title: Acute hemodynamic effects of riociguat in patients with pulmonary hypertension associated with diastolic heart failure (DILATE-1): a randomized, double-blind, placebo-controlled, single-dose study.
abstract: BACKGROUND
  Deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate signaling results from endothelial dysfunction and may underlie impaired cardiac relaxation in patients with heart failure with preserved left ventricular ejection fraction (HFpEF) and pulmonary hypertension (PH). The acute hemodynamic effects of riociguat, a novel soluble guanylate cyclase stimulator, were characterized in patients with PH and HFpEF.
  
  
  METHODS
  Clinically stable patients receiving standard HF therapy with a left ventricular ejection fraction > 50%, mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg, and pulmonary arterial wedge pressure (PAWP) > 15 mm Hg at rest were randomized to single oral doses of placebo or riociguat (0.5, 1, or 2 mg). The primary efficacy variable was the peak decrease in mPAP from baseline up to 6 h. Secondary outcomes included hemodynamic and echocardiographic parameters, safety, and pharmacokinetics.
  
  
  RESULTS
  There was no significant change in peak decrease in mPAP with riociguat 2 mg (n = 10) vs placebo (n = 11, P = .6). However, riociguat 2 mg significantly increased stroke volume (+9 mL [95% CI, 0.4-17]; P = .04) and decreased systolic BP (-12 mm Hg [95% CI, -22 to -1]; P = .03) and right ventricular end-diastolic area (-5.6 cm2 [95% CI, -11 to -0.3]; P = .04), without significantly changing heart rate, PAWP, transpulmonary pressure gradient, or pulmonary vascular resistance. Riociguat was well tolerated.
  
  
  CONCLUSIONS
  In patients with HFpEF and PH, riociguat was well tolerated, had no significant effect on mPAP, and improved exploratory hemodynamic and echocardiographic parameters.
  
  
  BACKGROUND
  ClinicalTrials.gov; No.: NCT01172756; URL: www.clinicaltrials.gov.
authors.affiliation: From the Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria. Electronic address: diana.bonderman@meduniwien.ac.at.
authors.forename: Diana
authors.initials: D
authors.lastname: Bonderman
authors.affiliation: Department of Internal Medicine II, Paracelsus Medical University Salzburg, Salzburg, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Pretsch
authors.affiliation: Second Department of Medicine, Public Hospital Elisabethinen, Linz, Austria.
authors.forename: Regina
authors.initials: R
authors.lastname: Steringer-Mascherbauer
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: Clinic III for Internal Medicine, Heart Center at the University Hospital of Cologne, Cologne, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Rosenkranz
authors.affiliation: From the Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
authors.forename: Caroline
authors.initials: C
authors.lastname: Tufaro
authors.affiliation: From the Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
authors.forename: Andja
authors.initials: A
authors.lastname: Bojic
authors.affiliation: National University Health System, Singapore.
authors.forename: Carolyn S P
authors.initials: CSP
authors.lastname: Lam
authors.affiliation: Bayer HealthCare Pharmaceuticals, Wuppertal, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Frey
authors.affiliation: Bayer HealthCare Pharmaceuticals, Milan, Italy.
authors.forename: Michael
authors.initials: M
authors.lastname: Ochan Kilama
authors.affiliation: Bayer HealthCare Pharmaceuticals, Wuppertal, Germany.
authors.forename: Sigrun
authors.initials: S
authors.lastname: Unger
authors.affiliation: Bayer HealthCare Pharmaceuticals, Wuppertal, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Roessig
authors.affiliation: From the Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Lang
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004452:Echocardiography; D005260:Female; D005500:Follow-Up Studies; D054144:Heart Failure, Diastolic / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000187:drug effects / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; C542595:riociguat