Introduction

Medical therapies are vital in managing pulmonary arterial hypertension (PAH), aiming to reduce disease progression and mortality. Endothelin receptor antagonists (ERAs) target the endothelin pathway, promoting vasodilation and antiproliferative effects. Three ERAs—bosentan, ambrisentan, and macitentan—are approved for PAH. Macitentan offers sustained receptor binding, better tissue penetration, and is the only ERA proven to significantly reduce morbidity and mortality both as monotherapy and combination therapy. Guidelines recommend upfront dual combination therapy of macitentan or ambrisentan with tadalafil for low/intermediate-risk PAH patients without cardiopulmonary comorbidities. In patients with PAH, hospitalization (PAH related and all cause), is a key prognostic factor and has been associated with worse survival and clinical worsening.

 Aim

To compare the clinical outcomes of treatment with macitentan compared to other ERAs in patients with PAH.

Method

Study Design

• Retrospective, observational, real-world comparative study which analyzed data from January 1, 2014 to December 31, 2023
• The index date was the date of the first claim entered for prescription of an ERA, the baseline period was 6 months prior to and including index date

Patient Inclusion Criteria 

• ERA-naïve, PAH patients aged ≥18 years
• Had atleast 1 claim for any ERA medication (macitentan, bosentan or ambrisentan) during the study period 
• Had continuous health plan enrolment for >12 months before the index date
• Had continuous medical enrolment >1 month after the index date
• Had at least one inpatient claim for pulmonary hypertension (PH)/PAH or at least two outpatient claims on two separate dates for PH/PAH before initiating ERA therapy
• Underwent right heart catheterization before starting ERA therapy

Study Measures 

• Patient demographics (sex, age, region) were recorded on the index date
• Clinical data and comorbidities were assessed during the 6-month pre-index baseline period
• Healthcare utilization was measured over the preceding 12 months and including index date

Endpoints

Primary Endpoint

Secondary Endpoints

• Composite endpoint of time to disease progression, all-cause hospitalization, morbidity and mortality and all-cause death
  1. Time to disease progression defined as time from the index date to earliest of any of the following during the follow-up period: period: initiation of parenteral prostanoid treatment (first claim of intravenous/subcutaneous prostanoids), all-cause death, lung transplant claim, or atrial septostomy claim)
  2. Time to first morbidity defined as PAH- related hospitalization, atrial septostomy, lung transplant, or progression to intravenous/subcutaneous prostanoid and mortality event
• All-cause and PAH-related healthcare resource utilization (HCRU) during follow-up period which included hospitalization, emergency room visits, outpatient visits, and intensive care unit (ICU) visits

Results

• A total of 897 PAH patients who had newly initiated an ERA were analyzed; of which 40% had received PDE5i/riociguat therapy in the baseline period
• Macitentan was the most commonly prescribed ERA (518, 57.7%), followed by ambrisentan (370, 41.2%) and bosentan (9,1.0%)
• Baseline demographics were similar, however, the macitentan cohort had more comorbidities and significantly higher mean Charles Comorbidity Index (CCI) scores (4.0 vs 3.6 in the other ERA groups)
• A similar proportion of patients received a PDE5i during baseline in each cohort
• Median follow-up period was 469 days [interquartile range (IQR:801 days)] in macitentan group and 569 days (IQR 996 days) in the other ERA group
• Macitentan was linked to significantly lower risk of PAH-related(HR 0.81, P=0.034) and all-cause hospitalizations( HR 0.80, P=0.020)
• Treatment with macitentan resulted in considerably longer time to first PAH-related hospitalization as seen in Figure 1

Figure 1. Time to first PAH-related hospitalization

• The risk of disease progression (HR 1.17, p=0.127), morbidity and mortality (HR 0.96, p=0.603) and all-cause death (HR 0.87, p=0.216) was similar in each cohort
• The rate of all cause ICU stays, and PAH related ICU stays was significantly lower in macitentan cohort as compared to other ERA cohort
• In the macitentan cohort, the mean length of all cause ICU stays was significantly lower and numerically shorter but trending towards significance for PAH related ICU stays as seen in Table 1.

Table 1. Comparison of HCRU outcomes

Outcome	Macitentan cohort	Other ERA cohorts	Incidence rate ratio (IRR)	P value
Rate of all-cause ICU stays (PPPY)	0.32	0.43	0.70	0.009
Rate of PAH-related ICU stays (PPPY)	0.20	0.28	0.68	0.013
Mean length of all-cause ICU stays (days PPPY)	2.38	3.68	0.54	0.003
Mean length of PAH-related ICU stays (days PPPY)	1.39	2.06	0.66	0.103
Duration of all-cause ICU stay/visit (days PPPY)	7.36	8.39	0.92	0.353
Duration of PAH-related ICU stay/visit (days PPPY)	6.96	7.29	1.00	0.967

PPPY: Per patient per year

Conclusion

Respir Med. 2025; 243:108112. doi: 10.1016/j.rmed.2025.108112.