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

Jan 23, 2024
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC; Kim A. Eagle, MD, MACC
Trial Sponsor:
Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson & Johnson
Date Presented:
03/06/2023
Date Published:
01/22/2024
Date Updated:
01/23/2024
Original Posted Date:
03/06/2023
References

Contribution To Literature:

Highlighted text has been updated as of January 23, 2024.

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 screened: 294
  • 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
  • Mean pulmonary arterial pressure ≥25 mm Hg and pulmonary arterial wedge pressure or left ventricular end-diastolic pressure ≤15 mm Hg and pulmonary vascular resistance (PVR) ≥3 Wood units (i.e., ≥240 dyn.sec/cm5)
  • Six-minute walk distance (6MWD) between 100 m and 450 m
  • 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
  • Treatment naïve: 53%

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). Treatment effect was similar in treatment-naïve vs. baseline-treated patients.

Secondary outcomes:

  • Change at 16 weeks from baseline in 6MWD, for macitentan vs. combination: 38.5 vs. 52.9 m (adjusted treatment effect was 16.0 m; 95% confidence limit [CL] -17.0 to 49.1; p = 0.38)
  • For tadalafil vs. combination: 15.9 vs. 43.4 (adjusted treatment effect was 25.4 m; 95% CL: -0.9 to 51.6; p = 0.059)
  • Change in N-terminal pro–B-type natriuretic peptide: treatment effect (geometric mean ratio) was 0.57 (95% CL 0.41-0.80; p = 0.0015) and 0.57 (95% CL 0.42-0.77; p = 0.0003) for the comparison of combination therapy with macitentan monotherapy or tadalafil monotherapy, respectively
  • Safety: anemia (18.7%) and hypotension (7.5%) were more common with combination therapy compared with either monotherapy

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 along expected lines, although anemia and hypotension were more common with combination therapy than with either monotherapy. The trial was too small to assess clinical endpoints. These data suggest an emerging role for combination therapy in this patient population.

References:

Grünig E, Jansa P, Fan F, et al. Randomized Trial of Macitentan/Tadalafil Single-Tablet Combination Therapy for Pulmonary Arterial Hypertension. J Am Coll Cardiol 2024;83:473-84.

Editorial Comment: Wessels JN, Bogaard HJ. Double Down on Single-Tablet Combination Therapy in Pulmonary Arterial Hypertension: Possible Benefits for Selected Patients. J Am Coll Cardiol 2024;83:485-7.

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, Pulmonary Hypertension and Venous Thromboembolism, Statins, Pulmonary Hypertension, Prevention

Keywords: ACC23, Pulmonary Arterial Hypertension, Tadalafil


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