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RESPITE: Riociguat in pulmonary arterial hypertension patients with an inadequate response to phosphodiesterase type 5 inhibitors (PDE5i)

Marius Hoeper


Andrea Allen

Paul Corris

James Klinger


David Langleben


Robert Naeije


G. Simmoneau

Raymond Benza


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Conference: 2017 PH Professional Network Symposium

Release Date: 10.06.2017

Presentation Type: Abstracts

File Download: 2017 PHPN Abstract 1006

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Abstract presented at the 2017 PH Professional Network Symposium held in Bethesda, MD on October 5-7, 2017

Purpose

RESPITE investigated the safety, feasibility, and clinical benefit of switching from PDE5i to riociguat in patients with pulmonary arterial hypertension (PAH) who had an inadequate response to PDE5i.

Background

PDE5i are widely used to treat PAH; however, some patients fail to reach or maintain treatment goals

Methods

RESPITE (NCT02007629) was a prospective, multicenter, uncontrolled, open-label, single-arm, Phase IIIb trial. PAH patients in World Health Organization (WHO) functional class (FC) III with 6-minute walking distance (6MWD) 165–440 m, cardiac index <3.0 L/min/m2, and pulmonary vascular resistance (PVR) >400 dyn·s·cm-5, despite receiving PDE5i either alone or with endothelin receptor antagonists (ERAs), were enrolled. Following a 1–3 day PDE5i treatment-free period, riociguat was individually adjusted to a maximum of 2.5 mg tid. Exploratory endpoints were assessed at Week 24 including 6MWD, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), pulmonary hemodynamics, WHO FC, and EuroQol 5-Dimensions questionnaire (EQ-5D) score to assess quality of life. A composite endpoint was also assessed, defined as patients who achieved freedom from clinical worsening, WHO FC I/II, and a ≥30 m increase in 6MWD. Safety ass essments and recording of adverse events (AEs) were undertaken during the treatment-free period and during the period following the switch to riociguat. At the end of the study, patients could participate in an extended drug-supply phase for 18 months or until reimbursement. Patients who discontinued the study drug or did not enter the extension phase underwent a 30-day safety follow-up.

Results

Of 61 patients enrolled, 51 (84%) completed the study. Fifty (82%) were receiving concomitant ERAs. Significant improvements were observed in mean 6MWD, NT-proBNP, cardiac index, PVR, and change in WHO FC from baseline to Week 24 (table). Six patients (10%) experienced clinical worsening, two of whom died (unrelated to the study drug). Sixteen patients (31%) achieved the composite endpoint at Week 24. Clinically meaningful improvements were observed in EQ-5D visual analog scale and utility scores with mean±SD increasing from baseline to Week 24 by +7±19 (n=61) and +0.07±0.28 (n=52), respectively. Switching was generally well tolerated, with 32 patients (52%) experiencing study drug-related AEs, the most frequently reported (>10% of patients) being headache (16%), dyspepsia (15%), hypotension (11%), and dizziness (11%). Ten patients (16%) experienced serious AEs, two (3%) of which were study drug-related (right ventricle failure and asthenia). No serious AEs occurred during the PDE5i treatment-free period. Syncope was not reported in the study and there was one mild case of hemoptysis, which was considered unrelated to the study drug. Four patients (7%) experienced AEs leading to discontinuation of the study drug, including two patients with right ventricular failure, one patient with asthenia, and one patient with symptomatic hypotension.

Conclusion

The clinical improvements in 6MWD and WHO FC, as well as in hemodynamic variables, NT-proBNP and EQ-5D scores, suggest that PAH patients with insufficient response to PDE5i may benefit from switching to riociguat.