Sodium Zirconium Cyclosilicate Enhances Spironolactone Tolerance in Heart Failure Patients with Hyperkalemia: JACC

"After 6 months, 71% of patients taking sodium zirconium cyclosilicate (SZC) maintained normokalemia on spironolactone ≥25 mg daily, compared to 36% on placebo," the researchers reported. The study, presented at the 2024 American Heart Association Scientific Sessions, highlights how hyperkalemia concerns often lead to MRA down-titration or discontinuation in HFrEF patients. The findings were also published online in the Journal of the American College of Cardiology.

Mineralocorticoid receptor antagonists have been shown to improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF), yet they are underutilized in clinical practice. Observational data indicate that hyperkalemia is a major barrier to their optimal use. To address this, Mikhail N. Kosiborod, Saint Luke’s Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, MO, USA, and colleagues assessed the impact of SZC in enhancing the use of spironolactone in patients with HFrEF and hyperkalemia.

For this purpose, the researchers conducted the REALIZE-K (NCT04676646) trial, a prospective, double-blind, randomized-withdrawal study involving participants with HFrEF (NYHA II–IV; left ventricular ejection fraction ≤40%). The participants were receiving optimal guideline-directed therapy, excluding mineralocorticoid receptor antagonists (MRA), and had prevalent or incident MRA-induced hyperkalemia. During the open-label run-in phase, participants underwent spironolactone titration (target: 50 mg/daily), and those with hyperkalemia started sodium zirconium cyclosilicate. Participants with normokalemia (potassium 3.5–5.0 mEq/L) on SZC and spironolactone ≥25 mg/daily were randomized to continue SZC or placebo for 6 months.

The primary endpoint was optimal treatment response, defined as normokalemia on spironolactone ≥25 mg/daily without rescue therapy for hyperkalemia (months 1–6). The trial also included five key secondary endpoints tested hierarchically, and exploratory endpoints focused on a composite of adjudicated cardiovascular death or worsening heart failure events (hospitalizations and urgent visits).

The following were the key findings of the study:

• A total of 203 participants were randomized (102 to SZC, 101 to placebo).
• A higher percentage of SZC-treated participants had an optimal response than placebo-treated participants (71% versus 36%; OR 4.45).
• SZC improved the first four key secondary endpoints compared to placebo:
  • Normokalemia on randomization dose of spironolactone without rescue therapy (58% versus 23%; OR 4.58).
  • Receiving spironolactone ≥25 mg/daily (81% versus 50%; OR 4.33).
  • Time to hyperkalemia (HR 0.51).
  • Time to decrease/discontinuation of spironolactone due to hyperkalemia (HR 0.37).
• There was no significant difference in KCCQ-CSS at 6 months between SZC and placebo (-1.01 points).
• Adverse events were similar between SZC and placebo (64% versus 63%), with serious adverse events also balanced (23% versus 22%).
• A composite of cardiovascular death or worsening heart failure occurred in 11% of the SZC group (1 CV death, 10 HF events) and 3% of the placebo group (1 CV death, 2 HF events).

The findings showed that in participants with HFrEF and hyperkalemia, SZC significantly increased the proportion of those achieving normokalemia while on the optimal spironolactone dose, and reduced the risk of hyperkalemia and the need for down-titration or discontinuation of spironolactone.

"Although the study was underpowered for clinical outcomes, a higher number of heart failure events were observed in the SZC group compared to placebo, which should be considered in clinical decision-making," the researchers concluded.

Reference:

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. 2024; Epub ahead of print.