title: Evaluation of the pharmacoDYNAMIC effects of riociguat in subjects with pulmonary hypertension and heart failure with preserved ejection fraction : Study protocol for a randomized controlled trial.
abstract: BACKGROUND
  The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFPEF) resulting in substantial morbidity and mortality. So far, neither established heart failure therapies nor pulmonary vasodilators have proven to be effective for this condition. Riociguat (Adempas®, BAY 63-2521), a stimulator of soluble guanylate cyclase, is a novel pulmonary and systemic vasodilator that has been approved for the treatment of precapillary forms of PH. With regard to postcapillary PH, the DILATE-1 study was a multicenter, double-blind, randomized, placebo-controlled single-dose study in subjects with PH associated with HFPEF. Although there was no significant change in the primary outcome measure, peak decrease in mean pulmonary artery pressure with riociguat versus placebo, riociguat significantly increased stroke volume without changing heart rate, pulmonary artery wedge pressure, transpulmonary pressure gradient or pulmonary vascular resistance. The present study is designed to test the efficacy of long-term treatment with riociguat in patients with PH associated with HFPEF.
  
  
  METHODS
  The DYNAMIC study is a randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical phase IIb trial evaluating the efficacy, safety and kinetics of riociguat in PH-HFPEF patients. The drug will be given over 26 weeks to evaluate the effects of riociguat versus placebo. The primary efficacy variable will be the change from baseline in cardiac output at rest, measured by right heart catheter after 26 weeks of study drug treatment. Additional efficacy variables will be changes from baseline in further hemodynamic parameters, changes in left and right atrial area, right ventricular volume, as well as right ventricular ejection fraction measured by cardiac magnetic resonance imaging, and changes from baseline in World Health Organization (WHO) class and N‑terminal prohormone B‑type natriuretic peptide (NT-proBNP). The trial was registered on 25 August 2014 (EudraCT Number: 2014-003055-60; www.clinicaltrialsregister.eu ).
authors: Department of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, 0190, Vienna, Austria. julia.mascherbauer@meduniwien.ac.at.
authors: Julia
authors: J
authors: Mascherbauer
authors: Centre for Pulmonary Hypertension, Thoraxclinic, University Hospital of Heidelberg, Heidelberg, Germany.
authors: Ekkehard
authors: E
authors: Grünig
authors: Department of Internal Medicine I, University Hospital Carl Gustav Carus Dresden, Dresden, Germany.
authors: Michael
authors: M
authors: Halank
authors: Medical Clinic II, Coburg Hospital, Coburg, Germany.
authors: Wolfgang
authors: W
authors: Hohenforst-Schmidt
authors: Department of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, 0190, Vienna, Austria.
authors: Andreas A
authors: AA
authors: Kammerlander
authors: Department of Cardiology, Paracelsus Medial University Salzburg, Salzburg, Austria.
authors: Ingrid
authors: I
authors: Pretsch
authors: Department of Cardiology, Public Hospital Elisabethinen Linz, Linz, Austria.
authors: Regina
authors: R
authors: Steringer-Mascherbauer
authors: Pulmonary Clinic, Department of Cardiovascular and Thoracic Medicine, University Hospital Zurich, Zurich, Switzerland.
authors: Silvia
authors: S
authors: Ulrich
authors: Department of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, 0190, Vienna, Austria.
authors: Irene M
authors: IM
authors: Lang
authors: M.A.R.C.O. GmbH & Co. KG, Düsseldorf, Germany.
authors: Manfred
authors: M
authors: Wargenau
authors: , Am Eckbusch 75, 42113, Wuppertal, Germany.
authors: Reiner
authors: R
authors: Frey
authors: Department of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, 0190, Vienna, Austria.
authors: Diana
authors: D
authors: Bonderman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004311:Double-Blind Method; D005260:Female; D005858:Germany; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D015990:Placebo Effect; D011720:Pyrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D012107:Research Design; D013318:Stroke Volume; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D011720:Pyrazoles; D011743:Pyrimidines; D014665:Vasodilator Agents; C542595:riociguat
keywords: Heart failure with preserved ejection fraction; Medical treatment; Pulmonary hypertension