title: Riociguat for the treatment of pulmonary arterial hypertension.
abstract: BACKGROUND
  Riociguat, a soluble guanylate cyclase stimulator, has been shown in a phase 2 trial to be beneficial in the treatment of pulmonary arterial hypertension.
  
  
  METHODS
  In this phase 3, double-blind study, we randomly assigned 443 patients with symptomatic pulmonary arterial hypertension to receive placebo, riociguat in individually adjusted doses of up to 2.5 mg three times daily (2.5 mg-maximum group), or riociguat in individually adjusted doses that were capped at 1.5 mg three times daily (1.5 mg-maximum group). The 1.5 mg-maximum group was included for exploratory purposes, and the data from that group were analyzed descriptively. Patients who were receiving no other treatment for pulmonary arterial hypertension and patients who were receiving endothelin-receptor antagonists or (nonintravenous) prostanoids were eligible. The primary end point was the change from baseline to the end of week 12 in the distance walked in 6 minutes. Secondary end points included the change in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, World Health Organization (WHO) functional class, time to clinical worsening, score on the Borg dyspnea scale, quality-of-life variables, and safety.
  
  
  RESULTS
  By week 12, the 6-minute walk distance had increased by a mean of 30 m in the 2.5 mg-maximum group and had decreased by a mean of 6 m in the placebo group (least-squares mean difference, 36 m; 95% confidence interval, 20 to 52; P<0.001). Prespecified subgroup analyses showed that riociguat improved the 6-minute walk distance both in patients who were receiving no other treatment for the disease and in those who were receiving endothelin-receptor antagonists or prostanoids. There were significant improvements in pulmonary vascular resistance (P<0.001), NT-proBNP levels (P<0.001), WHO functional class (P=0.003), time to clinical worsening (P=0.005), and Borg dyspnea score (P=0.002). The most common serious adverse event in the placebo group and the 2.5 mg-maximum group was syncope (4% and 1%, respectively).
  
  
  CONCLUSIONS
  Riociguat significantly improved exercise capacity and secondary efficacy end points in patients with pulmonary arterial hypertension. (Funded by Bayer HealthCare; PATENT-1 and PATENT-2 ClinicalTrials.gov numbers, NCT00810693 and NCT00863681, respectively.).
authors.affiliation: University of Giessen and Marburg Lung Center, Giessen, Germany. ardeschir.ghofrani@innere.med.uni-giessen.de
authors.forename: Hossein-Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Galiè
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Grünig
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.forename: Zhi-Cheng
authors.initials: ZC
authors.lastname: Jing
authors.forename: Anne M
authors.initials: AM
authors.lastname: Keogh
authors.forename: David
authors.initials: D
authors.lastname: Langleben
authors.forename: Michael Ochan
authors.initials: MO
authors.lastname: Kilama
authors.forename: Arno
authors.initials: A
authors.lastname: Fritsch
authors.forename: Dieter
authors.initials: D
authors.lastname: Neuser
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Rubin
mesh_terms: D000328:Adult; D000368:Aged; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D065128:Endothelin Receptor Antagonists; D017079:Exercise Tolerance / Q000187:drug effects; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D011453:Prostaglandins / Q000627:therapeutic use; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011788:Quality of Life; D014655:Vascular Resistance / Q000187:drug effects; D016138:Walking
chemical_list: D065128:Endothelin Receptor Antagonists; D010446:Peptide Fragments; D011453:Prostaglandins; D011720:Pyrazoles; D011743:Pyrimidines; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; C542595:riociguat