Fixed-dose macitentan plus tadalafil superior to either agent alone in PAH

Fixed-dose combination therapy with macitentan 10 mg daily + tadalafil 40 mg daily was superior to either agent as monotherapy in reducing pulmonary vascular resistance (PVR) at 6 weeks in patients with pulmonary arterial hypertension (PAH). This was the main finding of the phase 3 A DUE trial.

Macitentan 10 mg daily + tadalafil 40 mg is already recommended by most guidelines as a combination therapy in patients with newly diagnosed PAH and most patients at follow-up [1,2]. A fixed-dose combination as a single tablet could improve adherence and simplify treatment. The prospective, randomised, adaptive A DUE trial (NCT03904693) sought to confirm the safety and efficacy of macitentan 10 mg/tadalafil 40 mg daily as a fixed-dose combination by comparing it with macitentan and tadalafil monotherapies [3].

First author Prof. Kelly Chin (UT Southwestern Medical Center, TX, USA) explained that 187 treatment-naïve adult patients with PAH in WHO functional class II or III were enrolled. They had to be on a stable dose of an endothelin receptor antagonist (ERA) or a phosphodiesterase 5 inhibitor (PDE5i) for ≥3 months. The mean age was 51 years, 78% were women, and 50% had idiopathic pulmonary hypertension. The participants were randomised depending on their baseline therapy:

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  • Treatment-naïve participants were randomised 1:2:1 to macitentan 10 mg daily monotherapy, fixed-dose combination, or tadalafil 40 mg daily.
  • Participants who were on an ERA (prior-ERA) were randomised 1:2 to macitentan 10 mg daily monotherapy or fixed-dose combination.
  • Participants using a PDE5i (prior-PDS5i) were randomised to tadalafil 40 mg daily monotherapy or fixed-dose combination.

All in all, 35 patients received macitentan, 44 tadalafil, and 108 fixed-dose macitentan + tadalafil.

After a follow-up of 16 weeks, fixed-dose macitentan + tadalafil had led to a highly significant improvement in PVR compared with macitentan and tadalafil monotherapies, said Prof. Chin (see Figure).

 

Figure: Change in PVR from baseline at week 16 [3]



M/T FDC_M, fixed-dose macitentan + tadalafil (n=70; prior-ERA users n=21, treatment-naïve n=49); M/T FDC_T, fixed-dose macitentan + tadalafil (n=86; treatment-naïve n=49, prior-PDE5i n=36).

A trend was observed in favour of fixed-dose macitentan + tadalafil for clinically relevant improvement in 6-minute walking distance (6MWD) after 16 weeks, which was the secondary endpoint. The change in 6MWD versus macitentan monotherapy was 16.04 metres (95% CI 17.00 to 49.08; P=0.380); the change versus tadalafil monotherapy was 25.37 metres (95% CI -0.93 to 51.59; P=0.059). The nature and rate of adverse events (AEs) were as expected based on previous studies. Prof. Chin noted that there was a greater number of total and serious AEs in the fixed-dose macitentan + tadalafil groups, which was also in line with previous studies.

“A DUE supports fixed-dose macitentan + tadalafil as a single tablet for initial dual combination therapy and rapid escalation in PAH,” Prof. Chin concluded.

1. 
   
   1. Humbert M, et al. Eur Heart J. 2022;43(38):3618–731.
   2. Humbert M, et al. Eur Respir J. 2023;61(1):2200879.
   3. Chin K, et al. Efficacy and safety of macitentan tadalafil fixed dose combination in pulmonary arterial hypertension: Results from the randomized controlled phase III A DUE study. Session 409-14, ACC Scientific Session 2023, 4–6 March, New Orleans, USA.

 

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Posted on 7 June, 20238 June, 2023