Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients: results from a phase 3 randomized, double-blind, placebo-controlled trial

Abstract

Aims: Hyperkalaemia in heart failure patients limits use of cardioprotective renin-angiotensin-aldosterone system inhibitors (RAASi). Sodium zirconium cyclosilicate (ZS-9) is a selective potassium ion trap, whose mechanism of action may allow for potassium binding in the upper gastrointestinal tract as early as the duodenum following oral administration. ZS-9 previously demonstrated the ability to reduce elevated potassium levels into the normal range, with a median time of normalization of 2.2 h and sustain normal potassium levels for 28 days in HARMONIZE--a Phase 3, double-blind, randomized, placebo-controlled trial. In the present study we evaluated management of serum potassium with daily ZS-9 over 28 days in heart failure patients from HARMONIZE, including those receiving RAASi therapies.

Methods and results: Heart failure patients with evidence of hyperkalaemia (serum potassium ≥5.1 mmol/L, n = 94) were treated with open-label ZS-9 for 48 h. Patients (n = 87; 60 receiving RAASi) who achieved normokalaemia (potassium 3.5-5.0 mmol/L) were randomized to daily ZS-9 (5, 10, or 15 g) or placebo for 28 days. Mean potassium and proportion of patients maintaining normokalaemia during days 8-29 post-randomization were evaluated. Despite RAASi doses being kept constant, patients on 5 g, 10 g, and 15 g ZS-9 maintained a lower potassium level (4.7 mmol/L, 4.5 mmol/L, and 4.4 mmol/L, respectively) than the placebo group (5.2 mmol/L; P<0.01 vs. each ZS-9 group); greater proportions of ZS-9 patients (83%, 89%, and 92%, respectively) maintained normokalaemia than placebo (40%; P < 0.01 vs. each ZS-9 group). The safety profile was consistent with previously reported overall study population.

Conclusion: Compared with placebo, all three ZS-9 doses lowered potassium and effectively maintained normokalaemia for 28 days in heart failure patients without adjusting concomitant RAASi, while maintaining a safety profile consistent with the overall study population.

Keywords: RAAS; ZS-9; heart failure; hyperkalaemia.

Figure 1

Study design overview. Patients with hyperkalaemia and a history of heart failure (HF) in the Hyperkalaemia Randomized Intervention Multidose ZS‐9 Maintenance (HARMONIZE) study received ZS‐9 10 g during the 48‐h open‐label phase. Those who achieved normokalaemia were randomized to placebo (randomized withdrawal) or ZS‐9 (5 g, 10 g, or 15 g) for 28 days.

Figure 2

Mean serum potassium over time in patients treated with ZS‐9 10 g three times daily (circles) for 48 h during the open‐label phase. The shaded portion represents normal potassium levels. Bars indicate 95% confidence intervals. Triangles indicate administration of ZS‐9 dose. *P < 0.001 for comparisons against placebo.

Figure 3

Mean serum potassium, days 8–29 after randomization, placebo vs. ZS‐9 5 g, 10 g, and 15 g dose groups. Mean baseline serum potassium values before and after 48 h of ZS‐9 treatment are shown below the graph for each dose group. The shaded portion represents normal potassium levels. Bars indicate 95% confidence interval. *P < 0.001 for comparisons against placebo.

Figure 4

Mean serum potassium over time for the duration of the study (circles): (A) placebo (n = 25), (B) ZS‐9 5 g dose group (n = 18), (C) ZS‐9 10 g dose group (n = 18), and (D) ZS‐9 15 g dose group (n = 24). Triangles indicate administration of ZS‐9 dose or placebo. The shaded portion represents normal potassium levels. Bars indicate 95% confidence intervals. *P < 0.05 for comparisons against placebo.