This exploratory analysis assessed whether plasma biomarkers predict the response to switching from phosphodiesterase type 5 inhibitors (PDE5is) to the soluble guanylate cyclase stimulator riociguat in patients with pulmonary arterial hypertension. Selected biomarkers at baseline and their changes to Week 24 were evaluated in patients with and without a favorable response to riociguat in two trials: RESPITE, in which patients with an inadequate response to PDE5i were switched to riociguat; and REPLACE, in which patients at intermediate risk of 1-year mortality despite a PDE5i were randomized to remain on PDE5i or were switched to riociguat. A response was defined as absence of clinical worsening and at least two of the following criteria: 6-min walk distance increase by 10% or ≥ 30 m, World Health Organization functional class I/II, or N-terminal prohormone of brain natriuretic peptide reduction of ≥ 30% at Week 24. In REPLACE, responders had significantly higher baseline cyclic guanosine monophosphate (cGMP) and significantly lower baseline asymmetric dimethylarginine, and growth/differentiation factor 15 (GDF-15) than nonresponders. In RESPITE, responders had lower baseline GDF-15 than nonresponders, and nonresponders showed a significantly greater decrease in cGMP than responders. No baseline threshold value of any biomarker provided a good likelihood of predicting the response to riociguat. Overall, the biomarkers evaluated did not help to identify patients who were more likely to respond to switching from PDE5is to riociguat.

Assistance Publique Hôpitaux de Paris Service de Pneumologie Hôpital Bicêtre Université Paris Sud Laboratoire d'Excellence en Recherche sur le Médicament et Innovation Thérapeutique and Inserm U999 Le Kremlin Bicêtre France

Centre of Pulmonary Hypertension Thoraxklinik at Heidelberg University Hospital Translational Lung Research Center member of DZL Heidelberg Germany

Centro de Hipertensão Pulmonar Complexo Hospitalar Santa Casa de Porto Alegre Porto Alegre Brazil

CHRESTOS Concept GmbH and Co KG Essen Germany

Clinic for Respiratory Medicine Hannover Medical School member of the German Centre for Lung Research Hannover Germany

Clinical Department of Cardiology and Angiology 1st Faculty of Medicine 2nd Medical Department Charles University Prague Czech Republic

Clinical Research Department National Heart Institute Mexico City Mexico

Department of Cardiology Institute of Clinical and Experimental Medicine IKEM Prague Czech Republic

Department of Cardiology Severance Cardiovascular Hospital Yonsei University Health System Seoul South Korea

Department of Internal Medicine Justus Liebig University Giessen Universities of Giessen and Marburg Lung Center Giessen Germany

Department of Medicine Imperial College London London UK

Department of Pneumology Kerckhoff Heart and Thorax Center Bad Nauheim Germany

Division of Cardiology Department of Medicine Heart Vascular and Stroke Institute Samsung Medical Center Sungkyunkwan University School of Medicine Gangnam gu Seoul Republic of Korea

Division of Pulmonary Sleep and Critical Care Medicine Rhode Island Hospital Alpert Medical School of Brown University Providence Rhode Island USA

Global Medical Affairs Bayer AG Berlin Germany

Pulmonary Circulation Group Department of Medicine Universidade Federal de São Paulo Hospital São Paulo São Paulo Brazil

Pulmonary Hypertension Unit Department of Cardiovascular and Respiratory Disease La Sapienza University of Rome Rome Italy

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