Sodium Zirconium Cyclosilicate among Individuals with Hyperkalemia

Abstract

Background and objectives Oral sodium zirconium cyclosilicate (formerly ZS-9) binds and removes potassium via 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 potassium values (3.5-5.0 mmol/L) during the correction phase and maintenance of serum potassium #5.1 mmol/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,60 ml/min per 1.73 m 2 , and 65% used renin-angiotensin-aldosterone system inhibitors. Mean time on sodium zirconium cyclosilicate was 286 days. Mean daily sodium zirconium cyclosilicate dose was 7.2 g (SD=2.6). Over months 3-12, mean serum potassium was 4.7 mmol/L (95% confidence interval, 4.6 to 4.7); mean serum potassium values #5.1 and #5.5 mmol/L were achieved by 88% and 99% of participants, respectively. Of 483 renin-angiotensin-aldosterone system inhibitor users at baseline, 87% continued or had their dose increased; 11% discontinued. Among 263 renin-angiotensin-aldosterone system inhibitor-naïve 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 sodium zirconium cyclosilicate. 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.

Efficacy and safety of sodium zirconium cyclosilicate for hyperkalaemia: the randomized, placebo‐controlled HARMONIZE‐Global study

“…The findings of this study are consistent with those of previous clinical trials of SZC in patients with hyperkalaemia. [15][16][17] The Kosiborod et al study previously demonstrated significant reductions from baseline in mean serum K + of À0.7 and À1.1 mmol/L with SZC 10 g TID at 24 and 48 h, respectively, that were subsequently maintained with SZC 5, 10, or 15 g QD over 28 days. 15 Similarly, a study of 754 patients with hyperkalaemia showed significant and rapid reductions in mean central-laboratory K + levels with SZC 2.5, 5, or 10 g TID at 48 h (P < 0.001 vs. placebo for all three doses) that were maintained with SZC 5 or 10 g QD over 14 days.…”

“…17 Of 483 patients using RAASis at baseline, 87% continued RAASi therapy or the dose was increased, and only 11% discontinued; and of 263 patients not using RAASis at baseline, 14% initiated RAASi therapy. 17,20 Thus, SZC may facilitate optimal RAASi dosing among patients with cardiovascular disease and/or CKD. In addition, maintenance of normokalaemia with SZC may reduce the need for dietary restrictions and improve patients' quality of life.…”

Mineralcorticoid Receptor Antagonist Withdrawal for Hyperkalemia and Mortality in Patients with Heart Failure

“…These new drugs can link the potassium in the gastrointestinal tract, thus reducing its absorption and, as a consequence, its serum levels [15]. They have been shown to be better tolerated than sodium polystyrene sulfonate [15] and, recently, data on the efficacy of their long-term use have been also published [16]. Normokalemia was maintained for up to 12 months.…”

Reappraisal on pharmacological and mechanical treatments of heart failure

“…Lokelma was well-tolerated in patients with stable CKD and hyperkalaemia [173] and in those with predialysis hyperkalaemia with end-stage renal disease undergoing adequate hemodialysis [174]. Lokelma enables substantial RAAS inhibitors to change while achieving normokalaemia [175]. However, no new evidence is available for lokelma in the field of HF.…”

“…Omarigliptin: Gantz et al [151] AF ENGAGE AF-TIMI 48 [154], HF-ACTION [155], PARADIGM-HF/ATMOSPHERE [156], TOPCAT [157], ARISTOTLE [158], AATAC [159], CASTLE-AF [160], GENETIC-AF [163] MR MITRA-FR [165,166], COAPT [167] Hyperkalemia Patiromer: PEARL-HF [170], AMETHYST-DN [171], Patiromer-204 [172] Lokelma: Stephen et al [173], DIALIZE [174], ZS-005 [175] CSA SERVE-HF [177], Ponikowski et al [178], Pilot [179], Zhang et al [180] us to design trials to test whether a borderline EF is a signal of potential benefit from therapy targeting HFrEF and HFpEF simultaneously [186]. To date, a high-quality clinical trial specifically designed for HFpEF is still lacking, whether it is pharmacotherapy or device-based therapy.…”