FP007EFFICIENCY OF SODIUM ZIRCONIUM CYCLOSILICATE (ZS-9) INCREASES WITH SEVERITY OF HYPERKALAEMIA: SUBGROUP ANALYSIS OF PATIENTS STRATIFIED BY BASELINE POTASSIUM IN THE PHASE 3 HARMONIZE STUDY

Abstract

Introduction and Aims: Hyperkalaemia (potassium [K+] >5.0 mmol/L) is a common electrolyte disorder in patients with heart failure, chronic kidney disease, diabetes, and in those receiving renin-angiotensin-aldosterone system (RAAS) therapies. Sodium zirconium cyclosilicate (ZS-9) is a non-absorbed, selective cation exchanger that traps excess potassium (K+) in the gastrointestinal tract. Acute normalization and maintenance of serum potassium (K+) by ZS-9 has been demonstrated in 2 Phase 3 clinical studies in patients with hyperkalaemia. In the initial Phase 3 study, ZS-9 reduced K+ over 48 hours, independent of starting K+, suggesting a potential mechanism of homeostasis, promoting a return to normokalaemia regardless of disease severity (Packham, NEJM 2014). A second Phase 3 study, HARMONIZE, also reported rapid reduction of serum K+ over a 48-hour period with ZS-9 10g TID dosing (Kosiborod, JAMA 2014). Here we present a subgroup analysis of patients in the HARMONIZE study, stratified by baseline K+ levels (<5.5 mmol/L, 5.5 to <6.0 mmol/L and ≥6.0 mmol/L). Methods: HARMONIZE was a multicenter, randomized, double-blind, placebo-controlled trial designed to evaluate long-term efficacy and safety of ZS-9 in patients with hyperkalaemia (serum K+ ≥5.1 mmol/L). All patients received 10g of ZS-9 three times daily (TID) for 48 hours in the acute open-label phase (N=258). Patients achieving normal K+ (3.5-5.0 mmol/L) were randomized to one of 3 ZS-9 doses (5, 10, 15 g QID) or placebo for 28 days in the maintenance phase. For this subgroup analysis, patients were stratified into subgroups by starting serum K+ (<5.5 mmol/L [n=119]; 5.5 to <6.0 mmol/L [n=100]; ≥6.0 mmol/L [n=39]). Mean potassium levels were collected at 1, 2, 4, 24, and 48 hours from baseline. Results: Baseline K+ was 5.2, 5.7, and 6.3 mmol/L in the <5.5, 5.5 to <6.0, and ≥6.0 mmol/L groups, respectively. Across all time points, the magnitude of reduction in serum K+ was proportional to the severity of hyperkalaemia, with the largest absolute reduction observed in patients with the highest baseline K+. After 48 hours of ZS-9 TID, reduction of serum K+ was -0.8, -1.2, and -1.5 mmol/L for patients in the <5.5, 5.5 to <6.0, and ≥6.0 mmol/L groups, respectively (Figure), resulting in normalization of serum K+ in all subgroups, regardless of starting K+. Conclusions: This subgroup analysis demonstrates ZS-9's ability to normalize serum K + in patients with hyperkalaemia independent of baseline K+ levels. The magnitude of K+ reductions was proportional to the starting baseline K+ levels, suggesting that the efficiency of ZS-9 increases with severity of hyperkalaemia, enabling its use as an acute and chronic therapy.