Three- vs. Two-Drug Therapy in Pulmonary Arterial Hypertension

Quick Takes

  • In the TRITON study, the primary endpoint of change in pulmonary vascular resistance at week 26 was not met. Although marked improvements from baseline were observed in hemodynamic parameters and other clinical variables at week 26 following both initial triple and initial double oral therapy, there was no significant difference between groups.
  • Initial triple therapy is as well tolerated as initial double therapy.
  • Exploratory analyses suggest a signal for reduced risk for disease progression with initial triple versus initial double oral therapy, suggesting that incremental long-term benefit can be gained by oral targeting of three rather than two pathways.

Study Questions:

What is the efficacy and safety of initial triple oral therapy with macitentan, tadalafil, and selexipag compared with initial double oral therapy with macitentan and tadalafil in newly diagnosed, treatment-naive patients with pulmonary arterial hypertension (PAH)?


TRITON (The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension), a multicenter, double-blind, randomized phase 3b study, evaluated initial triple (macitentan, tadalafil, and selexipag) (n = 123 patients) versus initial double (macitentan, tadalafil, and placebo) (n = 124 patients) oral therapy in newly diagnosed, treatment-naive patients with PAH. The study investigators assessed efficacy until the last patient randomized completed week 26 (end of main observation period). The primary endpoint was change in pulmonary vascular resistance (PVR) at week 26, expressed as ratio of baseline. Secondary endpoints assessed at week 26 were change from baseline in 6-minute walk distance, N-terminal pro–B-type natriuretic peptide (NT-proBNP), and other right heart catheterization variables (mean pulmonary arterial pressure, cardiac index, mean right atrial pressure, mixed venous oxygen saturation, total pulmonary resistance), and absence of worsening in functional class from baseline.


The study investigators found that at week 26, both treatment strategies reduced PVR compared with baseline (by 54% and 52%), with no significant difference between groups (ratio of geometric means: 0.96; 95% confidence interval [CI], 0.86-1.07; p = 0.42). Six-minute walk distance and NT-proBNP improved by week 26, with no difference between groups. In the initial triple therapy group, 16 patients (13.0%) had a first disease progression event, compared with 27 (21.8%) in the initial double therapy group. Risk for disease progression (to end of main observation period) was reduced by 41% with initial triple versus initial double therapy (hazard ratio, 0.59; 95% CI, 0.32-1.09). Most common adverse events with initial triple therapy included headache, diarrhea, and nausea. By the end of the main observation period, two patients in the initial triple and nine in the initial double therapy groups had died.


The study authors concluded that in patients with newly diagnosed PAH, both treatment strategies markedly reduced PVR by week 26, with no significant difference between groups (primary endpoint not met). They also concluded based on the exploratory analyses that there are improved long-term outcomes with initial triple versus initial double oral therapy.


This is an important study because it suggests that triple therapy may change the natural history of this condition. Randomized clinical trials are the next step to confirm these findings.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Prevention, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Acetamides, Arterial Pressure, Atrial Pressure, Cardiac Catheterization, Diarrhea, Headache, Heart Failure, Natriuretic Peptide, Brain, Nausea, Peptide Fragments, Primary Prevention, Pulmonary Arterial Hypertension, Pyrazines, Pyrimidines, Sulfonamides, Tadalafil, Vascular Resistance

< Back to Listings