Macitentan/tadalafil fixed-dose combination significantly reduced pulmonary vascular resistance compared to macitentan (ratio 0.71; P<0.0001) and tadalafil (ratio 0.72; P<0.0001) monotherapies.
RCT (n=187)
Double-blind
randomized
Yes
Does a macitentan and tadalafil fixed-dose combination improve pulmonary vascular resistance compared to monotherapy in patients with pulmonary arterial hypertension?
A once-daily fixed-dose combination of macitentan and tadalafil significantly improves pulmonary vascular resistance compared to either monotherapy in patients with pulmonary arterial hypertension.
Effect estimate: Geometric mean ratio 0.71 (95% CI 0.61-0.82)
p-value: p=< 0.0001
BACKGROUND Endothelin receptor antagonist (ERA) and phosphodiesterase 5 inhibitor (PDE5i) combination therapy is recommended for low-/intermediate-risk pulmonary arterial hypertension (PAH) patients. A fixed-dose combination of the ERA macitentan and PDE5i tadalafil (M/T FDC) in a once-daily, single tablet would simplify treatment. OBJECTIVES The multicenter, double-blind, adaptive phase 3 A DUE study investigated the efficacy and safety of M/T FDC vs macitentan 10 mg and vs tadalafil 40 mg monotherapies in PAH patients, including treatment-naïve and prior ERA or PDE5i monotherapy-treated patients. METHODS World Health Organization functional class II-III patients were randomized to M/T FDC, macitentan, or tadalafil depending on their PAH treatment (treatment-naïve, ERA, or PDE5i monotherapy) at baseline. The primary endpoint was change in pulmonary vascular resistance (PVR) at week 16. RESULTS In total, 187 patients were randomized to single-tablet M/T FDC (n = 108), macitentan (n = 35), or tadalafil (n = 44). PVR reduction with M/T FDC was significantly greater vs macitentan (29%; geometric mean ratio 0.71; 95% CL: 0.61-0.82; P < 0.0001) and vs tadalafil (28%; geometric mean ratio 0.72; 95% CL: 0.64-0.80; P < 0.0001). Three patients died in the M/T FDC arm (judged unrelated to treatment). Adverse events (AEs) leading to discontinuation, serious AEs, and those of special interest (anemia, hypotension, and edema) were more frequent with M/T FDC. CONCLUSIONS Macitentan and tadalafil FDC significantly improved PVR vs monotherapies in PAH patients, with a safety and tolerability profile consistent with the individual components. The A DUE study supports M/T FDC as a once-daily, single-tablet combination for initial therapy and escalation to double combination therapy in patients with PAH. (Clinical Study to Compare the Efficacy and Safety of Macitentan and Tadalafil Monotherapies With the Corresponding Fixed-dose Combination Therapy in Subjects With Pulmonary Arterial Hypertension PAH) A DUE; NCT03904693).
“Targeting different pathways in the treatment of PAH has demonstrated clear clinical benefits, yet current treatment regimens are cumbersome and create a significant pill burden for patients, many of whom take a large number of pills each day to treat their PAH and various comorbidities. The results from this study demonstrate that a single tablet combination has the potential to support initial dual combination therapy and rapid escalation from monotherapy, which may improve functional outcomes and help close the gap from guideline recommendations to clinical practice.”
Grünig et al. (2024) conducted an RCT in Pulmonary Arterial Hypertension (n=187). Macitentan/Tadalafil fixed-dose combination vs. macitentan 10 mg or tadalafil 40 mg monotherapies was evaluated on change in pulmonary vascular resistance (PVR) at week 16 (Geometric mean ratio 0.71, 95% CI 0.61-0.82, p=< 0.0001). Macitentan/tadalafil fixed-dose combination significantly reduced pulmonary vascular resistance compared to macitentan (ratio 0.71; P<0.0001) and tadalafil (ratio 0.72; P<0.0001) monotherapies.