title: Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study.
abstract: To determine tolerability and the optimal dose regimen of the soluble guanylate cyclase stimulator vericiguat in patients with chronic heart failure and preserved ejection fraction (HFpEF).
  
  
  
  SOCRATES-PRESERVED was a prospective, randomized, placebo-controlled double-blind, Phase 2b dose-finding study in patients with HFpEF (ejection fraction ≥ 45%). Patients received vericiguat once daily at 1.25 or 2.5 mg fixed doses, or 5 or 10 mg titrated from a 2.5 mg starting dose, or placebo for 12 weeks. The two primary endpoints were change from baseline in log-transformed N-terminal pro-B-type natriuretic peptide (NT-ProBNP) and left atrial volume (LAV) at 12 weeks. Patients (N = 477; 48% women; mean age 73 ± 10 years; baseline atrial fibrillation 40%) were randomized within 4 weeks of HF hospitalization (75%) or outpatient treatment with intravenous diuretics for HF (25%) to vericiguat (n = 384) or placebo (n = 93). In the pooled three highest dose arms change in logNT-proBNP (vericiguat: +0.038 ± 0.782 log(pg/mL), n = 195; placebo: -0.098 ± 0.778 log(pg/mL), n = 73; one-sided P = 0.8991, two-sided P = 0.2017), and change in LAV [vericiguat: -1.7 ± 12.8 mL (n = 194); placebo:  -3.4 ± 12.7 mL (n = 67), one-sided P = 0.8156, two-sided P = 0.3688] were not different from placebo. Vericiguat was well tolerated (adverse events: vericiguat 10 mg arm, 69.8%; placebo, 73.1%), with low discontinuation rates in all groups, and no changes in blood pressure at 10 mg compared with placebo. The pre-specified exploratory endpoint of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score improved in the vericiguat 10 mg arm by mean 19.3 ± 16.3 points [median 19.8 (interquartile range 10.4-30.7)] from baseline (mean difference from placebo 9.2 points).
  
  
  
  Vericiguat was well tolerated, did not change NT-proBNP and LAV at 12 weeks compared with placebo but was associated with improvements in quality of life in patients with HFpEF. Given the encouraging results on quality of life, the effects of vericiguat in patients with HFpEF warrant further study, possibly with higher doses, longer follow-up and additional endpoints.
authors.affiliation: Charité Universitätsmedizin, Department of Internal Medicine and Cardiology, Charité University Medicine, Augustenburgerplatz 1, 13353 Berlin, Germany, and Department of Internal Medicine Cardiology, German Heart Center Berlin, DZHK (German Center for Cardiovascular Research) and Berlin Institute of Health (BIH).
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
authors.affiliation: Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Via La Marmora 36, 50121 Firenze, Italy.
authors.forename: Aldo P
authors.initials: AP
authors.lastname: Maggioni
authors.affiliation: National Heart Centre Singapore and Duke-NUS Graduate Medical School, 5, Hospital Drive, Singapore 169609, Singapore.
authors.forename: Carolyn S P
authors.initials: CSP
authors.lastname: Lam
authors.affiliation: Department of Internal Medicine and Cardiology, Charité University Medicine, Augustenburgerplatz 1, 13353 Berlin, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Pieske-Kraigher
authors.affiliation: National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital, Rimini 1, 12462, Athens, Greece.
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Filippatos
authors.affiliation: Division of Cardiology, Stony Brook University, 101 Nicolls Road, Stony Brook, NY 11794, USA.
authors.forename: Javed
authors.initials: J
authors.lastname: Butler
authors.affiliation: Wroclaw Medical University, 4th Military Hospital, Weigla 5, Wroclaw 50-981, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Ponikowski
authors.affiliation: Northwestern University, 676 N. St. Clair St., Suite 600, Chicago, IL 60611, USA.
authors.forename: Sanjiv J
authors.initials: SJ
authors.lastname: Shah
authors.affiliation: Brigham and Women's Hospital, Cardiovascular Division, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
authors.affiliation: Bayer AG, Aprather Weg 18, 42113 Wuppertal, Germany.
authors.forename: Andrea-Viviana
authors.initials: AV
authors.lastname: Scalise
authors.affiliation: Bayer AG, Aprather Weg 18, 42113 Wuppertal, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Mueller
authors.affiliation: Bayer AG, Aprather Weg 18, 42113 Wuppertal, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Roessig
authors.affiliation: Northwestern University Feinberg School of Medicine, 201 East Huron Street Galter 3-150, Chicago, IL 60601, USA.
authors.forename: Mihai
authors.initials: M
authors.lastname: Gheorghiade
mesh_terms: D000368:Aged; D016279:Atrial Function, Left / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D008297:Male; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011446:Prospective Studies; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D000071756:Soluble Guanylyl Cyclase / Q000008:administration & dosage* / Q000009:adverse effects; D013318:Stroke Volume / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D002316:Cardiotonic Agents; D006574:Heterocyclic Compounds, 2-Ring; D010446:Peptide Fragments; D011743:Pyrimidines; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D000071756:Soluble Guanylyl Cyclase; C000603960:vericiguat
keywords: Heart failure with preserved ejection fraction; Soluble guanylate cyclase stimulator; Vericiguat