Sodium zirconium cyclosilicate enables MRA optimization in HFrEF patients with hyperkalemia

More HFrEF patients with hyperkalemia treated with the potassium binder sodium zirconium cyclosilicate achieved normokalemia while receiving the optimal spironolactone dose and did not need rescue therapy for hyperkalemia, compared with placebo.

This summary is based on the publication of Kosiborod MN, Cherney DZI, Desai AS, et al. - Sodium Zirconium Cyclosilicate for Management of Hyperkalemia During Spironolactone Optimization in Patients With Heart Failure. J Am Coll Cardiol. 2025 Mar 18;85(10):971-984. doi: 10.1016/j.jacc.2024.11.014.

Introduction and methods

Background

Despite the proven efficacy of MRAs in HFrEF [1,2], more than half of the eligible patients do not receive this medication [3]. Observational data indicate that prevalent hyperkalemia or perceived risk thereof is the main reason for suboptimal use of MRA [4]. In patients with hyperkalemia, oral administration of the potassium binder sodium zirconium cyclosilicate (SZC) resulted in rapid reduction of potassium levels and long-term maintenance of normal potassium levels [5-7]. However, it is unknown whether SZC can optimize the use of MRAs in HFrEF patients.

Aim of the study

The authors investigated the efficacy and safety of SZC in optimizing the use of spironolactone in patients with symptomatic HFrEF and hyperkalemia.

Methods

The REALIZE-K (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients With Symptomatic HFrEF Receiving Spironolactone) study was an international, prospective, double-blind, placebo-controlled, phase 4 randomized-withdrawal trial that included 203 patients with HFrEF (NYHA class II–IV HF symptoms; LVEF ≤40%) who were receiving optimal GDMT comprising ACEi/ARB/ARNI and beta-blocker. They had prevalent hyperkalemia (i.e., serum potassium 5.1-5.9 mEq/L and eGFR ≥30 mL/min/1.73 m²) or were at high risk of hyperkalemia (i.e., history of serum potassium >5.0 mEq/L ≤36 months prior to enrollment and eGFR ≥30 mL/min/1.73 m² at screening, serum potassium 4.5–5.0 mEq/L with eGFR 30–60 mL/min/1.72 m² at screening, or aged >75 years at screening).

During the open-label run-in phase (4–6 weeks), participants underwent spironolactone titration (target dose: 50 mg/day), and those with hyperkalemia were started on SZC. At the end of the run-in period, patients who were still being treated with spironolactone ≥25 mg/day and SZC and who maintained normokalemia (3.5–5.0 mEq/L) were randomized to continued treatment with the same doses of spironolactone and SZC or continued treatment with spironolactone and placebo for 6 months.

Outcomes

The primary endpoint was the occurrence of optimal treatment response, defined as normokalemia on spironolactone ≥25 mg/day with no need for rescue therapy for hyperkalemia since the previous study visit (1–6 months after randomization).

Key secondary endpoints were: (1) normokalemia on randomization spironolactone dose and with no need for rescue therapy for hyperkalemia at 1–6 months; (2) treatment with spironolactone dose ≥25 mg/day at 1–6 months; (3) time to first hyperkalemia episode (serum potassium >5.0 mEq/L) during follow-up; (4) time to first decrease or discontinuation of spironolactone dose due to hyperkalemia during follow-up; and (5) between-group difference in change in KCCQ – Clinical Summary Score (CSS) from baseline to 6 months. To ensure strong control of type 1 error (α=0.05), the primary and key secondary endpoints were tested in a hierarchical fashion.

Exploratory endpoints included a composite outcome of adjudicated CV death or worsening HF events (i.e., HF hospitalization or urgent visit). Safety and tolerability assessment included the incidence of investigator-reported adverse events, serious adverse events, and edema.

Main results

Efficacy

• Patients randomized to SZC (n=102) were more likely to have an optimal treatment response than those assigned to placebo (n=101) (estimated rate: 71% vs. 36%; OR: 4.45; 95%CI: 2.89–6.86; P<0.001).
• Treatment with SZC also improved the first 4 key secondary endpoints compared with placebo: normokalemia on randomization spironolactone dose and with no rescue therapy (58% vs. 23%; OR: 4.58; 95%CI: 2.78–7.55; P<0.001); spironolactone dose ≥25 mg/day (81% vs. 50%; OR: 4.33; 95%CI: 2.50–7.52; P<0.001); time to first hyperkalemia episode (HR: 0.51; 95%CI: 0.37–0.71; P<0.001); and time to first decrease/discontinuation of spironolactone dose due to hyperkalemia (HR: 0.37; 95%CI: 0.17–0.73; P=0.006).
• There was no between-group difference in the KCCQ-CSS change at 6 months between the SCZ and placebo groups (mean treatment difference: –1.01 points; 95%CI: –6.64 to 4.63; P=0.72).
• The study was underpowered for clinical outcomes, but in an exploratory analysis, the incidence rate of the composite outcome of CV death or worsening HF events was 11% in the SZC group (1 CV death, 10 HF events) and 3% in the placebo group (1 CV death, 2 HF events; nominal log-rank P=0.034).

Safety

• The frequencies of adverse events (64% vs. 63%) and serious adverse events (23% vs. 22%) were similar in the SZC and placebo groups.
• Edema was reported in 22% of the SCZ-treated patients and 16% of the placebo-treated patients.

Conclusion

In the REALIZE-K study among HFrEF patients with hyperkalemia, more participants treated with SZC versus placebo achieved normokalemia while receiving the optimal spironolactone dose (≥25 mg/day) and did not need rescue therapy for hyperkalemia. There were no significant safety concerns. The authors point out that although the study was “underpowered for clinical outcomes, more participants had HF events with SZC than placebo, which should be factored into the clinical decision-making.”

Find this article online at J Am Coll Cardiol.

References

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