• Marius M Hoeper, James R Klinger, Raymond L Benza, Gerald Simonneau, David Langleben, Robert Naeije, and Paul A Corris.
• Department of Respiratory Medicine and German Center of Lung Research, Hannover Medical School, Hannover, Germany. Electronic address: Hoeper.Marius@mh-hannover.de.
• Respir Med. 2017 Jan 1; 122 Suppl 1: S18-S22.

AbstractPatients with pulmonary arterial hypertension (PAH) who do not have an adequate response to therapy with phosphodiesterase-5 inhibitors (PDE-5i) may have insufficient synthesis of cyclic guanosine monophosphate (cGMP). These patients may respond to a direct soluble guanylate cyclase (sGC) stimulator such as riociguat. RESPITE (NCT02007629) was an open-label, multicenter, uncontrolled, single-arm phase 3b study of riociguat in patients with PAH who demonstrated an insufficient response to treatment with PDE-5i. Insufficient response was defined as World Health Organization functional class (WHO FC) III despite PDE-5i therapy for at least 90 days; 6-min walk distance (6MWD) of 165-440 m, and right-heart catheterization showing mean pulmonary artery pressure >30 mmHg, cardiac index <3.0 L/min/m2, and pulmonary vascular resistance >400 dyn s cm-5. PAH patients with an insufficient response to stable doses of sildenafil or tadalafil-either as monotherapy or in combination with an endothelin receptor antagonist-for at least 90 days were switched to riociguat for 24 weeks. Starting at 1.0 mg TID, the dose of riociguat was increased during the 8-week titration phase in 0.5-mg increments in 2-week intervals if the patient had no signs or symptoms of hypotension. In the ensuing 16-week maintenance phase, riociguat was continued at the optimal individual dose. All efficacy outcomes were exploratory and include change from baseline to 24 weeks in 6MWD, cardiac index, N-terminal pro-brain natriuretic peptide, WHO FC, and quality of life and the proportion of patients with clinical worsening. The following biomarkers were to be measured: cGMP, asymmetric dimethyl arginine, growth-differentiation factor-15, and ST2. Results from RESPITE will help to determine if PAH patients who do not respond to PDE-5i are likely to benefit from treatment with an sGC stimulator. The study may also identify biomarkers that are able to suggest which patients are more likely to respond to sGC stimulators.Copyright © 2016 Elsevier Ltd. All rights reserved.

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