title: Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.
abstract: OBJECTIVE
  Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced left ventricular ejection fraction (HFrEF), but their use is limited by hyperkalaemia and/or worsening renal function (WRF). BAY 94-8862 is a highly selective and strongly potent non-steroidal MRA. We investigated its safety and tolerability in patients with HFrEF associated with mild or moderate chronic kidney disease (CKD).
  
  
  RESULTS
  This randomized, controlled, phase II trial consisted of two parts. In part A, the safety and tolerability of oral BAY 94-8862 [2.5, 5, or 10 mg once daily (q.d.)] was assessed in 65 patients with HFrEF and mild CKD. In part B, BAY 94-8862 (2.5, 5, or 10 mg q.d., or 5 mg twice daily) was compared with placebo and open-label spironolactone (25 or 50 mg/day) in 392 patients with HFrEF and moderate CKD. BAY 94-8862 was associated with significantly smaller mean increases in serum potassium concentration than spironolactone (0.04-0.30 and 0.45 mmol/L, respectively, P < 0.0001-0.0107) and lower incidences of hyperkalaemia (5.3 and 12.7%, respectively, P = 0.048) and WRF. BAY 94-8862 decreased the levels of B-type natriuretic peptide (BNP), amino-terminal proBNP, and albuminuria at least as much as spironolactone. Adverse events related to BAY 94-8862 were infrequent and mostly mild.
  
  
  CONCLUSIONS
  In patients with HFrEF and moderate CKD, BAY 94-8862 5-10 mg/day was at least as effective as spironolactone 25 or 50 mg/day in decreasing biomarkers of haemodynamic stress, but it was associated with lower incidences of hyperkalaemia and WRF.
authors.affiliation: University of Michigan School of Medicine, Ann Arbor, MI, USA. bpitt@med.umich.edu
authors.forename: Bertram
authors.initials: B
authors.lastname: Pitt
authors.forename: Lars
authors.initials: L
authors.lastname: Kober
authors.forename: Piotr
authors.initials: P
authors.lastname: Ponikowski
authors.forename: Mihai
authors.initials: M
authors.lastname: Gheorghiade
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Filippatos
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
authors.forename: Christina
authors.initials: C
authors.lastname: Nowack
authors.forename: Peter
authors.initials: P
authors.lastname: Kolkhof
authors.forename: So-Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Faiez
authors.initials: F
authors.lastname: Zannad
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000419:Albuminuria / Q000209:etiology; D000450:Aldosterone / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D059347:Cardio-Renal Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D003404:Creatinine / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology; D006801:Humans; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects*; D009287:Naphthyridines / Q000008:administration & dosage / Q000009:adverse effects*; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011188:Potassium / Q000097:blood
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D009287:Naphthyridines; D010446:Peptide Fragments; C576501:finerenone; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D000450:Aldosterone; D003404:Creatinine; D011188:Potassium
keywords: Aldosterone; Antagonist; Chronic kidney disease; Heart failure; Mineralocorticoid receptor