Key Points:
- REALIZE-K trial was a double-blind, placebo-controlled, randomized withdrawal study investigating SZC’s ability to maintain normokalemia (NK) and optimize spironolactone therapy (≥25 mg daily) in HFrEF patients with or at risk of HK.
- 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.
Heart failure with reduced ejection fraction (HFrEF) is a challenging condition often complicated by hyperkalemia (HK), limiting the use of life-extending mineralocorticoid receptor antagonists (MRAs). Sodium zirconium cyclosilicate (SZC), a novel potassium binder, offers potential to optimize MRA therapy in patients with HFrEF and HK.
The REALIZE-K trial was a double-blind, placebo-controlled, randomized withdrawal study investigating SZC’s ability to maintain normokalemia (NK) and optimize spironolactone therapy (≥25 mg daily) in HFrEF patients with or at risk of HK. The study enrolled 203 participants, stratified into two cohorts based on potassium levels, with follow-up over six months. The main results were presented at AHA 2024 and published in JACC. The primary endpoint of the study was percentage of participants achieving NK, on optimal spironolactone dose, without rescue therapy. Secondary endpoints included time to first HK episode, spironolactone discontinuation, and Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) at six months. The authors also assessed the incidence of adverse events (AEs) and serious adverse events (SAEs).
SZC significantly outperformed placebo in maintaining NK and enabling spironolactone optimization, with 58% of SZC-treated participants meeting primary endpoint criteria compared to 23% in the placebo group (OR 4.58; p < 0.001). Time to first HK episode was significantly prolonged in SZC-treated patients, demonstrating its efficacy in managing potassium levels. AEs and SAEs were balanced between groups, with no notable differences in cardiovascular deaths. Peripheral edema and hypokalemia were observed more frequently in the SZC group but were manageable. Participants with elevated baseline NT-proBNP (>4000 pg/mL) experienced more heart failure events, underscoring the importance of individualized risk assessment.
SZC enables safe and effective MRA optimization in HFrEF patients with or at risk of HK, addressing a critical barrier to achieving guideline-directed medical therapy (GDMT). While underpowered for clinical outcomes, the trial highlights SZC’s potential to improve care quality and mitigate risks associated with HK. Ongoing investigations, including broader trials, are warranted to assess SZC’s long-term impact on cardiovascular outcomes. Additionally, tailored strategies for high-risk populations, such as those with elevated NT-proBNP, could further refine its clinical application.
The REALIZE-K trial demonstrates that SZC is a valuable tool in optimizing MRA therapy for HFrEF patients with hyperkalemia, ensuring better adherence to GDMT and potentially improving patient outcomes. As evidence continues to evolve, SZC could become a cornerstone in the management of this complex condition.