Background Pulmonary arterial hypertension (PAH) requires a complex and multidisciplinary care approach with regular follow-up visits to monitor disease progression and adaptation of treatment regimens. Current ESC/ERS Guidelines recommend initial double oral treatment (Endothelin-receptor antagonist (ERA)+phosphodiesterase type 5 inhibitor (PDE-5i)) in patients presenting at diagnosis with intermediate risk according to the 3-strata risk score. Retrospective data analyses indicate a clinical benefit for upfront triple combination therapy including parenteral prostacyclins (PCA) in intermediate and high-risk patients. The multicentric TripleTRE trial aims to investigate the effect of initial triple combination therapy including parenteral PCA on risk status, compared to double oral in a prospective setting in patients at intermediate-high risk at diagnosis according to the 4-strata risk score. Methods A phase IV, multicentre, prospective, randomized, two-arm, open-label trial is conducted. The study will enrol a total of 110 patients with intermediate-high risk of death at PAH diagnosis. Patients are randomized (1:1) to receive either initial double-oral treatment or upfront triple combination treatment including parenteral treprostinil. The primary endpoint is the achievement of a low-risk status between week 24 and 48 assessed with the simplified 4-strata risk-assessment tool. Discussion Despite retrospective evidence for greater benefit, prospective investigation of upfront triple therapy including a parenteral PCA is lacking. The TripleTRE trial aims to fill this gap and test the hypothesis of “hit-hard-and-early“ in patients with newly diagnosed PAH. Trial registration EU Trial (CTIS) Number 2023-504351-26-01; NCT06317805
Sitbon et al. (Thu,) studied this question.