REPLACE: A prospective, randomized trial of riociguat replacing phosphodiesterase 5 inhibitor therapy in patients with pulmonary arterial hypertension who are not at treatment goal

Many patients with pulmonary arterial hypertension (PAH) have an insufficient response to PDE5i therapy, possibly due to impairment of the NO–sGC–cGMP pathway. Data from the RESPITE study indicate that such patients may benefit from switching from PDE5i to the sGC stimulator riociguat. REPLACE (NCT02891850) will evaluate the efficacy and safety of switching to riociguat vs continuing treatment with PDE5i in PAH patients not at treatment goal (WHO FC III, 6MWD 165–440 m) despite receiving stable doses of PDE5i with or without ERA. REPLACE is a prospective, randomized, multicenter, double-arm, 24-week, controlled, open-label study with planned enrolment of 218 subjects. Patients will be randomized to continue PDE5i therapy or switch to riociguat (up to 2.5 mg tid). The composite primary efficacy endpoint is satisfactory clinical response at Week 24, defined as fulfilment of at least 2 out of 3 efficacy parameters (≥10% or ≥30 m increase from baseline (BL) in 6MWD, WHO FC I/II or ≥30% reduction from BL in NT-proBNP) in the absence of clinical worsening (independent central adjudication). Secondary outcomes include change from BL in 6MWD and WHO FC (blinded assessment), NT-proBNP and clinical worsening. Exploratory endpoints include quality of life (Living with Pulmonary Hypertension), REVEAL risk score and MRI parameters of right heart function. Safety will be assessed by adverse events and all-cause mortality. The results of REPLACE will help determine whether switching PAH patients with an inadequate response to PDE5i to riociguat is an effective and safe strategy to improve clinical outcomes.