Efficacy and Safety of Initial Triple Oral Versus Initial Double Oral Combination Therapy in Patients with Newly Diagnosed Pulmonary Arterial Hypertension (PAH): Results of the Randomized Controlled TRITON Study

Abstract

Rationale: In PAH, initial double oral combination therapy is recommended. However, there are no data on initial triple oral combination therapy. TRITON evaluated efficacy and safety of initial triple oral therapy with selexipag, macitentan and tadalafil versus initial double oral therapy with macitentan and tadalafil. Methods: TRITON (NCT02558231), a multicenter, double-blind, placebo-controlled, phase 3b study, randomized 1:1 newly diagnosed, treatment-naïve PAH patients to initial triple or initial double therapy. Macitentan and tadalafil were initiated at randomization, selexipag/placebo at day 15 (up-titrated until week 12). Efficacy and safety were assessed in a blinded manner until the last patient randomized completed the week 26 visit (end of observation period). The primary endpoint was change in pulmonary vascular resistance (PVR) at week 26, expressed as ratio of baseline. Secondary endpoints, tested hierarchically, included change in 6-minute walk distance (6MWD) and N-terminal pro-brain natriuretic peptide (NT-proBNP) at week 26, time to disease progression (centrally adjudicated) until end of observation period +7 days, and absence of worsening WHO functional class (FC) at week 26. Safety is reported up to end of observation period. Results: 247 patients were randomized to initial triple (n=123) or initial double therapy (n=124). Baseline characteristics were balanced between groups. Median follow-up was 77.6 and 75.8 weeks in the initial triple and initial double therapy groups, respectively. Initial triple and initial double therapy improved PVR (by 54% and 52%), 6MWD, and NT-proBNP (Table), and no worsening in FC was seen for 99.2% and 97.5% of patients, respectively, with no difference between groups. There was a 41% reduction in the risk of disease progression with initial triple versus initial double therapy (hazard ratio 0.59 [95% CI 0.32-1.09], p=0.087). The most common adverse events (AEs) with initial triple therapy that were reported at a higher frequency with triple vs double therapy were headache, diarrhea, nausea, pain in extremity, jaw pain and vomiting. Proportions of patients with AEs leading to selexipag/placebo discontinuation were similar between groups. Two patients died in the initial triple and 9 in the initial double therapy group. Conclusions: In the TRITON study of newly diagnosed PAH patients, hemodynamics, NT-proBNP and clinical variables were markedly improved with initial triple oral and initial double oral therapy, with no difference between treatment regimens at week 26. Exploratory analysis indicated a signal for improved long-term outcome with initial triple versus initial double therapy. Reported AEs were consistent with known safety profiles for the study medications.