ACHIEVEMENT OF NORMOKALEMIA IN HEART FAILURE PATIENTS NOT ON RENIN:ANGIOTENSIN:ALDOSTERONE SYSTEM INHIBITORS: POOLED ANALYSIS FROM TWO PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE:BLIND, PLACEBO:CONTROLLED TRIALS OF SODIUM ZIRCONIUM CYCLOSILICATE FOR TREATMENT OF HYPERKALEMIA

Abstract Background: Reliable, rapidly-acting, oral treatments for patients with hyperkalemia are needed. We examined the efficacy and safety of sodium zirconium cyclosilicate (SZC; formerly ZS-9) treatment for ≤48 hours in patients with baseline serum potassium level ≥5.5 mmol/L. Methods: Data were pooled from two phase 3 studies (ZS-003 and HARMONIZE) among patients receiving SZC 10 g three times daily. Outcomes included mean and absolute change from baseline, median time to potassium level ≤5.5 and ≤5.0 mmol/L, and proportion achieving potassium level ≤5.5 and ≤5.0 mmol/L at 4, 24, and 48 hours. Outcomes were stratified by baseline potassium. Safety outcomes were evaluated. Results: At baseline, 125 of 170 patients (73.5%) had potassium level 5.5–<6.0, 39 (22.9%) had potassium level 6.0–6.5, and 6 (3.5%) had potassium level >6.5 mmol/L. Regardless of baseline potassium, mean potassium decreased at 1-hour post-initial dose. By 4 and 48 hours, 37.5% and 85.0% of patients achieved potassium level ≤5.0 mmol/L, respectively. Median (95% confidence interval) times to potassium level ≤5.5 and ≤5.0 mmol/L were 2.0 (1.1–2.0) and 21.6 (4.1–22.4) hours, respectively. Fifteen patients (8.8%) experienced adverse events; none were serious. Conclusions: SZC 10 g three times daily achieved rapid potassium reduction and normokalemia, with a favorable safety profile. ClinicalTrials.gov identifiers: NCT01737697 and NCT02088073

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Efficacy and safety of sodium zirconium cyclosilicate in patients with baseline serum potassium level ≥5.5 mmol/L: pooled analysis from two phase 3 trials

10.21203/rs.2.10962/v2 ◽

2019 ◽

Author(s):

Alpesh N. Amin ◽

Jose Menoyo ◽

Bhupinder Singh ◽

Christopher S. Kim

Keyword(s):

Serum Potassium ◽

Safety Profile ◽

Potassium Level ◽

Serum Potassium Level ◽

Efficacy And Safety ◽

Phase 3 ◽

Two Phase ◽

Baseline Serum ◽

Sodium Zirconium ◽

Sodium Zirconium Cyclosilicate

Abstract Background: Reliable, timely-onset, oral treatments with an acceptable safety profile for patients with hyperkalemia are needed. We examined the efficacy and safety of sodium zirconium cyclosilicate (SZC; formerly ZS-9) treatment for ≤48 hours in patients with baseline serum potassium level ≥5.5 mmol/L. Methods: Data were pooled from two phase 3 studies (ZS-003 and HARMONIZE) among patients receiving SZC 10 g three times daily. Outcomes included mean and absolute change from baseline, median time to potassium level ≤5.5 and ≤5.0 mmol/L, and proportion achieving potassium level ≤5.5 and ≤5.0 mmol/L at 4, 24, and 48 hours. Outcomes were stratified by baseline potassium. Safety outcomes were evaluated. Results: At baseline, 125 of 170 patients (73.5%) had potassium level 5.5–<6.0, 39 (22.9%) had potassium level 6.0–6.5, and 6 (3.5%) had potassium level >6.5 mmol/L. Regardless of baseline potassium, mean potassium decreased at 1-hour post-initial dose. By 4 and 48 hours, 37.5% and 85.0% of patients achieved potassium level ≤5.0 mmol/L, respectively. Median (95% confidence interval) times to potassium level ≤5.5 and ≤5.0 mmol/L were 2.0 (1.1–2.0) and 21.6 (4.1–22.4) hours, respectively. Fifteen patients (8.8%) experienced adverse events; none were serious. Conclusions: SZC 10 g three times daily achieved serum potassium reduction and normokalemia, with a favorable safety profile. ClinicalTrials.gov identifiers: NCT01737697 and NCT02088073

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Efficacy and safety of sodium zirconium cyclosilicate in patients with baseline serum potassium level ≥ 5.5 mmol/L: pooled analysis from two phase 3 trials

BMC Nephrology ◽

10.1186/s12882-019-1611-8 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 3

Author(s):

Alpesh N. Amin ◽

Jose Menoyo ◽

Bhupinder Singh ◽

Christopher S. Kim

Keyword(s):

Serum Potassium ◽

Safety Profile ◽

Potassium Level ◽

Serum Potassium Level ◽

Efficacy And Safety ◽

Phase 3 ◽

Two Phase ◽

Baseline Serum ◽

Sodium Zirconium ◽

Sodium Zirconium Cyclosilicate

Abstract Background Reliable, timely-onset, oral treatments with an acceptable safety profile for patients with hyperkalemia are needed. We examined the efficacy and safety of sodium zirconium cyclosilicate (SZC; formerly ZS-9) treatment for ≤ 48 h in patients with baseline serum potassium level ≥ 5.5 mmol/L. Methods Data were pooled from two phase 3 studies (ZS-003 and HARMONIZE) among patients receiving SZC 10 g three times daily. Outcomes included mean and absolute change from baseline, median time to potassium level ≤ 5.5 and ≤ 5.0 mmol/L, and proportion achieving potassium level ≤ 5.5 and ≤ 5.0 mmol/L at 4, 24, and 48 h. Outcomes were stratified by baseline potassium. Safety outcomes were evaluated. Results At baseline, 125 of 170 patients (73.5%) had potassium level 5.5–< 6.0, 39 (22.9%) had potassium level 6.0–6.5, and 6 (3.5%) had potassium level > 6.5 mmol/L. Regardless of baseline potassium, mean potassium decreased at 1 h post-initial dose. By 4 and 48 h, 37.5% and 85.0% of patients achieved potassium level ≤ 5.0 mmol/L, respectively. Median (95% confidence interval) times to potassium level ≤ 5.5 and ≤ 5.0 mmol/L were 2.0 (1.1–2.0) and 21.6 (4.1–22.4) h, respectively. Fifteen patients (8.8%) experienced adverse events; none were serious. Conclusions SZC 10 g three times daily achieved serum potassium reduction and normokalemia, with a favorable safety profile. Trial registration ClinicalTrials.gov identifiers: ZS-003: NCT01737697 and HARMONIZE: NCT02088073.

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Abstract 13555: Acute Efficacy of Sodium Zirconium Cyclosilicate (ZS-9) in Patients on Mineralocorticoid-Receptor Antagonists: Analysis From Two Phase 3 Studies

Circulation ◽

10.1161/circ.132.suppl_3.13555 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Mikhail Kosiborod ◽

Peter A McCullough ◽

Henrik Rasmussen ◽

Bhupinder Singh ◽

Philip T Lavin ◽

...

Keyword(s):

Mineralocorticoid Receptor ◽

Ion Trap ◽

Adverse Event Rate ◽

Mineralocorticoid Receptor Antagonists ◽

Receptor Antagonists ◽

Phase 3 ◽

Two Phase ◽

Pooled Data ◽

Sodium Zirconium ◽

Sodium Zirconium Cyclosilicate

Introduction: Although mineralocorticoid-receptor antagonists (MRAs) are strongly recommended by guidelines for chronic management of patients with heart failure (HF), less than 1/3 of eligible patients receive these cardio-protective medications due to the risk of hyperkalemia (hyperK; potassium [K+] ≥5.1 mEq/L). Sodium zirconium cyclosilicate (ZS-9) is a highly selective K+ ion trap that binds K+ throughout the GI tract. We examined the effectiveness of ZS-9 in treating hyperK in patients receiving MRAs using pooled data from 2 recently completed Phase 3 clinical trials. Methods: Data were pooled from 2 Phase 3 trials of patients with hyperK: ZS003 (N=753) and HARMONIZE (N=258). In both trials, patients receiving MRAs at baseline, and treated with 10 g, three times daily (TID), ZS-9 for 48 hrs were selected. Per protocol, MRA doses remained stable for the duration of the study. We examined absolute change in K+ from baseline, proportion of patients who achieved normokalemia by 24 and 48 hrs, and time to K+ normalization. Results: Across studies, 19 patients were on MRAs (age 73y; 74% HF; 90% eGFR <60; 74% diabetes mellitus). Mean baseline K+ was 5.7 mEq/L. ZS-9 significantly reduced K+ during 48 hrs after treatment initiation (Figure): by 0.3, 0.5, 0.5, 0.7 and 1.1 mEq/L at 1, 2, 4, 24 and 48 hrs, respectively (P<0.005 for each time point vs. baseline). Normokalemia was achieved in 84% and 95% of patients by 24 and 48 hours, respectively. Median time to K+ normalization was 3.8 hrs. During the initial 48 hrs of treatment of the overall population treated with 10 g ZS-9, the adverse event rate was 9% compared to 11% among patients who received placebo. Conclusions: In patients with hyperK while on MRA therapy, ZS-9 rapidly lowered K+ to normal range, with 95% of patients achieving normokalemia by 48 hrs. If confirmed in future studies, these results suggest that ZS-9 may enable optimization of cardio-protective MRA therapy in HF patients with or at high risk for hyperK.

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