Real-World Clinical Outcomes of Macitentan among CTD-PAH Population

Introduction

The largest etiological subgroup of pulmonary arterial hypertension (PAH) after idiopathic/heritable PAH (I/HPAH) is connective tissue disease associated with PAH (CTD-PAH), accounting for 15-30% of the overall PAH population. Results from previous trials have demonstrated beneficial effects of macitentan, as monotherapy and as part of combination therapy regimen in patients with CTD-PAH with a significant reduction in the risk of mortality/morbidity events and favorable effects on right ventricular function. Despite this, the real-world data on PAH-specific therapies and clinical outcomes in CTD-PAH population is lacking.

Aim

To describe the baseline characteristics, treatment patterns, clinical outcomes regarding hospitalization and survival, and safety profiles of patients with CTD-PAH newly initiating macitentan in the combined OPUS/OrPHeUS population.

Method

Study Design

• OPUS – Multicenter, prospective, long-term, US, observational drug registry (2014-2020)
• OrPHeUS – Multicenter, retrospective, US, medical chart review (2013-2017)
• Data from both these studies provide a real-world insight on clinical management of PAH including CTD-PAH with reporting real life clinical outcomes of these patients

Observations and Assessments

• Both registries recruited PAH patients newly initiating macitentan
• Adverse events, AEs of special interest (AESIs) including of edema and hemoglobin decrease and hepatic adverse events (HAEs), HAEs of special interest (HAE-SIs) were recorded in OPUS and OrPHeUS respectively
• Data on baseline characteristics, patient demographics, treatment patterns, safety, hospitalizations and death were collected as per routine clinical practice
• The CTD-PAH patients were further classified into subgroups, based on etiology, including systemic sclerosis-PAH (SSc-PAH), systemic lupus erythematosus-PAH (SLE-PAH), and mixed CTD-PAH (MCTD-PAH)
• Data of CTD-PAH patients was compared with I/HPAH patients, since I/HPAH are well characterized forms of PAH
• All the analyses were conducted till the end of observation period which was from the date macitentan was initiated upto the study end or until death, loss to follow-up, withdrawal of consent or 30 days after macitentan discontinuation; whichever was earlier

  Results

  Study Population and Patient Characteristics

• The combined OPUS/OrPHeUS cohort comprised 2498 patients with I/HPAH and 1192 patients with CTD-PAH (n=708 with SSc-PAH; n=159 with SLE-PAH; n=124 with MCTD-PAH, and n=201 with other CTD-PAH etiologies)
• The CTD-PAH group comprised of higher proportion of women (86.2 v/s 73.1%), in WHO FC III/IV (69.3 v/s 61.2%), and were less likely to be obese (20.6 v/s 34.1%) and diabetic (12.8 v/s 27.9%) as compared to I/HPAH group
• Among CTD-PAH subgroups, SSc-PAH patients were older (median age 64 years), with the longest time from diagnosis to macitentan initiation (7.9 months), a more impaired functional status (68.9% in WHO FC III/IV; median 6MWD 274 m) and higher proportion of patients with hypertension and edema
• The MCTD-PAH subgroup had the shortest time from diagnosis (4.6 months) with higher percentage of patients suffering from diabetes and renal insufficiency and in WHO FC III/IV (82.4%) versus other CTD-PAH subgroups

  Treatment Patterns

• Before initiation of macitentan, 61.4% and 68.4% received at least one PAH-specific therapy in the I/HPAH and CTD-PAH groups respectively
• At macitentan initiation, among patients across all groups, approximately half had been diagnosed less than 6 months before enrollment
• At macitentan initiation, higher proportion of CTD-PAH patients received macitentan as a part of combination therapy compared to I/HPAH patients (65.2 v/s 58.1%), with the most common combination being with a phosphodiesterase 5 inhibitor (PDE5i). Similar trends were also noted at 6 and 12 month follow up
• MCTD-PAH subgroup had the highest rate of combination therapy at macitentan initiation, 6 months and 12 months after macitentan initiation with SLE-PAH having the lowest rate
• The odds of escalating from monotherapy to combination therapy and from double therapy to triple therapy was higher in CTD-PAH patients as compared to I/HPAH patients at 1 and 2 years
• Patients were more likely to escalate from monotherapy to dual combination therapy, compared with dual to triple combination, with the exception of SLE-PAH at 1 year, among all CTD-PAH subgroups

  Clinical Outcomes

• At 1 year, 60.3% of I/HPAH and 59.3% of CTD-PAH patients were free from all- cause hospitalization, with more hospitalizations among the MCTD-PAH group, compared to other CTD-PAH subgroups
• The 1- and 3-year survival estimates were 90.5% and 75.7% for I/HPAH and 90.6% and 74.3% for CTD-PAH respectively, with the highest survival in SLE-PAH patients, when compared to other CTD-PAH subgroups

  Safety

• Median duration of macitentan exposure was 14.0 and 15.8 months for the I/HPAH and CTD-PAH groups respectively
• The incidence of AEs was 79% and 83% in the I/HPAH and CTD- PAH groups respectively, with the most common AEs being dyspnea, headache and peripheral edema
• The incidence of edema, anemia and HAEs was similar for both the groups

  The results are summarized in Figure 1.

  Figure 1. Comparison of key baseline characteristics and key clinical and safety outcomes between CTD-PAH and I/HPAH patient groups

  

  Conclusion

• Macitentan was used in clinical practice in both newly diagnosed and prevalent patients with CTD-PAH comprising of SSc-PAH, SLE-PAH, and MCTD-PAH with varying characteristics
• The safety and tolerability of macitentan, even as part of combination therapy in CTD-PAH patients, were comparable to that of I/HPAH patients

• Patients with CTD-PAH were more likely to escalate from monotherapy to combination therapy compared to I/HPAH

Cardiol Ther. 2024;13(2):315-339. doi: 10.1007/s40119-024-00361-w.