title: Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study.
abstract: BACKGROUND
  Pulmonary hypertension caused by systolic left ventricular dysfunction is associated with significant morbidity and mortality; however, no treatment is approved for this indication. We hypothesized that riociguat, a novel soluble guanylate cyclase stimulator, would have beneficial hemodynamic effects in patients with pulmonary hypertension caused by systolic left ventricular dysfunction.
  
  
  RESULTS
  Overall, 201 patients with heart failure resulting from pulmonary hypertension caused by systolic left ventricular dysfunction were randomized to double-blind treatment with oral placebo or riociguat (0.5, 1, or 2 mg 3 times daily) for 16 weeks in 4 parallel arms. The primary outcome was the placebo-corrected change from baseline at week 16 in mean pulmonary artery pressure. Although the decrease in mean pulmonary artery pressure in the riociguat 2 mg group (-6.1±1.3 mm Hg; P<0.0001 versus baseline) was not significantly different from placebo (P=0.10), cardiac index (0.4 L·min(-1)·m(-2); 95% confidence interval, 0.2-0.5; P=0.0001) and stroke volume index (5.2 mL·m(-2); 95% confidence interval, 2.0-8.4; P=0.0018) were significantly increased without changes in heart rate or systemic blood pressure compared with placebo. Both pulmonary (-46.6 dynes·s(-1)·cm(-5); 95% confidence interval, -89.4 to -3.8; P=0.03) and systemic vascular resistance (-239.3 dynes·s(-1)·cm(-5); 95% confidence interval, -363.4 to -115.3; P=0.0002) were significantly reduced with riociguat 2 mg. Riociguat reduced the Minnesota Living With Heart Failure score (P=0.0002). Discontinuation of treatment was similar between treatment groups.
  
  
  CONCLUSIONS
  Although the primary end point of the study was not met, riociguat was well tolerated in patients with pulmonary hypertension caused by systolic left ventricular dysfunction and improved cardiac index and pulmonary and systemic vascular resistance.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT01065454.
authors.affiliation: Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
authors.forename: Diana
authors.initials: D
authors.lastname: Bonderman
authors.forename: Stefano
authors.initials: S
authors.lastname: Ghio
authors.forename: Stephan B
authors.initials: SB
authors.lastname: Felix
authors.forename: Hossein-Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.forename: Evangelos
authors.initials: E
authors.lastname: Michelakis
authors.forename: Veselin
authors.initials: V
authors.lastname: Mitrovic
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Oudiz
authors.forename: Francis
authors.initials: F
authors.lastname: Boateng
authors.forename: Andrea-Viviana
authors.initials: AV
authors.lastname: Scalise
authors.forename: Lothar
authors.initials: L
authors.lastname: Roessig
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Semigran
mesh_terms: D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000453:epidemiology*; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000453:epidemiology*
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; C542595:riociguat
keywords: clinical trial; heart failure, systolic; hypertension, pulmonary; riociguat; soluble guanylate cyclase