title: Impact of eplerenone on cardiovascular outcomes in heart failure patients with hypokalaemia.
abstract: Although hypokalaemia is common among patients with heart failure (HF), the prognostic significance of baseline hypokalaemia and hypokalaemia during follow-up in HF patients receiving a mineralocorticoid receptor antagonist (MRA) remains uncertain.
  
  
  
  Results of the EMPHASIS-HF trial in patients (n = 2737) with HF and reduced EF with mild symptoms, randomized to eplerenone or placebo, were analysed with regard to the presence or occurrence of hypokalaemia (serum K+<4.0 mmol/L) and the risk of cardiovascular death or hospitalization for HF (primary endpoint). Median follow-up was 21 months. Baseline hypokalaemia and hypokalaemia during follow-up were common occurrences (19.6% and 40.6%, respectively). Hypokalaemia during follow-up was associated with worse outcomes in multivariable analyses [hazard ratio (HR) 1.26, 95% confidence interval (CI) 1.05-1.52, P = 0.01] without evidence of interaction with eplerenone. In contrast, baseline hypokalaemia was associated with outcomes in the placebo group (HR 1.37, 95% CI 1.05-1.79, P = 0.02) but not in the eplerenone group (HR 0.87, 95% CI 0.62-1.23, P = 0.44; P for interaction = 0.04). Concurrently, eplerenone was found to be more protective in patients with baseline hypokalaemia vs. patients without baseline hypokalaemia compared with placebo (HR 0.44, 95% 0.30-0.64, P < 0.0001 vs. 0.69, 95% CI 0.57-0.83, P = 0.0001; P for interaction = 0.04). In patients without baseline hypokalaemia, eplerenone use decreased the rate of hypokalaemia during follow-up (HR 0.69, 95% CI 0.59-0.80, P < 0.001). A potassium level >4.0 mmol/L at 1 month after randomization mediated 26.0% (0.6-51.4%) of the eplerenone treatment effect (P = 0.04).
  
  
  
  In HF patients receiving optimal therapy but not treated with eplerenone, baseline hypokalaemia was associated with worse outcomes. Conversely, hypokalaemia amplified the treatment effect of eplerenone.
authors.affiliation: Inserm, Centre d'Investigations Cliniques-Plurithématique 14-33, and Inserm U1116, Nancy, France.|CHU Nancy, Pôle de Cardiologie, Vandoeuvre lès Nancy, France.|Université de Lorraine, France.|F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Rossignol
authors.affiliation: Inserm, Centre d'Investigations Cliniques-Plurithématique 14-33, and Inserm U1116, Nancy, France.|CHU Nancy, Pôle de Cardiologie, Vandoeuvre lès Nancy, France.|Université de Lorraine, France.|F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Girerd
authors.affiliation: ASH Comprehensive Hypertension Center, The University of Chicago Medicine, Chicago, IL, USA.
authors.forename: George
authors.initials: G
authors.lastname: Bakris
authors.affiliation: University of Wisconsin School of Pharmacy, Madison, WI, USA.
authors.forename: Orly
authors.initials: O
authors.lastname: Vardeny
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Claggett
authors.affiliation: The British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: John J V
authors.initials: JJV
authors.lastname: McMurray
authors.affiliation: Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Swedberg
authors.affiliation: Monash University, Melbourne, VIC, Australia.
authors.forename: Henry
authors.initials: H
authors.lastname: Krum
authors.affiliation: University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.affiliation: Pfizer, NY, USA.
authors.forename: Harry
authors.initials: H
authors.lastname: Shi
authors.affiliation: Pfizer, NY, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Spanyers
authors.affiliation: Pfizer, NY, USA.
authors.forename: John
authors.initials: J
authors.lastname: Vincent
authors.affiliation: Inserm, Centre d'Investigations Cliniques-Plurithématique 14-33, and Inserm U1116, Nancy, France.|CHU Nancy, Pôle de Cardiologie, Vandoeuvre lès Nancy, France.|Université de Lorraine, France.|F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Fay
authors.affiliation: Inserm, Centre d'Investigations Cliniques-Plurithématique 14-33, and Inserm U1116, Nancy, France.|CHU Nancy, Pôle de Cardiologie, Vandoeuvre lès Nancy, France.|Université de Lorraine, France.|F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.
authors.forename: Zohra
authors.initials: Z
authors.lastname: Lamiral
authors.affiliation: Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
authors.affiliation: Inserm, Centre d'Investigations Cliniques-Plurithématique 14-33, and Inserm U1116, Nancy, France.|CHU Nancy, Pôle de Cardiologie, Vandoeuvre lès Nancy, France.|Université de Lorraine, France.|F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.
authors.forename: Faiez
authors.initials: F
authors.lastname: Zannad
authors.affiliation: University of Michigan School of Medicine, Ann Arbor, MI, USA.
authors.forename: Bertram
authors.initials: B
authors.lastname: Pitt
mesh_terms: D004305:Dose-Response Relationship, Drug; D000077545:Eplerenone; D005060:Europe / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D054143:Heart Failure, Systolic / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D006801:Humans; D007008:Hypokalemia / Q000097:blood / Q000188:drug therapy / Q000209:etiology*; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage; D011379:Prognosis; D013148:Spironolactone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015996:Survival Rate / Q000639:trends; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D000077545:Eplerenone
keywords: Eplerenone; Heart failure; Potassium; Prognosis