Background
For low- and intermediate-risk pulmonary arterial hypertension (PAH), guidelines favor dual therapy with an endothelin-receptor antagonist (ERA) plus a phosphodiesterase-5 inhibitor (PDE5i). A once-daily fixed-dose macitentan 10 mg/tadalafil 40 mg tablet could cut pill burden and boost adherence.
Objectives
A DUE, a multicenter, double-blind phase 3 trial, compared the efficacy and safety of the fixed-dose combination (M/T FDC) with each drug alone in treatment-naïve patients and in patients already on ERA or PDE5i monotherapy.
Methods
WHO functional class II–III adults were randomized to M/T FDC, macitentan, or tadalafil according to baseline therapy. The primary endpoint was change in pulmonary vascular resistance (PVR) at week 16.
Results
Of 187 randomized patients, 108 received M/T FDC, 35 macitentan, and 44 tadalafil. At week 16 the combination cut PVR 45% (geometric mean ratio 0.55) versus 23% with macitentan (ratio 0.77) and 22% with tadalafil (ratio 0.78). Relative to each monotherapy, M/T FDC further reduced PVR by ≈ 30% (P < 0.0001 for both). Six-minute walk distance and NT-proBNP also improved most with the combination. Adverse events—mainly headache, edema, anemia, and hypotension—were more frequent with M/T FDC but generally manageable; three unrelated deaths occurred in the combination arm.
Conclusions
A once-daily macitentan/tadalafil tablet produced a markedly larger PVR reduction than either drug alone while maintaining an expected safety profile. These data support its use for initial combination therapy or for escalation from ERA or PDE5i monotherapy in PAH (A DUE; NCT03904693).
https://www.sciencedirect.com/science/article/pii/S073510972308138X
