title: Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial.
abstract: Chronic 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.
  
  
  
  Eligible 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.
  
  
  
  237 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.
  
  
  
  Riociguat may be used long term in patients with CTEPH. 6MWD and NT-proBNP concentration are good prognostic markers.
  
  
  
  Bayer Pharma AG.
authors.affiliation: 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.
authors.forename: Gérald
authors.initials: G
authors.lastname: Simonneau
authors.affiliation: Division of Cardiothoracic Surgery, Foundation "I.R.C.C.S. Policlinico San Matteo", University of Pavia School of Medicine, Pavia, Italy.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: D'Armini
authors.affiliation: University of Giessen and Marburg Lung Centre (UGMLC), Giessen, Germany; German Centre of Lung Research (DZL), Giessen, Germany; Department of Medicine, Imperial College London, London, UK.
authors.forename: Hossein-Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.affiliation: University of Giessen and Marburg Lung Centre (UGMLC), Giessen, Germany; German Centre of Lung Research (DZL), Giessen, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.affiliation: Clinical Department of Cardiology and Angiology of the First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Jansa
authors.affiliation: Division of Pulmonary and Critical Care Medicine, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Nick H
authors.initials: NH
authors.lastname: Kim
authors.affiliation: Kerckhoff Heart and Lung Centre, Bad Nauheim, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mayer
authors.affiliation: National Heart Institute, Cardiopulmonary Department, Mexico City, Mexico.
authors.forename: Tomas
authors.initials: T
authors.lastname: Pulido
authors.affiliation: Beijing Institute of Respiratory Medicine, Beijing Chao Yang Hospital, Beijing, China; Department of Respiratory Medicine, Capital Medical University, Beijing, China; Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Global Clinical Development, Bayer Pharma AG, Barcelona, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Colorado
authors.affiliation: Global Clinical Development, Bayer HealthCare Pharmaceuticals, Wuppertal, Germany.
authors.forename: Arno
authors.initials: A
authors.lastname: Fritsch
authors.affiliation: Global Clinical Development, Bayer Pharma AG, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Meier
authors.affiliation: Global Clinical Development, Bayer Pharma AG, Berlin, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Nikkho
authors.affiliation: German Centre of Lung Research (DZL), Giessen, Germany; Clinic for Respiratory Medicine, Hannover Medical School, Hannover, Germany.
authors.forename: Marius M
authors.initials: MM
authors.lastname: Hoeper
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D002908:Chronic Disease; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D011655:Pulmonary Embolism / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D013995:Time; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000959:Antihypertensive Agents; D011720:Pyrazoles; D011743:Pyrimidines; D020097:Natriuretic Peptide, Brain; C542595:riociguat