scholarly journals Sodium Zirconium Cyclosilicate among Individuals with Hyperkalemia

2019 ◽  
Vol 14 (6) ◽  
pp. 798-809 ◽  
Author(s):  
Bruce S. Spinowitz ◽  
Steven Fishbane ◽  
Pablo E. Pergola ◽  
Simon D. Roger ◽  
Edgar V. Lerma ◽  
...  
Keyword(s):  
Adverse Events ◽  
Confidence Interval ◽  
Serum Potassium ◽  
Maintenance Phase ◽  
Renin Angiotensin Aldosterone System ◽  
Once Daily ◽  
Renin Angiotensin ◽  
Sodium Zirconium ◽  
Sodium Zirconium Cyclosilicate ◽  
Correction Phase

Background and objectivesOral 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, & measurementsIn 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.ResultsOf 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 m2, 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.ConclusionsAfter 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.

scholarly journals Effects and Safety of a Novel Oral Potassium-Lowering Drug-Sodium Zirconium Cyclosilicate for the Treatment of Hyperkalemia: a Systematic Review and Meta-Analysis

2021 ◽  
Author(s):  
Yaru Zhang ◽  
Ruiling Xu ◽  
Fanghao Wang ◽  
Youxia Liu ◽  
Junying Xu ◽  
...  
Keyword(s):  
Serum Potassium ◽  
Meta Analysis ◽  
Statistical Significance ◽  
Maintenance Phase ◽  
Cochrane Library ◽  
Therapeutic Effects ◽  
Rapid Reduction ◽  
Sodium Zirconium ◽  
Sodium Zirconium Cyclosilicate

Abstract Background Oral sodium zirconium cyclosilicate (SZC) is a novel potassium binder capable of achieving a rapid reduction of serum potassium (sK+) and maintaining a long-term normokalemia. We undertook a meta-analysis to summarize and evaluate the effects surrounding SZC in patients with hyperkalemia. Method We searched data sources from MEDLINE (from 1950 to Sep 2020), EMBASE (from 1970 to Sep 2020), and the Cochrane Library database (from 1950 to Sep 2020) for eligible studies. All randomized controlled trials (RCTs) regarding comparison of therapeutic effects of SZC in hyperkalemia participants were included. Results Seven studies, including 1697 patients with hyperkalemia, were analyzed. SZC significantly reduced mean sK+ (−0.42 mmol/L; 95% CI: −0.63 to −0.20 mmol/L, p = 0.0001) compared with placebo, with a significantly greater proportion of patients with normokalemia (RR 3.48, 95% CI 1.49 to 8.11, p = 0.004). Subgroup analyses showed that the longer durations of SZC treatment, the greater magnitudes of potassium reduction when compared with those of placebo (p between subgroups = 0.01) at correction phase. Besides, it also demonstrated sK+ tended to decrease more in patients who got longer treatment or larger dosage of SZC at maintenance phase; however, the difference did not reach statistical significance. Additionally, the drug was equally effective in studies with larger than 50% of patients with chronic kidney disease (CKD) or diabetes or patients using renin-angiotensin aldosterone system inhibitor (RAAS) inhibitors (all p < 0.05). The risk of edema (4.30, 1.17 to 15.84; p = 0.03) in SZC group was higher than those of placebo group. No statistically significant differences in the risks of other adverse events were observed between the two groups. Conclusions SZC effectively decreased the sK+ level in patients with hyperkalemia within 48 h and had benefits in the long-term control of serum potassium in patients who continued to receive SZC with a favorable safety profile from available data.

scholarly journals A phase 3 multicenter open-label maintenance study to investigate the long-term safety of sodium zirconium cyclosilicate in Japanese subjects with hyperkalemia

2020 ◽  
Author(s):  
Naoki Kashihara ◽  
Yoshimitsu Yamasaki ◽  
Takeshi Osonoi ◽  
Hiromasa Harada ◽  
Yugo Shibagaki ◽  
...  
Keyword(s):  
Study Drug ◽  
Maintenance Phase ◽  
Japanese Patients ◽  
Open Label ◽  
Phase 3 ◽  
Sodium Zirconium ◽  
Dose Study ◽  
Sodium Zirconium Cyclosilicate ◽  
Correction Phase

Abstract Background Hyperkalemia is associated with many chronic diseases and renin-angiotensin-aldosterone system inhibitor therapy. Sodium zirconium cyclosilicate (SZC), an oral, highly selective cation-exchanger, is approved for the treatment of hyperkalemia. Methods This phase 3, multicenter, open-label, single-arm, flexible-dose study assessed the safety and efficacy of SZC in Japanese patients with hyperkalemia during a correction phase of up to 3 days and long-term (1 year) maintenance phase (NCT03172702). Results Overall, 150 patients received treatment during both study phases; the study population was generally representative of hyperkalemic Japanese patients in clinical practice. Most patients (78.7%) had three doses of SZC during the correction phase. All but one patient received SZC for ≤ 48 h before transitioning to the maintenance phase. In the maintenance phase, mean (standard deviation; SD) exposure to the study drug was 319.4 (98.1) days and mean (SD) dose was 7.38 (2.85) g/day. Adverse events (AEs) were reported in 131 patients (87.3%); most were mild. The most common treatment-related AEs as evaluated by investigators were constipation (6.7%), peripheral edema (4.0%), and hypertension (2.7%). In the correction phase, 78.7% of patients were normokalemic at 24 h and 98.7% within 48 h; ≥ 65.5% maintained normokalemia throughout the maintenance phase. Conclusion After a year of exposure, SZC treatment was well tolerated by Japanese patients and potassium levels were well controlled.

scholarly journals Use of sodium zirconium cyclosilicate for up-titration of renin–angiotensin–aldosterone system inhibitor therapy in patients with heart failure: a case series

2021 ◽  
Vol 5 (8) ◽  
Author(s):  
Rhys Williams ◽  
Alexander James ◽  
Moira Ashton ◽  
Sian Vaughan ◽  
Aaron Wong
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Case Series ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Additional Patient ◽  
Renin Angiotensin Aldosterone System ◽  
Renin Angiotensin ◽  
Sodium Zirconium ◽  
Sodium Zirconium Cyclosilicate

Abstract Background Patients often receive suboptimal dosing of renin–angiotensin–aldosterone system inhibitor (RAASi) therapy over concerns of hyperkalaemia. However, studies have shown associations between suboptimal dosing or interruptions to therapy and adverse clinical events. Therefore, effective treatments for hyperkalaemia that can enable optimal RAASi therapy are needed. This case series examines eight patients whose commencement on the novel potassium binder sodium zirconium cyclosilicate (SZC) allowed for the initiation and/or up-titration of RAASi therapy. Case summary Eight patients aged 64–87 years with heart failure (HF) with reduced ejection fraction all developed hyperkalaemia (serum potassium (sK+) &gt;5.0 mmol/L) while receiving RAASi therapy. Following initiation of SZC, all patients experienced eventual stabilization of sK+ levels. All patients were able to initiate, restart, or up-titrate RAASi therapy with five patients achieving optimal medical therapy. Left ventricular ejection fraction improved in four patients, two patients are now re-classified as New York Heart Association Class I, and an additional patient had improved exercise tolerance. Follow-up for Patient 8 is still ongoing. Discussion These real-world cases demonstrate that use of SZC to manage hyperkalaemia in patients with HF is feasible and allows optimization of RAASi therapy.

scholarly journals Binding Potassium to Improve Treatment With Renin-Angiotensin-Aldosterone System Inhibitors: Results From Multiple One-Stage Pairwise and Network Meta-Analyses of Clinical Trials

2021 ◽  
Vol 8 ◽  
Author(s):  
Frank Lizaraso-Soto ◽  
Eduardo Gutiérrez-Abejón ◽  
Juan Bustamante-Munguira ◽  
Débora Martín-García ◽  
María Montserrat Chimeno ◽  
...  
Keyword(s):  
Heart Failure ◽  
Clinical Trials ◽  
Serum Potassium ◽  
Resistant Hypertension ◽  
Normal Serum ◽  
Sodium Polystyrene Sulfonate ◽  
Renin Angiotensin Aldosterone System ◽  
Renin Angiotensin ◽  
Optimal Dosing ◽  
Meta Analyses

This manuscript presents findings from the first dichotomous data pooling analysis on clinical trials (CT) regarding the effectiveness of binding potassium. The results emanated from pairwise and network meta-analyses aiming evaluation of response to commercial potassium-binding polymers, that is, to achieve and maintain normal serum potassium (n = 1,722), and the association between this response and an optimal dosing of renin-angiotensin-aldosterone system inhibitors (RAASi) needing individuals affected by heart failure (HF) or resistant hypertension, who may be consuming other hyperkalemia-inducing drugs (HKID) (e.g., β-blockers, heparin, etc.), and frequently are affected by chronic kidney disease (CKD) (n = 1,044): According to the surface under the cumulative ranking area (SUCRA), sodium zirconium cyclosilicate (SZC) (SUCRA &gt;0.78), patiromer (SUCRA &gt;0.58) and sodium polystyrene sulfonate (SPS) (SUCRA &lt;0.39) were different concerning their capacity to achieve normokalemia (serum potassium level (sK+) 3.5–5.0 mEq/L) or acceptable kalemia (sK+ ≤ 5.1 mEq/L) in individuals with hyperkalemia (sK+ &gt;5.1 mEq/L), and, when normokalemia is achieved, patiromer 16.8–25.2 g/day (SUCRA = 0.94) and patiromer 8.4–16.8 g/day (SUCRA = 0.41) can allow to increase the dose of spironolactone up to 50 mg/day in subjects affected by heart failure (HF) or with resistant hypertension needing treatment with other RAASi. The potential of zirconium cyclosilicate should be explored further, as no data exists to assess properly its capacity to optimize dosing of RAASi, contrarily as it occurs with patiromer. More research is also necessary to discern between benefits of binding potassium among all type of hyperkalemic patients, for example, patients with DM who may need treatment for proteinuria, patients with early hypertension, etc.Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/, identifier: CRD42020185614, CRD42020185558, CRD42020191430.

scholarly journals MO214EVALUATION OF THE EFFECT OF A POTASSIUM BINDER ON ARRHYTHMIA-RELATED CARDIOVASCULAR OUTCOMES IN PATIENTS ON CHRONIC HAEMODIALYSIS WITH RECURRENT HYPERKALAEMIA: DESIGN AND RATIONALE FOR THE SODIUM ZIRCONIUM CYCLOSILICATE DIALIZE-OUTCOMES STUDY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Steven Fishbane ◽  
Michel Jadoul ◽  
Laura M Dember ◽  
Csaba Kovesdy ◽  
Ian Sabir ◽  
...  
Keyword(s):  
Ventricular Tachyarrhythmia ◽  
Composite Endpoint ◽  
Primary Objective ◽  
Controlled Study ◽  
Chronic Haemodialysis ◽  
Double Blind ◽  
Once Daily ◽  
Sodium Zirconium ◽  
Outcomes Study ◽  
Sodium Zirconium Cyclosilicate

Abstract Background and Aims Patients with end-stage renal disease (ESRD) on chronic haemodialysis are at an elevated risk of arrhythmias that can increase the risk of sudden cardiac death (SCD) and stroke, along with the need for hospitalisation and interventions. These arrhythmias may be exacerbated by pre-dialysis hyperkalaemia and rapid serum potassium (sK+) shifts that occur during and after haemodialysis sessions. The DIALIZE study (NCT03303521) demonstrated that sodium zirconium cyclosilicate (SZC) was an effective and well-tolerated treatment for pre-dialysis hyperkalaemia, when administered once-daily on non-dialysis days for 8 weeks in patients with ESRD undergoing chronic haemodialysis. The DIALIZE-Outcomes study (EudraCT 2020-005561-14) will evaluate the effect of SZC treatment on arrhythmia-related cardiovascular (CV) outcomes in patients with ESRD on chronic haemodialysis with recurrent hyperkalaemia. Method The DIALIZE-Outcomes study is an international, multicentre, randomised, double-blind, parallel-group, placebo-controlled study, to be conducted at ∼300 study sites across ∼20 countries. Adults (≥18 years of age) with ESRD on haemodialysis three times weekly and with recurrent pre-dialysis sK+ ≥5.5 mmol/L after the long interdialytic interval (LIDI) will be eligible for enrolment. Approximately 2300 patients will be randomised 1:1 to SZC or placebo (Figure), starting at 5 g orally once daily on non-dialysis days (4 days/week) and uptitrated weekly in 5 g increments (maximum 15 g) to achieve pre-dialysis sK+ 4.0–5.0 mmol/L after the LIDI. Dose adjustments after the uptitration phase will be guided by sK+ monitoring, as per clinical practice. The primary objective is to evaluate the efficacy of SZC versus placebo in reducing the incidence of the primary composite endpoint of time to first occurrence of SCD, stroke or hospitalisation/intervention/emergency department visit due to arrhythmias (atrial fibrillation, bradycardia, asystole, ventricular tachyarrhythmia). Secondary endpoints include the efficacy of SZC versus placebo in maintaining normokalaemia (sK+ 4.0–5.5 mmol/L after the LIDI) and preventing severe hyperkalaemia (sK+ ≥6.5 mmol/L after the LIDI) at 1 year (assessed through measurement of sK+ at the 12-month study visit), and time to occurrence of CV outcomes. Safety and tolerability of SZC versus placebo will also be evaluated. The study is event-driven, with patients remaining on study treatment until a pre-specified number of primary endpoint events (770) has occurred. The anticipated average treatment period is ∼25 months. Conclusion The DIALIZE-Outcomes study is the first evaluation of a K+ binder in improving CV outcomes in patients with ESRD on chronic haemodialysis and with recurrent hyperkalaemia. The study findings will provide valuable information that may help to further our understanding of the relationship between hyperkalaemia and CV morbidity and mortality in patients on chronic haemodialysis, and to optimise treatment regimens in this high CV and SCD risk population.

scholarly journals Efficacy and safety of sodium zirconium cyclosilicate in patients with baseline serum potassium level ≥5.5 mmol/L: pooled analysis from two phase 3 trials

2019 ◽  
Author(s):  
Alpesh N. Amin ◽  
Jose Menoyo ◽  
Bhupinder Singh ◽  
Christopher S. Kim
Keyword(s):  
Serum Potassium ◽  
Safety Profile ◽  
Potassium Level ◽  
Serum Potassium Level ◽  
Efficacy And Safety ◽  
Phase 3 ◽  
Two Phase ◽  
Baseline Serum ◽  
Sodium Zirconium ◽  
Sodium Zirconium Cyclosilicate

Abstract Background: Reliable, timely-onset, oral treatments with an acceptable safety profile for patients with hyperkalemia are needed. We examined the efficacy and safety of sodium zirconium cyclosilicate (SZC; formerly ZS-9) treatment for ≤48 hours in patients with baseline serum potassium level ≥5.5 mmol/L. Methods: Data were pooled from two phase 3 studies (ZS-003 and HARMONIZE) among patients receiving SZC 10 g three times daily. Outcomes included mean and absolute change from baseline, median time to potassium level ≤5.5 and ≤5.0 mmol/L, and proportion achieving potassium level ≤5.5 and ≤5.0 mmol/L at 4, 24, and 48 hours. Outcomes were stratified by baseline potassium. Safety outcomes were evaluated. Results: At baseline, 125 of 170 patients (73.5%) had potassium level 5.5–<6.0, 39 (22.9%) had potassium level 6.0–6.5, and 6 (3.5%) had potassium level >6.5 mmol/L. Regardless of baseline potassium, mean potassium decreased at 1-hour post-initial dose. By 4 and 48 hours, 37.5% and 85.0% of patients achieved potassium level ≤5.0 mmol/L, respectively. Median (95% confidence interval) times to potassium level ≤5.5 and ≤5.0 mmol/L were 2.0 (1.1–2.0) and 21.6 (4.1–22.4) hours, respectively. Fifteen patients (8.8%) experienced adverse events; none were serious. Conclusions: SZC 10 g three times daily achieved serum potassium reduction and normokalemia, with a favorable safety profile. ClinicalTrials.gov identifiers: NCT01737697 and NCT02088073

scholarly journals A Phase 3b, Randomized, Double-Blind, Placebo-Controlled Study of Sodium Zirconium Cyclosilicate for Reducing the Incidence of Predialysis Hyperkalemia

2019 ◽  
Vol 30 (9) ◽  
pp. 1723-1733 ◽  
Author(s):  
Steven Fishbane ◽  
Martin Ford ◽  
Masafumi Fukagawa ◽  
Kieran McCafferty ◽  
Anjay Rastogi ◽  
...  
Keyword(s):  
Serum Potassium ◽  
Rescue Therapy ◽  
Controlled Study ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Interdialytic Weight Gain ◽  
Sodium Zirconium ◽  
Efficacy Outcome ◽  
Sodium Zirconium Cyclosilicate

BackgroundPatients with ESRD have minimal renal potassium excretion and, despite hemodialysis, often have persistent predialysis hyperkalemia. The DIALIZE study (NCT03303521) evaluated sodium zirconium cyclosilicate (SZC) in the management of hyperkalemia in hemodialysis patients.MethodsIn the DIALIZE study, a double-blind, placebo-controlled, phase 3b multicenter study, we randomized adults with ESRD who were managed by three-times weekly hemodialysis and had predialysis hyperkalemia to receive placebo or SZC 5 g once daily on non-dialysis days, and titrated towards maintaining normokalemia over 4 weeks, in 5 g increments to a maximum of 15 g. The primary efficacy outcome was proportion of patients during the 4-week stable-dose evaluation period who maintained predialysis serum potassium of 4.0–5.0 mmol/L during at least three of four hemodialysis treatments after the long interdialytic interval and did not require urgent rescue therapy to reduce serum potassium.ResultsIn total, 196 patients (mean [standard deviation (SD)] age =58.1 [13.7] years old) were randomized to sodium zirconium cyclosilicate or placebo. Of 97 patients receiving sodium zirconium cyclosilicate, 41.2% met the primary end point and were deemed treatment responders compared with 1.0% of 99 patients receiving placebo (P<0.001). Rescue therapy to reduce serum potassium during the treatment period was required by 2.1% of patients taking sodium zirconium cyclosilicate versus 5.1% taking placebo. Serious adverse events occurred in 7% and 8% of patients in sodium zirconium cyclosilicate and placebo groups, respectively. The two groups displayed comparable interdialytic weight gain. There were few episodes of hypokalemia.ConclusionsSodium zirconium cyclosilicate is an effective and well-tolerated treatment for predialysis hyperkalemia in patients with ESRD undergoing adequate hemodialysis.

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