Macitentan/Tadalafil Fixed-Dose Combination in Pulmonary Arterial Hypertension - A DUE

Mar 06, 2023
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, FACC
Date Presented:
03/06/2023
Date Published:
03/06/2023
Original Posted Date:
03/06/2023
References

Contribution To Literature:

The A DUE trial showed that fixed-dose combination therapy with macitentan 10 mg daily + tadalafil 40 mg daily is superior to either agent as monotherapy in reducing PVR at 6 weeks among patients with PAH.

Description:

The goal of the trial was to compare the safety and efficacy of macitentan/tadalafil combination therapy versus macitentan and tadalafil monotherapies in patients with pulmonary arterial hypertension (PAH).

Study Design

Patients were randomized depending on baseline therapy:

  • Prior endothelin receptor antagonist (ERA): 1:2 randomization to macitentan 10 mg daily monotherapy vs. macitentan 10 mg/tadalafil 40 mg daily fixed-dose combination
  • Treatment naïve: 1:2:1 randomization to macitentan 10 mg daily monotherapy vs. macitentan 10 mg/tadalafil 40 mg daily fixed-dose combination vs. tadalafil 40 mg daily
  • Prior phosphodiesterase type 5 inhibitor (PDE5i): 1:2 randomization to tadalafil 40 mg daily monotherapy vs. macitentan 10 mg/tadalafil 40 mg daily fixed-dose combination
  • Total number of enrollees: 187
  • Duration of follow-up: 16 weeks
  • Mean patient age: 51 years
  • Percentage female: 78%

Inclusion criteria:

  • Adult PAH patients in World Health Organization functional class II or III
  • Treatment naïve
  • On stable dose (≥3 months) of an ERA (prior ERA) or a PDE5i (prior PDE5i)

Other salient features/characteristics:

  • Idiopathic pulmonary hypertension: 50%
  • Time since PAH diagnosis: 2.5 years

Principal Findings:

The primary endpoint, % change at 6 weeks from baseline in pulmonary vascular resistance (PVR), for macitentan vs. combination, was: -23 vs. -45% (p ≤ 0.0001). For tadalafil vs. combination: -22 vs. -44% (p ≤ 0.0001).

Secondary outcomes:

  • Change at 16 weeks from baseline in 6-minute walk distance, for macitentan vs. combination: 38.5 vs. 52.9 m (p = 0.38)
  • For tadalafil vs. combination: 15.9 vs. 43.4 (p = 0.06)

Interpretation:

The results of this trial indicate that fixed-dose combination therapy with macitentan 10 mg daily + tadalafil 40 mg daily is superior to either agent as monotherapy in reducing PVR at 6 weeks among patients with PAH. Side-effect profile was similar. The trial was too small to assess clinical endpoints. These data suggest an emerging role for combination therapy in this patient population.

References:

Presented by Dr. Kelly Chin at the American College of Cardiology Annual Scientific Session (ACC.23/WCC), New Orleans, LA, March 6, 2023.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Statins, Pulmonary Hypertension

Keywords: ACC23, ACC Annual Scientific Session, Endothelin Receptor Antagonists, Phosphodiesterase 5 Inhibitors, Primary Prevention, Pulmonary Arterial Hypertension, Receptor, Endothelin A, Sulfonamides, Tadalafil


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