• Gérald Simonneau, Andrea M D'Armini, Hossein-Ardeschir Ghofrani, Friedrich Grimminger, Pavel Jansa, Nick H Kim, Eckhard Mayer, Tomas Pulido, Chen Wang, Pablo Colorado, Arno Fritsch, Christian Meier, Sylvia Nikkho, and Marius M Hoeper.
• Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, Université Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et Innovation Thérapeutique, Le Kremlin-Bicêtre, France; INSERM Unité 999, l'Hopital Bicêtre, Le Kremlin-Bicêtre, France. Electronic address: gerald.simonneau@abc.ap-hop-paris.fr.
• Lancet Respir Med. 2016 May 1; 4 (5): 372-80.

BackgroundChronic thromboembolic pulmonary hypertension (CTEPH) is a rare, debilitating, and life-threatening disease. We investigated associations between markers of disease severity and long-term outcomes in patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy (PEA) who were receiving the soluble guanylate cyclase stimulator riociguat. We also present safety and efficacy from the final data cutoff of CHEST-2, where most patients had received riociguat for at least 2 years.MethodsEligible patients from the CHEST-1 study entered the CHEST-2 open-label extension study, in which all patients received riociguat individually adjusted to a maximum dose of 2·5 mg three times per day. The primary endpoint was safety and tolerability. We did exploratory assessments of associations between markers of disease severity (6-min walking distance [6MWD], N-terminal prohormone of brain natriuretic peptide [NT-proBNP] concentration, and WHO functional class) at baseline and follow-up with overall survival and clinical worsening-free survival. We used Kaplan-Meier and Cox proportional hazards analyses. CHEST-2 is registered at ClinicalTrials.gov, number NCT00910429.Findings237 patients entered CHEST-2. At 2 years, overall survival was 93% (95% CI 89-96) and clinical worsening-free survival was 82% (77-87). A significant association with overall survival was seen for 6MWD and NT-proBNP concentration at baseline (p=0·0199 and p=0·0183, respectively) and at follow-up (p=0·0385 and p=0·0068, respectively). Change from baseline in 6MWD was also significantly associated with survival (p=0·0047). WHO functional class at baseline and follow-up showed no significant association with overall survival but was associated with clinical worsening-free survival. Riociguat was well tolerated by most patients and no new safety signals were identified. Serious adverse events were seen in 129 (54%) of 237 patients, and 14 (6%) discontinued riociguat therapy because of adverse events.InterpretationRiociguat may be used long term in patients with CTEPH. 6MWD and NT-proBNP concentration are good prognostic markers.FundingBayer Pharma AG.Copyright © 2016 Elsevier Ltd. All rights reserved.

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