Sodium Zirconium Cyclosilicate among Individuals with Hyperkalemia A 12-Month Phase 3 Study

Background and objectivesOral sodiumzirconiumcyclosilicate (formerly ZS-9) binds and removes potassiumvia the gastrointestinal tract. Sodium zirconium cyclosilicate-associated restoration and maintenance of normokalemia and adverse events were evaluated in a two-part, open label, phase 3 trial. Design, setting, participants, & measurements In the correction phase, adult outpatients with plasma potassium $ 5.1 mmol/L (i-STAT Point-of-Care) received sodium zirconium cyclosilicate 10 g three times daily for 24-72 hours until normokalemic (potassium = 3.5-5.0 mmol/L). Qualifying participants entered the # 12-month maintenance phase and received sodium zirconium cyclosilicate 5 g once daily titrated to maintain normokalemia without dietary or medication restrictions. Prespecified primary end points were restoration of normal serum potassiumvalues (3.5-5.0mmol/L) during the correction phase andmaintenance of serumpotassium# 5.1mmol/L during the maintenance phase. Adverse events were assessed throughout. Results Of 751 participants, 746 (99%) achieved normokalemia during the correction phase (mean serum potassium = 4.8 mmol/L; 95% confidence interval, 4.7 to 4.8) and entered the maintenance phase; 466 (63%) participants completed the 12-month trial. Participants were predominantly white, men, and age $ 65 years old; 74% had an eGFR, 60ml/min per 1.73m2, and 65% used renin-angiotensin-aldosterone systeminhibitors. Mean time on sodiumzirconium cyclosilicate was 286 days. Mean daily sodium zirconium cyclosilicate dose was 7.2 g (SD= 2.6). Overmonths 3-12, mean serumpotassiumwas 4.7mmol/L (95% confidence interval, 4.6 to 4.7); mean serumpotassium values # 5.1 and # 5.5mmol/L were achieved by 88% and 99% of participants, respectively. Of 483 renin-angiotensin-aldosterone systeminhibitor users at baseline, 87% continued or had their dose increased; 11% discontinued. Among 263 renin-angiotensin-aldosterone system inhibitor-naive participants, 14% initiated renin-angiotensin-aldosterone system inhibitor therapy. Overall, 489 (66%) participants experienced adverse events during the maintenance phase, and 22% experienced a serious adverse event. Of eight (1%) deaths, none were considered related to sodiumzirconiumcyclosilicate. Nine (1%) and 34 (5%) participants experienced serum potassium,3.0 and 3.0-3.4 mmol/L, respectively. Conclusions After achieving normokalemia, individualized once daily sodium zirconium cyclosilicate was associated with maintenance of normokalemia without substantial renin-angiotensin-aldosterone system inhibitor changes for # 12 months.