Sodium Zirconium Cyclosilicate in Hyperkalemia | Journal Scan

Study Questions:

Hyperkalemia (serum potassium level >5.0 mmol/L) is associated with increased mortality among patients with heart failure, chronic kidney disease, or diabetes. Does sodium zirconium cyclosilicate (ZS-9), a novel selective cation exchanger, lower serum potassium levels in patients with hyperkalemia?


In this multicenter, two-stage, double-blind, phase 3 trial, 753 patients with hyperkalemia (5.0-6.5 mmol/L) were randomized to receive either ZS-9 (at a dose of 1.25 g, 2.5 g, 5 g, or 10 g) or placebo three times daily for 48 hours. Patients with normokalemia (serum potassium level, 3.5-4.9 mmol/L) at 48 hours were randomly assigned to receive either ZS-9 or placebo once daily on days 3-14. The primary endpoint was the exponential rate of change in the mean serum potassium level at 48 hours. All concomitant medications were kept constant throughout the study, including diuretics, renin-angiotensin-aldosterone system (RAAS) inhibitors, and antidiabetic therapies, and no dietary restrictions were recommended.


Mean age was 65.6 years, 62% were male, 26% had a mean serum potassium 5.6-6.5 mmol/L, 61% chronic kidney disease, and 64% a RAAS inhibitor. Of the 753 patients, 72% continued to days 3-14, of whom 90% completed day 14. At 48 hours, the mean serum potassium level had decreased from 5.3 mmol/L at baseline to 4.9 mmol/L in the group of patients who received 2.5 g of ZS-9, 4.8 mmol/L in the 5-g group, and 4.6 mmol/L in the 10-g group, for mean reductions of 0.5, 0.5, and 0.7 mmol/L, respectively (p< 0.001 for all comparisons) and to 5.1 mmol/L in the 1.25-g group and the placebo group (mean reduction, 0.3 mmol/L). In patients who received 5 g of ZS-9 and those who received 10 g of ZS-9, serum potassium levels were maintained at 4.7 mmol/L and 4.5 mmol/L, respectively, during days 3-15, as compared with a level of >5.0 mmol/L in the placebo group (p < 0.01 for all comparisons). Rates of adverse events were similar in the ZS-9 group and the placebo group (12.9% and 10.8%, respectively, in the initial phase; 25.1% and 24.5%, respectively, in the maintenance phase). Diarrhea was the most common complication in the two study groups.


Patients with hyperkalemia who received ZS-9, as compared with those who received placebo, had a significant reduction in potassium levels at 48 hours, with normokalemia maintained during 12 days of maintenance therapy.


Patients with severe hyperkalemia (>6.5 mmol/L or electrocardiogram changes) were excluded. Therapies for initial treatment of hyperkalemia (insulin, beta-2 stimulants, and sodium bicarbonate) simply promote translocation of potassium from the extracellular space to the intracellular space, providing temporary benefit, for approximately 1-4 hours. The current mainstay for the acute removal of potassium is the use of nonspecific polymeric exchange resins (sodium or calcium polystyrene sulfonate), which have a poor side-effect profile and unpredictable efficacy. ZS-9 is a potent (9x polystyrene sulfonate) selective potassium trap (125-fold for potassium than calcium) that corrects hyperkalemia in a dose-dependent fashion within 48 hours. Significant decline in potassium was rapid and dose-dependent starting at 2.5 g three times daily.

Clinical Topics: Heart Failure and Cardiomyopathies

Keywords: Hyperkalemia, Zirconium, Sodium, Renal Insufficiency, Chronic, Diabetes Mellitus, Diarrhea, Diuretics, Potassium, Renin-Angiotensin System, Double-Blind Method

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