title: Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial.
abstract: Pulmonary arterial hypertension is a chronic disease associated with poor long-term outcomes. Identifying predictors of long-term outcome in pulmonary arterial hypertension is important to assess disease severity and guide treatment. We investigate associations between efficacy parameters and long-term outcomes in patients with pulmonary arterial hypertension receiving riociguat in the PATENT-2 study. We also present safety and efficacy data from the final data cutoff of PATENT-2, where most patients had received at least 2 years of riociguat treatment.
  
  
  
  Eligible patients from the PATENT-1 study entered the PATENT-2 open-label extension, which will continue until all patients transition to the commercial drug. All patients received riociguat individually adjusted to a maximum dose of 2·5 mg three times a day. The primary endpoint was safety and tolerability, assessed with recording adverse events, serious adverse events, discontinuations, and deaths; exploratory assessments included 6-min walking distance (6MWD), WHO functional class, N-terminal prohormone of brain natriuretic peptide (NT-proBNP)concentrations, Borg dyspnoea score, health-related quality of life (EQ-5D score), survival, and clinical worsening-free survival. Association between efficacy parameters and long-term outcomes was assessed using Kaplan-Meier analyses and a Cox proportional-hazards regression model. PATENT-2 is registered at ClinicalTrials.gov, number NCT00863681.
  
  
  
  396 patients entered PATENT-2, of whom 197 patients were receiving riociguat monotherapy and 199 were receiving riociguat in combination with endothelin receptor antagonists or prostanoids, or both. A significant association was noted between 6MWD, NT-proBNP concentration, and WHO functional class and overall survival at baseline (p=0·0006, 0·0225, and 0·0191, respectively), and at follow-up (p=0·021, 0·0056, and 0·0048, respectively). Riociguat was well tolerated in PATENT-2. Serious adverse events were recorded in 238 (60%) of the total population, and 45 (11%) patients discontinued treatment because of an adverse event. Improvements in 6MWD, WHO functional class, and NT-proBNP concentrations were maintained after 2 years of treatment.
  
  
  
  These results support the long-term use of riociguat in patients with pulmonary arterial hypertension, and emphasise the prognostic value of 6MWD, WHO functional class, and NT-proBNP concentrations.
  
  
  
  Bayer Pharma AG.
authors.affiliation: University of Giessen and Marburg Lung Center (UGMLC) and German Centre of Lung Research (DZL), Giessen, Germany; Department of Medicine, Imperial College London, London, UK. Electronic address: Ardeschir.Ghofrani@innere.med.uni-giessen.de.
authors.forename: Hossein-Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.affiliation: University of Giessen and Marburg Lung Center (UGMLC) and German Centre of Lung Research (DZL), Giessen, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.affiliation: Centre for Pulmonary Hypertension at the Thoraxclinic of University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Grünig
authors.affiliation: Department of Cardiology, Guangdong General Hospital and Guangdong Cardiovascular Institute, Guangzhou, Guangdong, China.
authors.forename: Yigao
authors.initials: Y
authors.lastname: Huang
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: State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Zhi-Cheng
authors.initials: ZC
authors.lastname: Jing
authors.affiliation: Discipline of Medicine, University of Tasmania, Hobart, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Kilpatrick
authors.affiliation: Center for Pulmonary Vascular Disease and Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Langleben
authors.affiliation: Department III of Internal Medicine and Cologne Cardiovascular Research Center (CCRC), Cologne University Heart Center, Cologne, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Rosenkranz
authors.affiliation: Bayer HealthCare Pharmaceuticals, São Paulo, Brazil.
authors.forename: Flavia
authors.initials: F
authors.lastname: Menezes
authors.affiliation: Global Clinical Development, Bayer Pharma AG, Wuppertal, Germany.
authors.forename: Arno
authors.initials: A
authors.lastname: Fritsch
authors.affiliation: Global Clinical Development, Bayer Pharma AG, Berlin, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Nikkho
authors.affiliation: Université Paris-Sud, Université Paris-Saclay, Le Kremlin Bicêtre, France; AP-HP, Service de Pneumologie, Hôpital Bicêtre, Le Kremlin Bicêtre, France; Inserm UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists / Q000008:administration & dosage; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D011453:Prostaglandins / Q000008:administration & dosage; D011651:Pulmonary Artery; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D011788:Quality of Life; D013995:Time; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D011453:Prostaglandins; D011720:Pyrazoles; D011743:Pyrimidines; D020097:Natriuretic Peptide, Brain; C542595:riociguat