Systematic Review and Meta-Analysis of Patiromer and Sodium Zirconium Cyclosilicate: A New Armamentarium for the Treatment of Hyperkalemia

Abstract

Objective: To compare and contrast the efficacy and safety of patiromer and sodium zirconium cyclosilicate (ZS-9) in the treatment of hyperkalemia.

Design: A systematic review and meta-analysis of phase II and III clinical trial data was completed.

Patients or participants: Eight studies (two phase II and four phase III trials with two subgroup analyses) were included in the qualitative analysis, and six studies (two phase II and four phase III trials) were included in the meta-analysis.

Measurements and results: Significant heterogeneity was found in the meta-analysis with an I² value ranging from 80.6-99.6%. A random-effects meta-analysis was applied for all end points. Each clinical trial stratified results by hyperkalemia severity and dosing; therefore, these were considered separate treatment groups in the meta-analysis. For patiromer, a significant -0.70 mEq/L (95% confidence interval [CI] -0.48 to -0.91 mEq/L) change was noted in potassium at 4 weeks. At day 3 of patiromer treatment, potassium change was -0.36 mEq/L (range of standard deviation 0.07-0.30). The primary end point for ZS-9-change in potassium at 48 hours-was -0.67 mEq/L (95% CI -0.45 to -0.89 mEq/L). By 1 hour after ZS-9 administration, change in potassium was -0.17 mEq/L (95% CI -0.05 to -0.30). Analysis of pooled adverse effects from these trials indicates that patiromer was associated with more gastrointestinal upset (7.6% constipation, 4.5% diarrhea) and electrolyte depletion (7.1% hypomagnesemia), whereas ZS-9 was associated with the adverse effects of urinary tract infections (1.1%) and edema (0.9%).

Conclusion: Patiromer and ZS-9 represent significant pharmacologic advancements in the treatment of hyperkalemia. Both agents exhibited statistically and clinically significant reductions in potassium for the primary end point of this meta-analysis. Given the adverse effect profile and the observed time-dependent effects, ZS-9 may play more of a role in treating acute hyperkalemia.

Keywords: ZS-9; hyperkalemia; patiromer; sodium polystyrene sulfonate; sodium zirconium cyclosilicate.

Figure 1. Flow Diagram for Study Selection Process

This flow diagram shows the results of the literature search, screening, and selection process according to the PRISMA statement. Other sources used to identify literature included review of the citation lists of applicable studies. ^a At the screening phase, records were excluded because they were not evaluative studies of patiromer or ZS-9 (e.g. editorial, review, commentary, etc.), not conducted in humans, or not published in English.

Figure 2. Meta-Analysis Results for Patiromer Clinical Trials

These Forest plots indicate the mean difference (black box) with 95% confidence interval (horizontal bars) for the meta-analysis effect estimates. The primary endpoint, change in potassium at 4 weeks, is displayed in Panel A. Heterogeneity was I²=97.3%. Change in potassium at study day 3 was the secondary endpoint as shown in Panel B. Heterogeneity for this endpoint was I²=99.6%. The range for the meta-analytic effect estimates (for both fixed- and random-effects) in Panel B represent the range of standard deviation. g/d=grams per day; Mild=Mild hyperkalemia (potassium 5.1–5.5mEq/L or 5.1–5.4mEq/L); Moderate=Moderate hyperkalemia (potassium 5.6–5.9mEq/L or 5.5–6.4mEq/L).

Figure 2. Meta-Analysis Results for Patiromer Clinical Trials

These Forest plots indicate the mean difference (black box) with 95% confidence interval (horizontal bars) for the meta-analysis effect estimates. The primary endpoint, change in potassium at 4 weeks, is displayed in Panel A. Heterogeneity was I²=97.3%. Change in potassium at study day 3 was the secondary endpoint as shown in Panel B. Heterogeneity for this endpoint was I²=99.6%. The range for the meta-analytic effect estimates (for both fixed- and random-effects) in Panel B represent the range of standard deviation. g/d=grams per day; Mild=Mild hyperkalemia (potassium 5.1–5.5mEq/L or 5.1–5.4mEq/L); Moderate=Moderate hyperkalemia (potassium 5.6–5.9mEq/L or 5.5–6.4mEq/L).

Figure 3. Meta-Analysis Results for Sodium Zirconium Cyclosilicate (ZS-9) Clinical Trials

These Forest plots indicate the mean difference (black box) with 95% confidence interval (horizontal bars) for the meta-analysis effect estimates. Change in potassium at 48 hours was the primary endpoint shown in Panel A and had a heterogeneity of I²=98.3%. The secondary endpoint was change in potassium at 1 hour with a heterogeneity of I²=80.6%. g=gram; TID=three times per day; ZS-9=sodium zirconium cyclosilicate.

Figure 3. Meta-Analysis Results for Sodium Zirconium Cyclosilicate (ZS-9) Clinical Trials

These Forest plots indicate the mean difference (black box) with 95% confidence interval (horizontal bars) for the meta-analysis effect estimates. Change in potassium at 48 hours was the primary endpoint shown in Panel A and had a heterogeneity of I²=98.3%. The secondary endpoint was change in potassium at 1 hour with a heterogeneity of I²=80.6%. g=gram; TID=three times per day; ZS-9=sodium zirconium cyclosilicate.