title: Effect of Vericiguat, a Soluble Guanylate Cyclase Stimulator, on Natriuretic Peptide Levels in Patients With Worsening Chronic Heart Failure and Reduced Ejection Fraction: The SOCRATES-REDUCED Randomized Trial.
abstract: OBJECTIVE
  Worsening chronic heart failure (HF) is a major public health problem.
  
  
  OBJECTIVE
  To determine the optimal dose and tolerability of vericiguat, a soluble guanylate cyclase stimulator, in patients with worsening chronic HF and reduced left ventricular ejection fraction (LVEF).
  
  
  METHODS
  Dose-finding phase 2 study that randomized 456 patients across Europe, North America, and Asia between November 2013 and January 2015, with follow-up ending June 2015. Patients were clinically stable with LVEF less than 45% within 4 weeks of a worsening chronic HF event, defined as worsening signs and symptoms of congestion and elevated natriuretic peptide level requiring hospitalization or outpatient intravenous diuretic.
  
  
  METHODS
  Placebo (n = 92) or 1 of 4 daily target doses of oral vericiguat (1.25 mg [n = 91], 2.5 mg [n = 91], 5 mg [n = 91], 10 mg [n = 91]) for 12 weeks.
  
  
  METHODS
  The primary end point was change from baseline to week 12 in log-transformed level of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The primary analysis specified pooled comparison of the 3 highest-dose vericiguat groups with placebo, and secondary analysis evaluated a dose-response relationship with vericiguat and the primary end point.
  
  
  RESULTS
  Overall, 351 patients (77.0%) completed treatment with the study drug with valid 12-week NT-proBNP levels and no major protocol deviation and were eligible for primary end point evaluation. In primary analysis, change in log-transformed NT-proBNP levels from baseline to week 12 was not significantly different between the pooled vericiguat group (log-transformed: baseline, 7.969; 12 weeks, 7.567; difference, -0.402; geometric means: baseline, 2890 pg/mL; 12 weeks, 1932 pg/mL) and placebo (log-transformed: baseline, 8.283; 12 weeks, 8.002; difference, -0.280; geometric means: baseline, 3955 pg/mL; 12 weeks, 2988 pg/mL) (difference of means, -0.122; 90% CI, -0.32 to 0.07; ratio of geometric means, 0.885, 90% CI, 0.73-1.08; P = .15). The exploratory secondary analysis suggested a dose-response relationship whereby higher vericiguat doses were associated with greater reductions in NT-proBNP level (P < .02). Rates of any adverse event were 77.2% and 71.4% among the placebo and 10-mg vericiguat groups, respectively.
  
  
  CONCLUSIONS
  Among patients with worsening chronic HF and reduced LVEF, compared with placebo, vericiguat did not have a statistically significant effect on change in NT-proBNP level at 12 weeks but was well-tolerated. Further clinical trials of vericiguat based on the dose-response relationship in this study are needed to determine the potential role of this drug for patients with worsening chronic HF.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01951625.
authors.affiliation: Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Mihai
authors.initials: M
authors.lastname: Gheorghiade
authors.affiliation: Division of Cardiology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Greene
authors.affiliation: Division of Cardiology, Stony Brook University, Stony Brook, New York.
authors.forename: Javed
authors.initials: J
authors.lastname: Butler
authors.affiliation: Heart Failure Unit, Department of Cardiology, Athens University Hospital Attikon, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Filippatos
authors.affiliation: Department of Cardiology, National Heart Centre Singapore and Duke, National University of Singapore, Singapore.
authors.forename: Carolyn S P
authors.initials: CS
authors.lastname: Lam
authors.affiliation: Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy.
authors.forename: Aldo P
authors.initials: AP
authors.lastname: Maggioni
authors.affiliation: Department of Heart Diseases, Medical University, Military Hospital, Wroclaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Ponikowski
authors.affiliation: Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors.forename: Sanjiv J
authors.initials: SJ
authors.lastname: Shah
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
authors.affiliation: Department of Internal Medicine and Cardiology, Charité University Medicine Berlin-Campus Virchow Klinikum, Berlin, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kraigher-Krainer
authors.affiliation: Bayer, São Paulo, Brazil.
authors.forename: Eliana T
authors.initials: ET
authors.lastname: Samano
authors.affiliation: Bayer Pharma, Wuppertal, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Müller
authors.affiliation: Bayer Pharma, Wuppertal, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Roessig
authors.affiliation: Department of Internal Medicine and Cardiology, Charité University Medicine Berlin-Campus Virchow Klinikum, Berlin, Germany13Department of Internal Medicine and Cardiology, German Heart Center Berlin, Berlin, Germany.
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002908:Chronic Disease; D005260:Female; D006162:Guanylate Cyclase / Q000187:drug effects*; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy*; D006574:Heterocyclic Compounds, 2-Ring / Q000627:therapeutic use*; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain; D010446:Peptide Fragments; D011743:Pyrimidines / Q000627:therapeutic use*; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000150:complications / Q000188:drug therapy*
chemical_list: D006574:Heterocyclic Compounds, 2-Ring; D010446:Peptide Fragments; D011743:Pyrimidines; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D006162:Guanylate Cyclase; C000603960:vericiguat