Could SZC Help Facilitate MRA Utilization for HFrEF?

Mineralocorticoid receptor antagonists (MRAs), which include spironolactone and eplerenone, are a recommended therapy for heart failure with reduced ejection fraction (HFrEF). However, they remain underutilized due to concerns that their use will lead to hyperkalemia. The use of potassium (K+) binders may help improve the tolerability of MRAs, but early K+ binders could not be used long term due to resulting gastrointestinal issues.

Sodium zirconium cyclosilicate (SZC) is a newer, nonabsorbed, crystal K+ binder that may provide an alternative. Previous trials found that SZC can rapidly lower K+ levels to a normal range in patients with hyperkalemia and maintain normal levels for ≤12 months. However, it is unknown whether SZC use could allow for quick and safe initiation and titration of MRAs and long-term optimal dosing.

REALIZE-K is a study by Mikhail N. Kosiborod, MD, and others examining the ability of long-term treatment with SZC to enable spironolactone initiation and titration in patients with HFrEF (New York Heart Association functional class II-IV; left ventricular ejection fraction ≤40%) and prevalent hyperkalemia or high risk of hyperkalemia. The researchers shared details of the ongoing study’s design and baseline characteristics in JACC: Heart Failure.

The prospective, double-blind, placebo-controlled trial launched in March 2021 and was fully enrolled by January 2024. There were 365 patients enrolled, of whom 202 were randomized at 85 sites across eight countries in Europe, North America, and Latin America. In the open-label run-in phase, the average participant age was 70.1 years; 24% were female. Baseline K+ level was 4.8 mEq/L. Baseline estimated glomerular filtration rate was 58.5 mL/min/1.73 m². There was a high incidence of comorbidities, including chronic kidney disease (37.5%), diabetes (24.1%), and atrial fibrillation/flutter (37.8%). Baseline median N-terminal pro-B-type natriuretic peptide was high, at 1093 pg/mL.

Use of non-MRA therapy for HFrEF was high; for example, >90% of patients received angiotensin-converting enzyme inhibitors, angiotensin 2 receptor blockers, or angiotensin receptor/neprilysin inhibitors, and 96% received beta-blockers. Almost half (47.9%) of enrollees were untreated with MRAs before the study began; the remainder were on low-dose spironolactone or eplerenone (12.5 mg). Most patients needed diuretics.

All study participants received spironolactone titration (target: 50 mg daily) during the open-label run-in period. Patients with prevalent or incident hyperkalemia during titration began SZC. Participants who achieved normokalemia while receiving spironolactone ≥25 mg daily were randomized to continuing SZC or matching placebo for 6 months.

The primary composite end point was the percentage of patients with optimal treatment response in months 1-6. Optimal treatment response was defined as maintenance of normokalemia (serum K+ 3.5-5.0 mEq/L) on a spironolactone dose of ≥25 mg daily without additional rescue therapy for hyperkalemia. The study is currently in the follow-up phase for randomized patients.

The authors summarized, “The REALIZE-K trial is investigating the role of the K+ binder SZC in enabling rapid and safe optimization of MRA therapy in patients with HFrEF and maintaining treatment with MRAs in the long term, as well as providing additional information regarding the safety of SZC in this patient group.”

Source: JACC: Heart Failure