Adv Ther. 2025 May 19. doi: 10.1007/s12325-025-03180-0. Online ahead of print.
ABSTRACT
INTRODUCTION: Patients diagnosed with pulmonary arterial hypertension (PAH) often present with risk factors associated with cardiovascular disease, including diabetes mellitus (DM), hypertension (HTN), and obesity. The 2022 ESC/ERS pulmonary hypertension treatment guidelines recommend initial monotherapy with an endothelin receptor antagonist (ERA) or phosphodiesterase-5 inhibitor (PDE5i) for patients with PAH and cardiopulmonary comorbidities, with treatment escalation to be considered on an individual basis. Data on safety, tolerability, and effectiveness of combination therapy in these patients are lacking.
METHODS: OPUS (prospective, observational drug registry) and OrPHeUS (retrospective, medical chart review) were multicenter US studies of patients newly initiating the ERA macitentan (2013-2020). Patients in the combined OPUS/OrPHeUS dataset with PAH receiving combination therapy with macitentan and the PDE5i tadalafil were identified. Descriptive analyses were performed for patients with ≥ 1 of DM/HTN/obesity and those without these comorbidities.
RESULTS: In OPUS/OrPHeUS, 1336 patients with PAH received macitentan plus tadalafil during the observation period. Of these, 820 (61.4%) had ≥ 1 of DM/HTN/obesity and 516 (38.6%) had none of these comorbidities at or before enrollment. Median (Q1, Q3) exposure to macitentan and tadalafil combination therapy was similar at 13.7 (3.5, 28.0) and 14.8 (5.4, 27.4) months, respectively. For patients with ≥ 1 of DM/HTN/obesity versus those without, 1-year Kaplan-Meier estimates (95% confidence limits) for survival were 92.3% (89.9, 94.1) and 91.9% (88.8, 94.1), for patients free from hospitalization were 63.6% (59.6, 67.2) and 60.0% (55.1, 64.5), and for patients persisting on combination therapy were 66.5% (63.1, 69.8) and 68.5% (64.1, 72.4). Adverse events (AE; OPUS only) were reported in 78.4% and 80.0%, respectively, with no unexpected AEs observed. There was a trend towards higher AE incidence with increasing comorbidity number and in patients with cardiovascular comorbidities who were treatment-naïve.
CONCLUSION: Patients with PAH and ≥ 1 of diabetes mellitus, hypertension, or obesity treated with macitentan and tadalafil combination therapy had similar hospitalization, survival, and safety profiles as those without these comorbidities, though patients with comorbidities initiated on combination therapy and those with multiple comorbidities may require closer monitoring. These real-world data suggest that combination therapy may be considered for patients with PAH and cardiovascular comorbidities.
TRIAL REGISTRATION: OPsumit® Users Registry (OPUS): NCT02126943; Opsumit® Historical Users cohort (OrPHeUS): NCT03197688; URL https://www.
CLINICALTRIALS: gov/.
PMID:40388087 | DOI:10.1007/s12325-025-03180-0
