RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors

Marius M Hoeper, Gérald Simonneau, Paul A Corris, Hossein-Ardeschir Ghofrani, James R Klinger, David Langleben, Robert Naeije, Pavel Jansa, Stephan Rosenkranz, Laura Scelsi, Ekkehard Grünig, Carmine Dario Vizza, MiKyung Chang, Pablo Colorado, Christian Meier, Dennis Busse, Raymond L Benza, Marius M Hoeper, Gérald Simonneau, Paul A Corris, Hossein-Ardeschir Ghofrani, James R Klinger, David Langleben, Robert Naeije, Pavel Jansa, Stephan Rosenkranz, Laura Scelsi, Ekkehard Grünig, Carmine Dario Vizza, MiKyung Chang, Pablo Colorado, Christian Meier, Dennis Busse, Raymond L Benza

Abstract

A proportion of pulmonary arterial hypertension (PAH) patients do not reach treatment goals with phosphodiesterase-5 inhibitors (PDE5i). RESPITE investigated the safety, feasibility and benefit of switching from PDE5i to riociguat in these patients.RESPITE was a 24-week, open-label, multicentre, uncontrolled study. Patients in World Health Organization (WHO) functional class (FC) III, with 6-min walking distance (6MWD) 165-440 m, cardiac index <3.0 L·min-1·m-2 and pulmonary vascular resistance >400 dyn·s·cm-5 underwent a 1-3 day PDE5i treatment-free period before receiving riociguat adjusted up to 2.5 mg maximum t.i.d Exploratory end-points included change in 6MWD, WHO FC, N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and safety.Of 61 patients enrolled, 51 (84%) completed RESPITE. 50 (82%) were receiving concomitant endothelin receptor antagonists. At week 24, mean±sd 6MWD had increased by 31±63 m, NT-proBNP decreased by 347±1235 pg·mL-1 and WHO FC improved in 28 patients (54%). 32 patients (52%) experienced study drug-related adverse events and 10 (16%) experienced serious adverse events (2 (3%) study drug-related, none during the PDE5i treatment-free period). Six patients (10%) experienced clinical worsening, including death in two (not study drug-related).In conclusion, selected patients with PAH may benefit from switching from PDE5i to riociguat, but this strategy needs to be further studied.

Trial registration: ClinicalTrials.gov NCT02007629.

Conflict of interest statement

Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com

Copyright ©ERS 2017.

Figures

FIGURE 1
FIGURE 1
Patient disposition and flow in RESPITE over 24 weeks of treatment. #: primary reason for discontinuation; ¶: two patients died during the main study (days 27 and 49). Of the two deaths during the study period, one was attributed to pneumonia (after withdrawal by patient, the primary reason for discontinuation) and one to subdural haematoma.
FIGURE 2
FIGURE 2
Change from baseline (the last documented value while still receiving phosphodiesterase-5 inhibitor) in 6-min walking distance (6MWD) over time in RESPITE. Data are mean±sem; observed values.
FIGURE 3
FIGURE 3
Change from baseline (the last documented value while still receiving phosphodiesterase-5 inhibitor) in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) over time in RESPITE. Data are mean±sem; observed values. #: p-value calculated for relative change from baseline; ¶: value missing for one patient at baseline; n=52 for change from baseline at week 24 due to one patient withdrawal at day +159 having undergone a week 24 assessment of NT-proBNP.
FIGURE 4
FIGURE 4
World Health Organization functional class (WHO FC) at baseline (the last documented value while still receiving phosphodiesterase-5 inhibitor), week 12 and week 24 in RESPITE. Data are observed values. *: p#: n=52 due to one patient withdrawal at day +159 having undergone a week 24 assessment of WHO FC.

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