Management of hyperkalemia in chronic heart failure using sodium zirconium cyclosilicate

Abstract Background Sodium zirconium cyclosilicate (SZC), a newly‐developed selective potassium binder, has been clinically available to treat hyperkalemia. SZC might be a promising option to manage hyperkalemia, particularly in patients with heart failure, who often require potassium‐sparing medications. However, the optimal initial dose of SZC therapy at a loading dose (30 g per day for the initial 2 days) versus a maintenance dose (5 g per day) remains unknown. Methods Consecutive patients with heart failure and hyperkalemia who received 2‐day SZC therapy were retrospectively included. Safety and efficacy of SZC therapy were compared between the two strategies (maintenance versus loading). Results We had 16 patients (76 years old, 11 men) who received 2‐day SZC therapy (4 maintenance dose group and 12 loading dose group). Serum potassium decreased 0.7 mEqL/L by 2‐day maintenance dose therapy and 1.3 mEq/L by 2‐day loading dose therapy. Following 2‐day SZC therapy, 25% of patients had hypokalemia, which was defined as serum potassium <4.0 mEq/L. Baseline lower serum potassium level was associated with the post‐SZC hypokalemia. Conclusions SZC immediately decreases approximately 1.0 mEq/L of serum potassium in patients with heart failure and hyperkalemia. However, caution should be exercised when utilizing SZC at a loading dose specifically in those with mild hyperkalemia to prevent iatrogenic hypokalemia.

2-day therapy. If post-treatment hypokalemia that sometimes triggers cardiac arrhythmia is worried, a maintenance dose with 5 g per day of SZC might be preferred. 4 Appropriate usage of SZC would be essential for the management of hyperkalemia and successful administration and up-titration of renin-angiotensin aldosterone inhibitors and mineralocorticoid receptor antagonists, preventing fatal abnormality in the serum potassium level. In this study, we investigated (1) the actual degree of reduction in serum potassium levels following the 2-day SZC therapy with both loading and maintenance dose in a representative heart failure cohort (efficacy analysis) and (2) factors associating with hypokalemia following the 2-day SZC therapy (safety analysis).

| Patient selection
Consecutive patients with heart failure and hyperkalemia, who received SZC at least for 2 days during the index hospitalization between July 2020 and November 2020, were included in this retrospective study. Definition of heart failure was based on the Framingham criteria. Patients dependent on hemodiafiltration and those receiving sodium polystyrene sulphonate did not receive SZC and were excluded from this study. No patients had mineralocorticoid receptor antagonists given the existence of hyperkalemia.
Serum potassium levels were measured at baseline (day 0) and 2 days later (day 2). Informed consent was obtained from all participants and this study was approved by the institutional ethical board beforehand.

| SZC therapy
In patients with hyperkalemia, SZC was initiated at a loading dose (30 g per day) or as a maintenance dose (5 g per day) for 2 days at the attending physicians' discretion. All other medical therapies were continued without adjustment.

| Data collection
Baseline demographic, laboratory, and medication data obtained within 24 h prior to the SZC administration were collected. Of note, baseline (day 0) and day 2 serum potassium levels were obtained. The change in serum potassium level during the two-day SZC therapy was calculated as a primary endpoint.

| Statistical analyses
Statistical analyses were performed using the SPSS Statistics 22 (SPSS Inc, Armonk, IL). Two-sided p-values <0.05 were considered statistically significant. All variables were assumed as nonparametric data given a small sample size. Changes in serum potassium levels during the two-day SZC therapy were compared between the loading dose group and maintenance dose group using a Mann-Whitney U test as a primary outcome (efficacy analysis). Baseline characteristics were compared between those who suffered hypokalemia (defined as serum potassium level < 4.0 mEq/L) on day 2 and those without hypokalemia on day 2 (safety analysis).  (Figure 1(B)).

| Factors associating with hypokalemia following SZC therapy (safety analysis)
Four out of 16 patients suffered hypokalemia following the 2-day SZC therapy. Of them, two patients had non-sustained ventricular tachycardia.

| DISCUSSION
In this study, we investigated the change in serum potassium level

| Efficacy of SZC
The HARMONIZE phase III double-blind randomized control study demonstrated that a 2-day SZC therapy at a loading dose decreased 1.28 mEq/L of serum potassium level. 3 This study included only 19% of heart failure patients. The efficacy of SZC might differ in heart failure populations due to the presence of therapies which directly modulate potassium absorption and excretion. 1 In this study of patients with heart failure, we confirmed that the average decrease in serum potassium was similar to the HARMONIZE results (À1.3 mEq/L in the loading group). We notably observed a reduced efficacy of the maintenance dose compared to the loading dose. The finding should be useful to determine which strategy (loading or maintenance) to choose as an initial dose considering the target serum potassium level.

| Safety of SZC to avoid hypokalemia
The development of hypokalemia following the SZC initiation remains an apparent risk that requires close monitoring. 3

| Limitations and future directions
This study is a proof of concept and consisted of a small sample size.
We believe these findings are relevant nevertheless in regards to the risk of loading therapy in patients with heart failure and mild hyperkalemia (serum potassium between 5.0 and 5.5 mEq/L). For those with risks of post-SZC hypokalemia, we recommend initiating SZC at a maintenance dose, instead of a loading dose, particularly when hyperkalemia is mild.
We acknowledge the presence of confounding variables in this study which may be better mitigated in a larger prospective analysis.
Our findings should be validated in a larger-scale cohort including comprehensive clinical data. We observed only 2-day SZC therapy, and a long-term study should be conducted. Our patients received potassium-restricting diet and none of them had anorexia. Our findings might not simply be adopted in such cohort.

| CONCLUSION
SZC is a promising therapeutic option that immediately decreases approximately 1.0 mEq/L of serum potassium in patients with heart failure and hyperkalemia. However, caution should be exercised when utilizing SZC at a loading dose specifically in those with mild hyperkalemia. A maintenance dose, instead of loading dose, would be recommended in such a cohort as an initial dose.