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Sodium zirconium cyclosilicate (zs-9) for hyperkalaemia treatment: efficacy and tolerability in heart failure patients on renin-angiotensin-aldosterone system inhibitors (raasi) from a phase 3 study

Session Poster session 4

Speaker Stefan Anker

Event : ESC Congress 2015

  • Topic : heart failure
  • Sub-topic : Chronic Heart Failure - Other
  • Session type : Poster Session

Authors : SD Anker (Göttingen,DE), A Mebazaa (Paris,FR), F Zannad (Vandoeuvre-Les-Nancy,FR), HS Rasmussen (Coppell, TX,US), PT Lavin (Framingham, MA,US), S Bhupinder (Coppell, TX,US), A Yang (Coppell, TX,US), M Kosiborod (Kansas City,US)

Authors:
S.D. Anker1 , A. Mebazaa2 , F. Zannad3 , H.S. Rasmussen4 , P.T. Lavin5 , S. Bhupinder4 , A. Yang4 , M. Kosiborod6 , 1University Medicine Göttingen - Göttingen - Germany , 2University Paris Diderot - Paris - France , 3Inserm, Université de Lorraine - Vandoeuvre-Les-Nancy - France , 4ZS Pharma, Inc. - Coppell, TX - United States of America , 5Boston Biostatistics Research Foundation - Framingham, MA - United States of America , 6St. Luke's Mid America Heart Institute - Kansas City - United States of America ,

Citation:
European Heart Journal ( 2015 ) 36 ( Abstract Supplement ), 673

Background: Renin-angiotensin-aldosterone system inhibitors (RAASi) increase risk of hyperkalaemia (HK; serum K+ >5.0 mmol/L), often leading to suboptimal dosing or discontinuation of these agents, despite proven cardioprotective benefits in heart failure (HF) patients (pts). Sodium zirconium cyclosilicate (ZS-9) is a first-in-class, highly selective, non-absorbed cation exchanger designed to trap K+ in the GI tract. In the Phase 3 HARMONIZE trial, ZS-9 rapidly achieved and maintained normal serum K+ for 28 days in HK pts.

Purpose: This pre-specified analysis from HARMONIZE was to examine efficacy/tolerability of ZS-9 in HF pts on RAASi.

Methods: HARMONIZE was a multicenter, randomized, double-blind, placebo (PBO)-controlled trial which evaluated efficacy and safety of ZS-9 in pts with HK (N=258). All pts received ZS-9 10g TID for 48h (open-label phase). Pts achieving normal K+ (3.5–5.0 mmol/L) were randomized to ZS-9 (5, 10, or 15g QID) or PBO for 28 days (randomized phase). Per protocol, RAASi therapy was maintained.

Results: In HF pts on RAASi (n=65), median age was 69; 79% had eGFR<60. Within 48h, mean K+ declined from 5.6 to 4.4 mmol/L, with a median time to normalization of 2.0h; 91% and 98% of pts achieved normal K+ by 24h and 48h, respectively. During the randomized phase, pts in the 5, 10, and 15g ZS-9 groups maintained significantly lower K+ at 4.6, 4.5, and 4.5 mmol/L, respectively, vs. 5.3 mmol/L in the PBO group (P<0.05 for all doses; Figure). ZS-9 was well tolerated with GI adverse events similar to PBO.

Conclusions: ZS-9 rapidly normalized K+ within hours of the first dose, maintained normal K+ for up to 28 days, and was well tolerated in HF pts on RAASi. These results suggest that ZS-9 may enable optimization of cardioprotective RAASi therapy in high-risk pts with HF and HK.

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