Discussion

Our study focused on the efficacy and safety of transitioning from bosentan to macitentan in patients receiving bosentan treatment.

A reduction in World Health Organization functional class (WHO FC) was observed in patients after switching from bosentan to macitentan. Our findings in the adult age group are consistent with those of the study conducted by Blok et al.^[10] However, in the study by Aypar et al.,^[11] conducted in pediatric and young adult populations, no significant difference in functional assessment was found before and after macitentan treatment.

In our study, the proportion of patients classified as WHO FC III decreased from 66% to 19%, correlating with the observed improvement in the six-minute walk test (6MWT). Patients whose functional classification improved also demonstrated an increase in walking distance. Based on these findings, we consider the improvement in functional classification to be clinically significant.

In our study, NT-proBNP levels showed a statistically significant decrease after the medication switch. Similar reductions have been observed in both adult and pediatric studies.^[12,13] When evaluated alongside improvements in functional capacity and increased six-minute walk test (6MWT) distances, our findings align with expected outcomes.

When patients were assessed according to PAH classification, those with idiopathic pulmonary arterial hypertension had higher baseline NT-proBNP levels. After transitioning to macitentan therapy, these patients exhibited a decrease in NT-proBNP levels along with an improvement in WHO functional classification.

In the evaluation of systolic pulmonary artery pressure (sPAP) measured by transthoracic echocardiography, a significant reduction was observed after switching to macitentan therapy, and this decrease was statistically significant (p=0.001).

Similarly, in Aypar’s study involving a pediatric patient group, a reduction in sPAP was observed, but it was not statistically significant.

Our study also found that patients who transitioned from bosentan monotherapy to macitentan, as well as those in the idiopathic pulmonary arterial hypertension (IPAH) group, benefited more from the treatment.

When evaluating the six-minute walk test (6MWT) based solely on distance, it tends to be more subjective in pediatric patients than in adults. Due to shorter stride lengths in younger children, the total distance covered appears relatively shorter. Therefore, the use of percentile curves and z-scores is recommended for assessing walking distance in pediatric patients.^[14]

In our study, we also analyzed changes in z-scores and percentiles for comparison. The increase in walking distance after switching to macitentan therapy was statistically significant when evaluated in terms of percentile change.

The six-minute walk test has been evaluated in studies by Safdar, Bloch, and Aypar. While Safdar and Aypar reported improvements in walking distance, these improvements were not statistically significant. In contrast, Bloch’s study did not find any changes in the test results.

We believe that the differences between our study and previous research may be attributed to factors such as the higher prevalence of comorbidities in adult studies and the lack of cooperation in pediatric studies, particularly among patients with Down syndrome. Although our study also included patients with Down syndrome, we did not encounter any cognitive or compliance-related issues affecting test performance.

In pediatric patients, congenital heart disease is known to be the most common cause of pulmonary arterial hypertension (PAH).^[15] One of the primary goals in the surgical management of congenital heart disease is to correct the anatomical defect. However, the timing of the intervention is critical to ensure that the defect is repaired before it leads to pulmonary hypertension.

In our study, it was notable that patients who developed PAH due to congenital heart disease were often diagnosed at an advanced age because of delayed medical consultation. This delay was primarily observed in foreign patients or those with socioeconomic barriers that limited early access to healthcare. Although these patients underwent surgical correction of their anatomical defects, their pulmonary artery pressures remained elevated during follow-up.

When comparing the IPAH group in our study with patients who developed PAH due to congenital heart disease, we observed that those with IPAH were able to maintain their clinical condition with monotherapy. Additionally, they showed greater improvement in the six-minute walk test, a more pronounced decrease in NT-proBNP levels, and a greater reduction in systolic pulmonary artery pressure measured by transthoracic echocardiography.

In the pathophysiology of IPAH, vascular remodeling and endothelial dysfunction of the pulmonary arteries play a central role, distinguishing it from secondary pulmonary hypertension caused by congenital heart disease. In secondary PAH due to congenital heart disease, increased pulmonary vascular resistance is the primary pathophysiological mechanism. Conversely, in IPAH, defective endothelin receptor signaling leads to predominant vasoconstriction.

Given that macitentan is a potent endothelin receptor antagonist (ERA), its superior efficacy in improving the aforementioned parameters in patients with IPAH compared with those with congenital heart disease may provide insight into its mechanism of action.

With appropriate timing and surgical care, pediatric patients with congenital heart disease would not be expected to develop pulmonary arterial hypertension (PAH). Therefore, in this patient group, the development of PAH is typically associated with social factors. Nevertheless, in our patients with congenital heart disease-related PAH, we observed improvements in all parameters after transitioning to macitentan therapy in the majority of cases.

The once-daily dosing of macitentan enhances treatment adherence, thereby increasing the benefits derived from therapy. All patients in our study had good treatment adherence. Patients with adherence issues were excluded from the study, and the effects of macitentan were objectively assessed. Interestingly, patients who were not initially included because of nonadherence but later transitioned to macitentan therapy showed clinical improvement, and the once-daily dosing regimen was reported to be well tolerated by the patients.

Macitentan is administered to patients aged 12 years and older, and since this age group is typically in or beyond adolescence, patients usually take responsibility for their medication use. In this context, treatment adherence becomes a crucial factor, although it was not evaluated in our study. This issue remains an area for further investigation.

In our study, patients who transitioned to macitentan therapy demonstrated clinical improvements in transthoracic echocardiographic systolic pulmonary artery pressure, six-minute walk test distance, NT-proBNP levels, and WHO functional class. These improvements were statistically significant.

Following the transition to macitentan, none of the patients required hospitalization, and no significant changes were observed in liver function tests or hemoglobin levels. Based on these findings, macitentan therapy appears to be a safe and effective treatment option for pediatric patients with pulmonary arterial hypertension.

Limitations

Some limitations of this study should be considered. First, the relatively small number of cases included in the study limits the generalizability of the findings. The transition to macitentan therapy is less frequently observed in pediatric patients than in adults, making it difficult for single-center studies to achieve larger sample sizes. Second, the lack of clear and widely accepted guidelines specifically addressing the transition to macitentan therapy in pediatric patients represents another important limitation. The heterogeneity of the study population, including patients with idiopathic PAH and congenital heart disease-associated PAH, is also an important limitation and may affect the generalizability of the findings. Consequently, treatment decisions are often based on clinician experience and extrapolation from adult data, which may lead to variability in clinical practice. Multicenter studies including larger and more heterogeneous pediatric populations would enhance the reliability and external validity of the findings and contribute to the development of stronger evidence-based recommendations for pediatric patients.

Conclusion

In this retrospective cohort, switching from bosentan to macitentan was associated with improvements in functional status, exercise capacity, NT-proBNP levels, and echocardiographic sPAP in pediatric patients with PAH who showed clinical deterioration while receiving bosentan therapy. However, due to the absence of a control group and the heterogeneous nature of the study population, these findings should be interpreted with caution. Larger prospective multicenter studies are needed to better define the role of macitentan in the management of pediatric pulmonary hypertension.

Disclosures

Ethics Approval

Ethics committee approval for this study was obtained from the University of Health Sciences, Dr Behcet Uz Pediatric Diseases And Surgery Training And Research Hospital (Approval no: 2024/04-03; date: March 28, 2024)

Informed consent

In accordance with the Ministry’s regulations, informed consent forms for off-label drug use were obtained from the families of patients transitioning to macitentan treatment.

Conflict of Interest

The authors declare that there is no conflict of interest.

Financial Disclosure

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Use of AI for Writing Assistance

The authors declare that no artificial intelligence (AI)–assisted technologies, such as large language models, chatbots, or image creation tools, were used in the production of this manuscript.

Authorship Contributions

Concept – M.M.Y.; Design – M.M.B.; Supervision – T.M.; Materials − G.V., C.D.; Data collection &/or processing – O.H., Y.I.D.; Analysis and/or interpretation – M.M.B.; Literature search – T.M.; Writing – M.M.B.; Critical review – T.M.

Peer-review

Externally peer-reviewed.