title: Rationale and design of the SOluble guanylate Cyclase stimulatoR in heArT failurE Studies (SOCRATES).
abstract: OBJECTIVE
  The clinical outcomes for patients with worsening chronic heart failure (WCHF) remain exceedingly poor despite contemporary evidence-based therapies, and effective therapies are urgently needed. Accumulating evidence supports augmentation of cyclic guanosine monophosphate (cGMP) signalling as a potential therapeutic strategy for HF with reduced or preserved ejection fraction (HFrEF and HFpEF, respectively). Direct soluble guanylate cyclase (sGC) stimulators target reduced cGMP generation due to insufficient sGC stimulation and represent a promising method for cGMP enhancement.
  
  
  METHODS
  The phase II SOluble guanylate Cyclase stimulatoR in heArT failurE Study (SOCRATES) programme consists of two randomized, parallel-group, placebo-controlled, double-blind, multicentre studies, SOCRATES-REDUCED (in patients with LVEF <45%) and SOCRATES-PRESERVED (in those with LVEF ≥ 45%), that will explore the pharmacodynamic effects, safety and tolerability, and pharmacokinetics of four dose regimens of the once-daily oral sGC stimulator vericiguat (BAY 1021189) over 12 weeks compared with placebo. These studies will enrol patients stabilized during hospitalization for HF at the time of discharge or within 4 weeks thereafter. The primary endpoint in SOCRATES-REDUCED is change in NT-proBNP at 12 weeks. The primary endpoints in SOCRATES-PRESERVED are change in NT-proBNP and left atrial volume at 12 weeks.
  
  
  CONCLUSIONS
  SOCRATES will be the first programme to enrol specifically both inpatients and outpatients with WCHF and patients with reduced or preserved ejection fraction. Results will inform the benefits of pursuing subsequent event-driven clinical outcome trials with sGC stimulators in this patient population.
authors: Department of Cardiology, Medical University Graz, Graz, Austria.
authors: Burkert
authors: B
authors: Pieske
authors: Javed
authors: J
authors: Butler
authors: Gerasimos
authors: G
authors: Filippatos
authors: Carolyn
authors: C
authors: Lam
authors: Aldo Pietro
authors: AP
authors: Maggioni
authors: Piotr
authors: P
authors: Ponikowski
authors: Sanjiv
authors: S
authors: Shah
authors: Scott
authors: S
authors: Solomon
authors: Elisabeth
authors: E
authors: Kraigher-Krainer
authors: Eliana Tibana
authors: ET
authors: Samano
authors: Andrea Viviana
authors: AV
authors: Scalise
authors: Katharina
authors: K
authors: Müller
authors: Lothar
authors: L
authors: Roessig
authors: Mihai
authors: M
authors: Gheorghiade
mesh_terms: D000284:Administration, Oral; D000368:Aged; D004311:Double-Blind Method; D005260:Female; D006162:Guanylate Cyclase / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D011379:Prognosis; D011498:Protein Precursors; D018160:Receptors, Cytoplasmic and Nuclear / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000071756:Soluble Guanylyl Cyclase; D013318:Stroke Volume / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D010446:Peptide Fragments; D011498:Protein Precursors; D018160:Receptors, Cytoplasmic and Nuclear; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase
keywords: Left atrial volume; Natriuretic peptides; Preserved ejection fraction; Reduced ejection fraction; Soluble guanylate cyclase; Worsening chronic heart failure