title: Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients: results from a phase 3 randomized, double-blind, placebo-controlled trial.
abstract: OBJECTIVE
  Hyperkalaemia in heart failure patients limits use of cardioprotective renin-angiotensin-aldosterone system inhibitors (RAASi). Sodium zirconium cyclosilicate (ZS-9) is a selective potassium ion trap, whose mechanism of action may allow for potassium binding in the upper gastrointestinal tract as early as the duodenum following oral administration. ZS-9 previously demonstrated the ability to reduce elevated potassium levels into the normal range, with a median time of normalization of 2.2 h and sustain normal potassium levels for 28 days in HARMONIZE--a Phase 3, double-blind, randomized, placebo-controlled trial. In the present study we evaluated management of serum potassium with daily ZS-9 over 28 days in heart failure patients from HARMONIZE, including those receiving RAASi therapies.
  
  
  RESULTS
  Heart failure patients with evidence of hyperkalaemia (serum potassium ≥5.1 mmol/L, n = 94) were treated with open-label ZS-9 for 48 h. Patients (n = 87; 60 receiving RAASi) who achieved normokalaemia (potassium 3.5-5.0 mmol/L) were randomized to daily ZS-9 (5, 10, or 15 g) or placebo for 28 days. Mean potassium and proportion of patients maintaining normokalaemia during days 8-29 post-randomization were evaluated. Despite RAASi doses being kept constant, patients on 5 g, 10 g, and 15 g ZS-9 maintained a lower potassium level (4.7 mmol/L, 4.5 mmol/L, and 4.4 mmol/L, respectively) than the placebo group (5.2 mmol/L; P<0.01 vs. each ZS-9 group); greater proportions of ZS-9 patients (83%, 89%, and 92%, respectively) maintained normokalaemia than placebo (40%; P < 0.01 vs. each ZS-9 group). The safety profile was consistent with previously reported overall study population.
  
  
  CONCLUSIONS
  Compared with placebo, all three ZS-9 doses lowered potassium and effectively maintained normokalaemia for 28 days in heart failure patients without adjusting concomitant RAASi, while maintaining a safety profile consistent with the overall study population.
authors.affiliation: Innovative Clinical Trials, Department of Cardiology & Pneumology, University Medical Centre Göttingen (UMG), Robert-Koch-Strasse 40, D-37075, Göttingen, Germany.
authors.forename: Stefan D
authors.initials: SD
authors.lastname: Anker
authors.affiliation: Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, MO, USA.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kosiborod
authors.affiliation: Inserm, Université de Lorraine, Vandoeuvre-Les-Nancy, France.
authors.forename: Faiez
authors.initials: F
authors.lastname: Zannad
authors.affiliation: Albert Einstein COM/Montefiore Medical Center, Bronx, NY, USA.
authors.forename: Ileana L
authors.initials: IL
authors.lastname: Piña
authors.affiliation: Baylor University Medical Center, Baylor Heart and Vascular Institute, Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, TX, and The Heart Hospital, Plano, TX, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: McCullough
authors.affiliation: Athens University Hospital Attikon, Athens, Greece.
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Filippatos
authors.affiliation: University of Groningen, University Medical Centre Groningen, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: van der Meer
authors.affiliation: Wroclaw Medical University, Wrocław, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Ponikowski
authors.affiliation: ZS Pharma, Inc., Coppell, TX, USA.
authors.forename: Henrik S
authors.initials: HS
authors.lastname: Rasmussen
authors.affiliation: Boston Biostatistics Research Foundation, Framingham, MA, USA.
authors.forename: Philip T
authors.initials: PT
authors.lastname: Lavin
authors.affiliation: ZS Pharma, Inc., Coppell, TX, USA.
authors.forename: Bhupinder
authors.initials: B
authors.lastname: Singh
authors.affiliation: ZS Pharma, Inc., Coppell, TX, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Yang
authors.affiliation: University of California San Francisco, CA, USA.
authors.forename: Prakash
authors.initials: P
authors.lastname: Deedwania
mesh_terms: D004311:Double-Blind Method; D006333:Heart Failure / Q000097:blood*; D006801:Humans; D006947:Hyperkalemia / Q000097:blood / Q000188:drug therapy*; D011188:Potassium / Q000097:blood*; D017640:Silicates / Q000627:therapeutic use*
chemical_list: D017640:Silicates; C000597310:sodium zirconium cyclosilicate; D011188:Potassium
keywords: RAAS; ZS-9; heart failure; hyperkalaemia