Abstract 8895: Design of Phase IV, Double-Blind, Placebo-Controlled, Randomized-Withdrawal Trial Evaluating Sodium Zirconium Cyclosilicate for the Management of Hyperkalemia in Patients With Symptomatic Heart Failure With Reduced Ejection Fraction (REALIZE-K Trial)

Abstract

Introduction: International guideline-recommended therapies for heart failure (HF) with reduced ejection fraction (HFrEF), including mineralocorticoid receptor antagonists (MRA), are underutilized, in part due to concerns of hyperkalemia (HK) especially among those at high risk. The REALIZE-K trial aims to evaluate the efficacy and safety of sodium zirconium cyclosilicate (SZC), a selective potassium (K + ) binder, to enable MRA use in patients with HFrEF at high risk for HK. Methods: REALIZE-K is a prospective, double-blind, placebo (PBO)-controlled randomized withdrawal trial enrolling symptomatic HFrEF (NYHA class II-IV and LVEF ≤40%) patients on guideline-directed medical therapy (but not full-dose MRA) with either HK (serum K + 5.1-5.9 mmol/L) or high risk for HK during MRA titration. All eligible patients enter a 1-month open-label run-in phase, during which patients with hyperkalemia receive SZC to correct HK; all patients undergo protocol-mandated titration of spironolactone (SPL) as tolerated to a target of 50 mg QD with supplemental SZC to maintain normokalemia (serum K + 3.5-5.0 mmol/L; Figure ). All patients tolerating ≥25 mg QD of SPL will be randomly assigned to continued SPL+SZC or SPL+PBO during an 8-month double-blind withdrawal phase. Serial K + monitoring will guide protocol-directed dosing of SZC/PBO and SPL during the randomized period. The primary study endpoint is the occurrence at 8 months of normokalemia on SPL ≥25 mg QD without the need for rescue therapy for severe HK in the SZC vs PBO group. Secondary endpoints include individual components of the primary endpoint and health status assessed by Kansas City Cardiomyopathy Questionnaire Total Symptom Score. Exploratory endpoints include time to first occurrence of the composite of CV death or worsening HF, and change in mean urine albumin-creatinine ratio. Conclusions: REALIZE-K will evaluate the efficacy and safety of SZC, enabling MRA therapy for HFrEF patients at high risk for HK.