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Purpose: Potassium binders are frequently utilized for the treatment of hyperkalemia in hospitalized patients; however, there is limited data directly comparing individual agents. The purpose of this study was to compare the effectiveness and safety of sodium polystyrene sulfonate (SPS) and sodium zirconium cyclosilicate (SZC) for hyperkalemia treatment in hospitalized patients., Methods: This retrospective cohort study evaluated adult patients who were admitted within a 7-hospital health system and received SPS or SZC for a serum potassium level greater than 5.0 mEq/L. Patients receiving dialysis prior to SPS/SZC administration, those receiving other potassium-lowering medications within 6 hours prior to blood sampling for a repeat potassium level, and those started on kidney replacement therapy prior to sampling for a repeat potassium level were excluded., Results: Following evaluation of 3,903 patients, the mean reduction in serum potassium 4 to 24 hours after binder administration was 0.96 mEq/L with SPS and 0.78 mEq/L with SZC (P < 0.0001). The median dose of SPS was 30 g (interquartile range [IQR], 15-30 g) while the median (IQR) dose of SZC was 10 g (10-10 g). Resolution of hyperkalemia within 24 hours was achieved in a higher percentage of patients with use of SPS (74.9%) versus SZC (68.8%) (P < 0.001)., Conclusion: One of the largest comparisons of SPS and SZC conducted to date, this study demonstrated the effectiveness and safety of both agents. While a statistically greater reduction in serum potassium was observed with use of SPS, there was significant dosing variability among agents that limited the ability to directly compare specific doses. Further investigation is needed to determine the optimal dose of each agent for acute hyperkalemia management. This data will inform clinical decisions about the choice of potassium binder for acute hyperkalemia., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)