FP003ACHIEVEMENT AND MAINTENANCE OF NORMOKALAEMIA IN PATIENTS WITH NON-DIALYSIS STAGE 5 CHRONIC KIDNEY DISEASE

Abstract

Introduction and Aims: Hyperkalaemia (potassium [K+] >5.0 mmol/L) is a common electrolyte disorder in patients with heart failure, chronic kidney disease (CKD), and diabetes. It is associated with an increased risk for mortality, and it limits the use of renin‐angiotensin‐aldosterone system (RAAS) therapies. End stage renal disease (Stage 5 CKD) patients are at especially high risk for hyperkalaemia and are difficult to treat as they prepare for dialysis. Sodium zirconium cyclosilicate (ZS‐9) is a non‐absorbed, cation exchanger that selectively traps excess K+ in the gastrointestinal tract and has demonstrated efficacy and safety in three prospective randomized placebo‐controlled trials (Ash, KI 2015; Packham, NEJM 2014; Kosiborod, JAMA 2014). In the Phase 3 HARMONIZE study, treatment of hyperkalaemic patients with ZS‐9 resulted in acute reduction of serum K+ within 48 hours, followed by maintenance of normokalaemia for 28 days (Kosiborod, JAMA 2014). Here we present a prospective prespecified analysis of patients with non‐dialysis Stage 5 CKD (eGFR <15 mL/min/1.73m2) from the HARMONIZE study. 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 3 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 daily) or placebo for 28 days in the maintenance phase. The primary endpoint was mean K+ in each ZS‐9 dose vs placebo during days 8‐29 of the maintenance. For this analysis, patients with non‐dialysis Stage 5 CKD were evaluated. Results: Of 258 patients, 32 (12.4%) had baseline eGFR<15. Mean baseline K+ was 5.8 mmol/L. Significant reductions in serum K+ (‐0.2, ‐0.4, ‐0.4, ‐0.7, and ‐1.3 mmol/L) were observed at 1, 2, 4, 24, and 48 hours, respectively (P<0.001; Figure, panel A). The proportion of patients achieving normokalaemia (K+ 3.5‐5.0 mmol/L) was 58% by 24 hours and 87% by 48 hours. In the extended phase, mean K+ over Days 8‐29 were maintained at 4.9, 4.5, and 4.1 for ZS‐9 5g (n=6), 10g (n=8), and 15g (n=8), respectively, compared with 5.4 mmol/L for placebo (Figure, panel B). ZS‐9 was generally well tolerated with a low rate of adverse events. Conclusions: ZS‐9 rapidly restored and maintained normokalaemia for up to 28 days in patients with non‐dialysis Stage 5 CKD. These data suggest that ZS‐9 may fulfill an unmet clinical need in this population of patients at especially high risk of hyperkalaemia and address one of the indications for the start of dialysis.