Efficacy of Triple vs Double Oral Therapy in Newly Diagnosed PAH Patients

Table of Content


Pulmonary arterial hypertension (PAH) management involves targeting multiple pathways with combination therapy. Double therapy with endothelin receptor antagonist (ERA) and phosphodiesterase type-5 inhibitor (PDE5i) delays disease progression and is recommended for patients with newly diagnosed PAH. However, patients receiving double oral therapy including initial double therapy continue to have progression, warranting the need for an intensive treatment. Addition of selexipag, a prostacyclin receptor was shown to reduce the risk of composite morbidity and mortality. However, there is paucity of data comparing initial triple oral therapy with initial double oral therapy.


The TRITON (The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients with Newly Diagnosed Pulmonary Arterial Hypertension) study compared the efficacy of initial triple (macitentan, tadalafil, and selexipag) with initial double (macitentan, tadalafil, and placebo) oral therapy in newly diagnosed, treatment-naive patients with PAH.


Study Design

  • Multicenter, double-blind, randomized phase 3b study.

Patient Profile

  • Patients aged between 18 to 75 years diagnosed with PAH

Treatment Strategy

  • Patients were randomized to receive initial triple oral therapy or initial double oral therapy
  • Macitentan 10 mg once daily and tadalafil 20 mg once daily were initiated on day 1.
  • Depending on the tolerability, dose of tadalafil was increased to 40 mg daily on day 8+3.
  • Double-blinded selexipag or placebo was received by the cohort at 200 µg twice daily.
  • Until week 12, the dose was increased at weekly increments of 200 µg twice daily to reach an individualized maintenance dose range 200-1600 µg twice daily
  • The treatment was continued until week 26 (end of main observation period).  

End Points

Primary Endpoints

  • Change in pulmonary vascular resistance (PVR) at week 26.

Secondary Endpoints

  • Change from baseline in
    • 6-min walk distance (6MWD)
    • N-terminal pro-brain natriuretic peptide (NT-proBNP)
  • Time to first disease progression event
  • Adverse events (AEs).  


  • The cohort comprised 247 patients, out of which 123 were assigned to initial triple therapy and 124 to initial double therapy.
  • Majority of the cohort were females (75.7%), 46.6% had idiopathic PAH and 34.4% had connective tissue disease-associated PAH.
  • Nine and 7 patients discontinued the study before week 26 from the triple and double therapy groups respectively.
  • At week 26,  there was no significant difference between the two groups for change in PVR, 6MWD and NT-pro BNP levels.
  • A first disease progression event occurred in 11.4% in the initial triple therapy group vs 20.2% in the double therapy group, demonstrating reduction in the risk of disease progression in the triple therapy group (hazard ratio: 0.59).
  • The incidence of AEs and mortality has been shown in Figure 1.
  • The most common AEs with initial triple therapy included headache, diarrhea, and nausea.
Figure 1. Safety outcomes


  • Although both the treatment regimens - initial triple and double therapy significantly reduced the pulmonary vascular resistance (PVR) in newly diagnosed pulmonary arterial hypertension (PAH) patients by week 26, the difference was insignificant between groups.
  • Both the treatment regimens improved the hemodynamic parameters and other clinical outcomes; however, there were no significant differences between the groups.
  • Both the treatments were well tolerated by the patients.
  • Exploratory analyses suggested a signal for reduced risk of disease progression with initial triple versus initial double oral therapy.

J Am Coll Cardiol. 2021 Oct 5;78(14):1393-1403. Doi: 10.1016/j.jacc.2021.07.057.