Sodium Zirconium Cyclosilicate for Management of Hyperkalemia During Spironolactone Optimization in Patients with Heart Failure

Abstract

Background

Mineralocorticoid receptor antagonists (MRA) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF) but are underused in clinical practice. Observational data suggest that hyperkalemia is the leading obstacle for the suboptimal use of MRA.

Objectives

We evaluated the effects of sodium zirconium cyclosilicate (SZC) in optimizing use of spironolactone among participants with HFrEF and hyperkalemia.

Methods

REALIZE-K (NCT04676646) was a prospective, double-blind, randomized- withdrawal trial in participants with HFrEF (NYHA II–IV; left ventricular ejection fraction ≤40%), optimal guideline-directed therapy (except MRA), and prevalent or incident MRA- induced hyperkalemia. During open-label run-in, participants underwent spironolactone titration (target: 50 mg/daily); those with hyperkalemia started SZC. Participants with normokalemia (potassium 3.5–5.0 mEq/L) on SZC and spironolactone ≥25 mg/daily were randomized to continued SZC or placebo for 6 months. The primary endpoint was optimal treatment response (normokalemia on spironolactone ≥25 mg/daily without rescue therapy for hyperkalemia [months 1–6]). The five key secondary endpoints were tested hierarchically. Exploratory endpoints included a composite of adjudicated cardiovascular death or worsening HF events (hospitalizations and urgent visits).

Results

Overall, 203 participants were randomized (SZC 102, placebo 101). Higher percentage of SZC- versus placebo-treated participants had optimal response (71% vs 36%; OR 4.45 [95% CI 2.89–6.86]; p<0.001). SZC (versus placebo) improved the first four key secondary endpoints: normokalemia on randomization dose of spironolactone and without rescue therapy (58% vs 23%; OR 4.58 [2.78–7.55]; p<0.001), receiving spironolactone ≥25 mg/daily (81% vs 50%; OR 4.33 [2.50–7.52]; p<0.001), time to hyperkalemia (HR 0.51 [0.37–0.71]; p<0.001), time to decrease/discontinuation of spironolactone due to hyperkalemia (HR 0.37 [0.17–0.73]; p=0.006). There was no between-group difference in KCCQ-CSS at 6 months (-1.01 points [-6.64–4.63]; p=0.72). Adverse events (64% vs 63%) and serious adverse events (23% vs 22%) were balanced between SZC and placebo, respectively. Composite of CV death or worsening HF occurred in 11 (11%) participants in the SZC group (1 with CV death, 10 with HF events) and 3 (3%) participants in the placebo group (1 with CV death, 2 with HF events; log-rank nominal p=0.034).

Conclusions

In participants with HFrEF and hyperkalemia, SZC led to large improvements in the percentage of participants with normokalemia while on optimal spironolactone dose, and reduced risk of hyperkalaemia and down-titration/discontinuation of spironolactone.Although underpowered for clinical outcomes, more participants had HF events with SZC than placebo, which should be factored into the clinical decision making.