Research Article: Emergency Potassium Normalization Treatment Including Sodium Zirconium Cyclosilicate: A Phase II, Randomized, Double‐blind, Placebo‐controlled Study (ENERGIZE)

Date Published: March 28, 2020

Publisher: John Wiley and Sons Inc.

Author(s): W. Frank Peacock, Zubaid Rafique, Konstantin Vishnevskiy, Edward Michelson, Elena Vishneva, Tatiana Zvereva, Rajaa Nahra, Dao Li, Joseph Miller, Kennon J. Heard.


Sodium zirconium cyclosilicate (SZC) is a novel, highly selective potassium binder currently approved in the United States and European Union for treatment of hyperkalemia. This pilot evaluation explored the efficacy of SZC with insulin and glucose as hyperkalemia treatment in the emergency department (ED).

This exploratory, phase II, multicenter, randomized, double‐blind, placebo‐controlled study (NCT03337477) enrolled adult ED patients with blood potassium ≥ 5.8 mmol/L. Patients were randomized 1:1 to receive SZC 10 g or placebo, up to three times during a 10‐hour period, with insulin and glucose. The primary efficacy outcome was the mean change in serum potassium (sK+) from baseline until 4 hours after start of dosing.

Overall, 70 patients were randomized (SZC n = 33, placebo n = 37), of whom 50.0% were male. Their mean (± standard deviation [±SD]) age was 59.0 (±13.8) years and mean initial sK+ was similar between groups (SZC 6.4 mmol/L, placebo 6.5 mmol/L). The least squares mean (±SD) sK+ change from baseline to 4 hours was –0.41 (±0.11) mmol/L and –0.27 (±0.10) mmol/L with SZC and placebo, respectively (difference = –0.13 mmol/L, 95% confidence interval [CI] = –0.44 to 0.17). A greater reduction in mean (±SD) sK+ from baseline occurred with SZC compared with placebo at 2 hours: –0.72 (±0.12) versus –0.36 (±0.11) mmol/L (LSM difference = –0.35 mmol/L, 95% CI = –0.68 to –0.02), respectively. A numerically lower proportion of patients in the SZC group required additional potassium‐lowering therapy due to hyperkalemia at 0 to 4 hours versus placebo (15.6% vs. 30.6%, respectively; odds ratio = 0.40, 95% CI = 0.09 to 1.77). Comparable proportions of patients experienced adverse events in both treatment groups at 0 to 24 hours.

This pilot study suggested that SZC with insulin and glucose may provide an incremental benefit in the emergency treatment of hyperkalemia over insulin and glucose alone.

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Although the study planned to randomize 132 patients to enable adequate statistical power according to sample size calculations, a total of 126 were screened and enrolled and only 70 were randomized: 33 to SZC and 37 to placebo (Figure 1). Of these, 87.9% (29/33) and 89.2% (33/37) of patients in the SZC and placebo groups, respectively, received treatment. Of the 56 patients who were enrolled but not randomized, 55 were not randomized due to screening failures; most of these patients did not meet the inclusion criteria of whole blood potassium ≥5.8 mmol/L.

To our knowledge, the phase II ENERGIZE study is the first of its kind to evaluate the efficacy of SZC, a novel and highly selective potassium binder, in the emergency treatment of hyperkalemia. This pilot study was based on a patient population requiring emergency treatment for hyperkalemia, for whom achievement of normokalemia in a relatively short period of time is important to reduce the risk of adverse cardiac events and mortality.

The ENERGIZE study has several limitations. As a pilot study, the total number of patients enrolled was limited. Given these small patient numbers and the assessment of multiple secondary outcomes, it is plausible that differences in at least one outcome may have been driven by chance. Furthermore, enrollment in all ED hyperkalemia studies is complicated by the unpredictable availability of dialysis, which would be unethical to withhold. This resulted in the loss of about one‐third of enrolled patients and their blood draw assessments, despite being administered the first dose of study drug, as they subsequently received dialysis. Approximately half of patients were missing central laboratory potassium measurements at 4 hours, for whom i‐STAT data were used. i‐STAT data were adjusted in these patients to correct for the difference between i‐STAT and central laboratory measurements to remove potential bias from this substitution. Data were imputed for patients who were missing both central laboratory and i‐STAT measurements at 4 hours. This may have introduced some bias; however, given the comparable results of the nonmissing i‐STAT data sensitivity analysis with the main analysis, it is unlikely that data imputation for patients with missing values introduced substantial bias in the effect estimate.

Sodium zirconium cyclosilicate in combination with insulin and glucose was well tolerated. Although the reduction of sK+ at 4 hours was similar in the sodium zirconium cyclosilicate and placebo groups, there were signals indicative of incremental benefit of sodium zirconium cyclosilicate when used in addition to insulin and glucose for the emergency treatment of hyperkalemia. However, the study faced challenges with small sample size, high withdrawal rate, and missing data, which preclude any firm conclusions. Additional research is required to elucidate the clinical utility of sodium zirconium cyclosilicate in the emergency treatment of hyperkalemia.

Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing policy described at




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