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09-02-2024 | Pulmonary Hypertension | News

Support for macitentan plus tadalafil as a fixed-dose single tablet for PAH

Author: Ajay Jha

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medwireNews: Patients with pulmonary arterial hypertension (PAH) gain greater improvements in pulmonary hemodynamics when they are treated with a fixed-dose combination of macitentan and tadalafil as a single tablet than with either drug taken alone, suggest findings from the phase 3 A DUE study.

Kelly Chin (UT Southwestern Medical Center, Dallas, Texas, USA) and colleagues report: “Macitentan and tadalafil combined as a single tablet would simplify the treatment regimen, offer a convenient treatment option for patients, and potentially improve treatment adherence.”

The study involved 187 patients with class II or III PAH, of whom 53% were treatment-naïve, 17% had previously received an endothelin receptor antagonist (ERA), and 30% had previously received a phosphodiesterase inhibitor (PDE5i).

The patients were randomly assigned to receive the ERA macitentan 10 mg combined with the PDE5i tadalafil 40 mg in a single tablet (n=107), macitentan 10 mg monotherapy (n=35), or tadalafil 40 mg monotherapy (n=44).

The combined treatment group comprised 49 treatment-naïve patients, 37 with prior PDE5i use and 21 with prior ERA use. In the macitentan group there were 24 patients who were treatment naïve and 11 who had prior ERA use, and in the tadalafil group, there were 25 patients who were treatment naïve and 19 who had prior PDE5i use.

The majority (78%) of the study participants were women and the mean age was 51 years. The results, published in the Journal of the American College of Cardiology, indicate that patients receiving combination treatment had a significant 29% greater reduction in pulmonary vascular resistance (PVR) at 16 weeks than those receiving macitentan monotherapy, with decreases of 45% versus 23%, from respective baseline values of 834.3 and 815.9 dynes/second per cm5.

A similar benefit with the combined treatment was also seen versus tadalafil monotherapy, with corresponding decreases in PVR of 44% versus 22%, from baseline values of 884.7 and 802.1 dynes/second per cm5, respectively, equating to a 28% greater reduction with the combination.

The findings were consistent irrespective of treatment status at randomization, the researchers note, with the reduction in PVR 30–34% greater with combined treatment versus either monotherapy in treatment-naïve patients, and 19–32% greater in patients with prior ERA or PDE5i use.

The investigators comment that there were “no new or unexpected safety findings” with macitentan plus tadalafil, although rates of any-grade adverse events (AEs) were higher, at 82.2%, than with macitentan or tadalafil monotherapy (71.4 and 79.5%, respectively). 

Rates were also higher for serious AEs (14 vs 8.6 and 9.1%) and AEs leading to discontinuation (8.4 vs 0.0 and 4.5%). The most common serious AEs were cardiac failure and dyspnea.

There were three deaths, all of which occurred among patients in the combination treatment group, but none were considered related to the treatment. 

The investigators conclude: “The A DUE study supports the single-tablet combination therapy for initial double combination therapy and rapid escalation, in line with the ESC/ERS 2022 guidelines on the use of double combination therapy in PAH.”

Jeroen Wessels and Harm Bogaard, both from Vrije Universiteit Amsterdam in the Netherlands, comment in an accompanying editorial: “Because oral combination therapy will probably remain the cornerstone of treatment in classical PAH patients, a single-tablet [fixed-dose combination] may be a patient-friendly alternative to the individual components.”

However, they add that for some patients it may be preferable to start with monotherapy before proceeding to combination therapy, such as in older patients with multiple cardiopulmonary comorbidities, for whom current guidelines do not recommend upfront combination therapy.

The editorialists conclude: “Clinicians will therefore have to consider patient preferences, characteristics, and cost of medication before prescribing a [fixed-dose combination].”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group.

J Am Coll Cardiol 2024; 83: 473–484
J Am Coll Cardiol 2024; 83: 485–487

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