Initial Triple vs Dual Oral Combination Therapy for Newly Diagnosed PAH

pulmonary hypertension
A study investigated the efficacy of double or triple pharmacotherapy in pulmonary arterial hypertension.

Associated symptoms of pulmonary arterial hypertension (PAH) were improved to a similar extent with either triple or double oral therapy strategies among newly diagnosed patients, however, the triple therapy was more effective at slowing disease progression. These findings were published in the Journal of the American College of Cardiology.

The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension (TRITON, Identifier: NCT02558231) study recruited treatment-naïve patients (N=247) with PAH between 2016 and 2018 at 67 sites worldwide. Patients were randomized in a 1:1 ratio to receive macitentan, tadalafil, and selexipag triple therapy (n=123) or macitentan, tadalafil, and placebo dual therapy (n=124) for 26 weeks. Patients were observed through 30 days after treatment cessation for clinical outcomes.

Patients were 75.7% women, aged mean 51.9±13.7 years, 85.0% were White, and most had idiopathic PAH (46.6%) or connective tissue disease-associated PAH (34.4%).

At week 26, pulmonary vascular resistance was decreased by 54% (geometric mean ratio [GMR], 0.46; 95% CI, 0.42-0.52) among the triple therapy and by 52% (GMR, 0.48; 95% CI, 0.44-0.53) among the dual therapy recipients. These rates did not differ significantly (effect, 0.96; 95% CI, 0.86-1.07; P =.42).

Similar improvements, which were not significantly different between treatments, were observed for N-terminal pro-brain natriuretic peptide, 6-minute walk distance, mean pulmonary artery pressure, cardiac index, total pulmonary resistance, mean right atrial pressure, and mixed venous oxygen saturation.

Disease progression occurred among 13.0% of the triple therapy and 21.8% of the dual therapy cohorts (hazard ratio [HR], 0.59; 95% CI, 0.32-1.09). Among patients with disease progression, the time to first event tended to be shorter among the double therapy recipients (HR, 0.59; 95% CI, 0.30-1.13).

Compared with dual therapy, the rate ratio for progression among the triple therapy group with 0.39 (95% CI, 0.15-1.00) and all-cause mortality HR was 0.23 (95% CI, 0.05-1.04).

Serious adverse events occurred among 42.9% of the triple and 31.5% of the double therapy groups. Selexipag was discontinued by 19 patients and placebo by 17.

This study was not powered to detect long-term outcomes and the study authors noted that the analyses of disease progression and mortality were exploratory.

These data indicated there were not clear differences between a triple or dual therapy among patients newly diagnosed with PAH for clinical measurements of disease, however, there was some evidence to suggest the triple therapy reduced risk for disease progression and all-cause mortality. Additional, longer-term studies are needed to confirm these findings.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Chin KM, Sitbon O, Doelberg M, et al. Three- Versus Two-Drug Therapy for Patients With Newly Diagnosed Pulmonary Arterial Hypertension. JACC. 2021;78(14):1393-403.