Late Breaking Abstract - Switching From Pde5i To Riociguat In Patients With Pah: The Replace Study

Background: Pulmonary arterial hypertension (PAH) treatment guidelines recommend patients achieve/maintain a low-risk profile. Many patients treated with PAH-targeted therapy do not meet this treatment goal. Aim: Compare switching to riociguat (RIO) with continued phosphodiesterase type 5 inhibitors (PDE5i) in intermediate risk patients with PAH. Methods: REPLACE (NCT02891850) was a randomized, open-label, 24-week Phase 4 study. Patients in WHO functional class [FC] III, with 6-minute walking distance [6MWD] 165–440 m were randomized to remain on PDE5i or switch to RIO 2.5 mg tid–max. Endothelin receptor antagonist pretreatment continued in both arms. The blinded, centrally adjudicated composite primary endpoint was defined as no clinical worsening (CW) plus clinical improvement (two of the following: ≥10%/≥30 m increase in 6MWD, WHO FC I/II, or ≥30% reduction in N-terminal pro-brain natriuretic peptide [NT-proBNP]). Secondary endpoints included 6MWD, WHO FC (both blinded assessment), NT-proBNP, and CW (death from any cause, hospitalization for worsening PAH or disease progression). Safety was evaluated throughout. Results: 111 patients were randomized to RIO, 115 to PDE5i. The primary endpoint was met in 45 patients (41%) with RIO and 23 (20%) with PDE5i (OR 2.8; 95% CI 1.5–5.1; p=0.0007). Of those not achieving the endpoint, 1 RIO patient (1%) and 10 PDE5i patients (9%) had CW including 3 PDE5i patients (3%) who died. AEs were similar between arms, with a higher incidence of serious AEs with PDE5i (17%) than RIO (7%). Conclusions: REPLACE demonstrated that patients on PDE5i at intermediate risk are more likely to show clinical improvement without CW upon switching to RIO than those who remain on PDE5i.