SWITCHING TO RIOCIGUAT IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION NOT AT TREATMENT GOAL WITH PHOSPHODIESTERASE TYPE-5 INHIBITORS: SUBGROUP ANALYSIS RESULTS OF THE REPLACE STUDY

SESSION TITLE: Advances in the Diagnosis and Management of Pulmonary Hypertension SESSION TYPE: Original Investigations PRESENTED ON: October 18-21, 2020 PURPOSE: Preliminary data suggest that pts with pulmonary arterial hypertension (PAH) at intermediate risk on phosphodiesterase-5 inhibitors (PDE5i)-based therapy may benefit from switching to riociguat (RIO), a soluble guanylate cyclase stimulator. Here we compare switching to RIO vs continued PDE5i in intermediate-risk PAH pts not at treatment goal, including prespecified subgroups in the open-label, Phase 4 REPLACE study (NCT02891850). METHODS: Intermediate-risk PAH pts (WHO functional class [FC] III, 6-minute walk distance [6MWD] 165–440 m) on stable doses of PDE5i +/- endothelin receptor antagonist (ERA) were randomized to continue PDE5i or receive RIO up to 2.5 mg tid for 24 weeks. ERAs were continued in both arms. The blinded, centrally adjudicated composite primary endpoint was defined as no clinical worsening (CW) (death from any cause, hospitalization for worsening PAH, or disease progression) plus clinical improvement (2 of: ≥10%/≥30 m 6MWD increase; WHO FC I/II; or ≥30% decrease in N-terminal pro-brain natriuretic peptide [NT-proBNP]). Secondary endpoints included 6MWD, WHO FC (blinded assessment), NT-proBNP, and CW. RESULTS: Of 226 pts randomized, 111 received RIO and 115 remained on PDE5i. 155 (69%) had idiopathic PAH (IPAH)/heritable PAH (HPAH)/drug- and toxin-induced PAH (DPAH); 26 (12%) PAH associated with congenital heart disease (PAH-CHD) or portal hypertension (PoPH); and 43 (19%) PAH associated with connective tissue disease (PAH-CTD). At Week 24 in the overall population, the primary endpoint was met in 45 RIO pts (41%) vs 22 PDE5i pts (20%) (odds ratio [OR] 2.78; 95% confidence interval [CI] 1.53–5.06; p=0.0007). The primary endpoint favored the RIO cohort in each subgroup: IPAH/HPAH/DPAH: 33 (45%) vs 19 (23%) (OR 2.63; 95% CI 1.32–5.23); PAH-CHD/PoPH: 6 (46%) vs 1 (8%) (OR 10.29; 95% CI 1.02–103.95); PAH-CTD: 6 (25%) vs 3 (16%) (OR 1.78; 95% CI 0.38–8.30). In the overall population, CW was significantly lower in the RIO vs PDE5i arms: 1 pt (1%) vs 10 pts (9%), respectively (OR 0.10; 95% CI 0.01–0.73; p=0.0047). Three PDE5i pts had CW events leading to death and a further 1 PDE5i pt died in safety follow-up. There were no deaths with RIO. Similar results were seen in PAH subgroups: in the IPAH/HPAH/DPAH subgroup, 1 RIO pt and 4 PDE5i pts had CW; of these, 2 PDE5i pts died (1 in safety follow-up). In the PAH-CHD/PAH-PoPH and PAH-CTD subgroups, 3 PDE5i pts had CW in each subgroup including 1 death in each. In the overall population, adverse events (AEs) were similar between RIO and PDE5i (71 vs 66%); severe AEs were more frequent with PDE5i (17% vs 7%). CONCLUSIONS: The primary endpoint of the REPLACE study was met. Consistently more pts achieved clinical improvement without CW in the RIO vs the PDE5i maintenance arm across PAH subgroups. CLINICAL IMPLICATIONS: These data suggest that switching to RIO from PDE5i is effective and well tolerated in PAH pts at intermediate risk. DISCLOSURES: no disclosure on file for Hikmet Al-Hiti; No relevant relationships by Raymond Benza, source=Web Response No relevant relationships by Sung-A Chang, source=Web Response no disclosure on file for Mikyung Chang; Advisory Committee Member relationship with Bayer Please note: $1001 - $5000 Added 06/12/2020 by Paul Corris, source=Web Response, value=Consulting fee no disclosure on file for Hossein Ghofrani; Consultant relationship with Complexa Please note: $5001 - $20000 Added 04/20/2020 by J Simon Gibbs, source=Web Response, value=Honoraria Consultant relationship with Acceleron Please note: $5001 - $20000 Added 04/20/2020 by J Simon Gibbs, source=Web Response, value=Honoraria Consultant relationship with Actelion Please note: $5001 - $20000 Added 04/20/2020 by J Simon Gibbs, source=Web Response, value=Honoraria Consultant relationship with Bayer Please note: $5001 - $20000 Added 04/20/2020 by J Simon Gibbs, source=Web Response, value=Honoraria Consultant relationship with Pfizer Please note: $5001 - 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