15 February 2020 by Gerald Simonneau

Assessment of the REPLACE study composite endpoint in the PATENT study and association with long-term outcomes in riociguat-treated patients

Introduction: REPLACE will evaluate switching to riociguat in patients with pulmonary arterial hypertension (PAH) and an insufficient response to phosphodiesterase-5 inhibitors. The primary outcome is a composite clinical improvement endpoint (no clinical worsening and two of: ≥10% or ≥30 m improvement in 6-minute walking distance; World Health Organization functional class I/II; ≥30% decrease in N-terminal pro-brain natriuretic peptide). We assessed whether the endpoint could differentiate between the riociguat and placebo arms of the PATENT-1 study, and whether achieving the endpoint was associated with long-term outcomes.

Methods: In PATENT-1, patients received placebo or riociguat up to 2.5 mg three times/day (tid). In PATENT-2, former placebo patients received riociguat up to 2.5 mg tid. This post-hoc analysis applied the REPLACE composite endpoint to the PATENT-1 database and evaluated the association between achieving the composite endpoint in PATENT-1 and survival and clinical worsening-free survival in PATENT-2.

Results: The PATENT-1 analysis included 126 patients who received placebo and 254 who received riociguat up to 2.5 mg tid, with long-term outcomes assessed in 340 patients who entered PATENT-2. At Week 12, 50% of riociguat-treated and 25% of placebo-treated patients achieved the composite endpoint (odds ratio, 3.13; 95% confidence interval, 1.88–5.26; p<0.001). Similar results were observed irrespective of background therapy, although more treatment-naïve patients achieved the endpoint than pretreated patients in the riociguat arm. Patients who achieved the endpoint in PATENT-1 had a 45% reduction in relative risk of death and a 19% reduction in relative risk of clinical worsening in PATENT-2 compared with those who did not.

Conclusion: In this post-hoc analysis of PATENT-1 data, riociguat-treated patients were
more likely than placebo-treated patients to achieve the REPLACE composite endpoint of
improvement, which was associated with improved long-term outcomes. Use of this endpoint
in patients with PAH is a viable assessment of treatment response.

About the author

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Gerald Simonneau

Professeur respiratory medicine and senior consultant

Assistance publique hôpitaux de Paris


Key Contributors

Simonneau G, Hoeper MM, Corris PA, Rosenkranz S, Grünig E,White J, Langleben D, Meier C, Busse D, Kleinjung F, Benza RL 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 Unité 999, Le Kremlin-Bicêtre, France; Clinic for Respiratory Medicine, Hannover Medical School, Hannover, Germany, member of the German Center for Lung Research (DZL); Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; Department III of Internal Medicine, Cologne University Heart Center, Cologne, Germany; Centre for Pulmonary Hypertension at Thoraxklinik Heidelberg, Heidelberg, Germany; Division of Pulmonary and Critical Care Medicine and the Mary M. Parkes Center, University of Rochester Medical Center, Rochester, NY, USA; Center for Pulmonary Vascular Disease and Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada; Bayer AG, Berlin, Germany; Chrestos Concept GmbH & Co. KG, Essen, Germany; Cardiovascular Institute, Allegheny General Hospital, Pittsburgh, PA, USA

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