Macitentan and Tadalafil Combination Therapy in Patients with Pulmonary Arterial Hypertension and Cardiovascular Comorbidities: Real-World Evidence from OPUS and OrPHeUS

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. 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. 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. 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. OPsumit® Users Registry (OPUS): NCT02126943; Opsumit® Historical Users cohort (OrPHeUS): NCT03197688; URL https://www.clinicaltrials.gov/ Patients with pulmonary arterial hypertension (PAH) often have other conditions affecting their heart or blood vessels, known as cardiovascular comorbidities. It is recommended that patients with PAH and cardiovascular comorbidities start with one PAH medication and later add another, if possible. However, there is limited information on the safety and effectiveness of combining two PAH medications in these patients. The OPUS and OrPHeUS studies collected information on patients with PAH treated in United States clinics between 2013 and 2020. We identified patients who were treated with two PAH medications, macitentan and tadalafil (referred to as combination therapy). We grouped them into patients with cardiovascular comorbidities (any medical history of diabetes mellitus, hypertension or obesity; 820 patients) and patients without these conditions (516 patients) and looked at how they did over time. Both groups were treated with combination therapy for approximately 14–15 months. After 1 year, outcomes were similar for patients with and without cardiovascular comorbidities: survival for both groups was 92%; 64% and 60% of patients remained hospitalization-free; and 67% and 69% remained on combination therapy. Side effects were consistent with those expected for these medications, with generally more side effects seen in patients with more comorbidities and in those new to PAH medications. Patients with PAH and cardiovascular comorbidities treated with macitentan and tadalafil combination therapy had similar results as those without cardiovascular comorbidities. This suggests that combination therapy may be used in select patients with PAH and cardiovascular comorbidities, although those who have more comorbidities or are new to PAH treatment may need closer observation.