PP.35.03

Abstract

Objective: Inhibitors of the renin-angiotensin-aldosterone system (RAAS) increase the risk of hyperkalaemia (serum K+ >5.0 mmol/L). This often leads to suboptimal dosing or RAASi treatment discontinuation, despite proven benefit in hypertensive and chronic kidney disease (CKD) patients. Sodium zirconium cyclosilicate (ZS-9) is a non-absorbed cation exchanger specifically designed to trap excess K+ in the gastrointestinal (GI) tract. ZS-9 rapidly controlled normal serum K+ in 2 Phase 3 trials (Packham, NEJM 2014; Kosiborod, JAMA 2014). Here we present results from a pre-specified analysis of patients from the Phase 3 HARMONIZE study who were receiving RAASi. Design and method: HARMONIZE was a multicenter, randomised, double-blind, placebo-controlled trial designed to evaluate efficacy and safety of ZS-9 in patients with hyperkalaemia. All patients received 10 g of ZS-9 thrice daily (TID) for 48 hours (open-label phase). Patients achieving normal K+ (3.5–5.0 mEq/L) were randomised to one of 3 ZS-9 doses (5 g, 10 g, or 15 g QID) or placebo for 28 days (randomised phase). Per protocol, RAASi dose was unchanged for the duration of the study. Results: Among 258 enrolled patients, the median age was 65 years, 36% had heart failure, 69% had eGFR<60 mL/min/1.73m2, 66% had diabetes and 70% were receiving RAASi at baseline. During the open-label phase in the overall population, mean K+ declined from 5.6 to 4.5 mmol/L following ZS-9 10 g TID, with 83% and 98% of patients showing normalized K+ by 24 h and 48 h, respectively. During the randomised phase in the RAASi subgroup, patients in the 5 g, 10 g, and 15 g ZS-9 groups maintained serum K+ at 4.8, 4.6, and 4.4 mmol/L, respectively, compared with 5.1 mmol/L in the placebo group (P < 0.05 across all ZS-9 groups; Figure). Overall, ZS-9 was well tolerated, with a GI adverse event profile similar to that of placebo.Conclusions: In patients on RAASi, ZS-9 led to rapid and sustained reduction of serum K+ and was well tolerated. The results of this prospective analysis of the 3rd randomised, placebo-controlled study of ZS-9 provide further evidence that ZS-9 may enable continued optimal use of cardiorenal protective and life-saving RAASi therapies in patients with hyperkalaemia.