Purpose: The REPLACE study showed that PAH patients treated with phosphodiesterase-5 inhibitors (PDE5i) still at intermediate risk could achieve clinical improvement when switched to riociguat. Significant improvements in risk status with riociguat versus PDE5i were seen using the COMPERA and non-invasive French Pulmonary Hypertension Network (FPHN) risk scores, but not the REVEAL risk score (RRS). We investigated possible reasons for this difference.
Methods: Achievement of the REPLACE primary endpoint of clinical improvement at week 24 was assessed in patients stratified into low- and intermediate-/high-risk status by RRS at baseline. Change in RRS from baseline, clinical worsening and deaths were also assessed in responders (patients achieving the endpoint) versus non-responders. Individual components of RRS, COMPERA and FPHN were calculated for both groups at baseline and week 24.
Results: At baseline, more than half of the patients in each group (riociguat, 53%; PDE5i, 57%) were low risk by their RRS.Nonetheless,41% of low-risk riociguat patients and 17% of low-risk PDE5i patients were responders, similar to intermediate-/high-risk patients (40% vs. 24%). Low-risk responders also experienced significant improvements in RRS versus baseline and versus low-risk non-responders. Of 11 clinical worsening events, two were in low-risk PDE5i patients. No deaths occurred in low-risk patients. All risk-assessment tools showed similar trends in shared components; however, at week 24, more patients on riociguat (46%) versus PDE5i (31%) had 1–2 points added to their RRS owing to the systolic blood pressure aspect of the vital signs component. When RRS was recalculated excluding vital signs, the difference between the riociguat and PDE5i groups was significant, as with the COMPERA and FPHN risk scores.
Conclusions: The inclusion of vital signs in the RRS can explain the different risk-assessment results in REPLACE. Patients considered low risk by RRS are still capable of achieving clinical improvement if switched to riociguat from PDE5i.
Disclosures: The REPLACE study was co-funded by Bayer AG (Berlin, Germany) and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (Kenilworth, NJ, USA). R.L.B. reports grants from Actelion, Bellerophon, Bayer AG and EIGER.
R. L. Benza, Division of Cardiovascular Diseases, Ohio State University, Columbus, Ohio, USA G. Simonneau, Assistance Publique–Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, Université Paris-Saclay, Laboratoire d’Excellence en Recherche sur le Médicament et Innovation Thérapeutique, and Inserm U999, Le Kremlin-Bicêtre, France H. A. Ghofrani, University of Giessen and Marburg Lung Center, member of the German Center for Lung Research (DZL), Giessen, Germany, Department of Pneumology, Kerckhoff Clinic, Bad Nauheim, Germany and Department of Medicine, Imperial College London, London, UK P. A. Corris, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK S. Rosenkranz, Clinic III for Internal Medicine (Cardiology), Cologne Cardiovascular Research Center (CCRC) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany D. Langleben, Center for Pulmonary Vascular Disease and Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada C. Meier, Global Medical Affairs, Bayer AG, Berlin, Germany C. Rahner, Chrestos Concept GmbH & Co. KG, Essen, Germany M. M. Hoeper, Clinic for Respiratory Medicine, Hannover Medical School, member of the German Center for Lung Research (DZL), Hannover, Germany