BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF). However, MRAs are often underused because of hyperkalemia concerns. OBJECTIVES: The purpose of this study was to assess whether sodium zirconium cyclosilicate (SZC), a nonabsorbed crystal that traps and rapidly lowers potassium, enables MRA use in patients with HFrEF and prevalent hyperkalemia (or at high risk). METHODS: REALIZE-K is a prospective, double-blind, placebo-controlled trial in patients with HFrEF (NYHA functional class II-IV; left ventricular ejection fraction ≤40%), optimal therapy (except MRA), and prevalent hyperkalemia (or at high risk). During the open-label run-in, all participants underwent protocol-mandated spironolactone titration (target: 50 mg daily); those with prevalent (cohort 1) or incident (cohort 2) hyperkalemia during titration started SZC. Participants achieving normokalemia while on spironolactone ≥25 mg daily were randomized to continuing SZC or matching placebo for 6 months. The primary composite endpoint was proportion of participants with optimal response (normokalemia, on spironolactone ≥25 mg daily, no rescue for hyperkalemia [months 1-6]). RESULTS: Of 365 patients (run-in), 202 were randomized. Baseline characteristics included mean age 70 years, prevalent comorbidities (78% estimated glomerular filtration rate <60 mL/min/1.73 m2, 38% atrial fibrillation/flutter), high N-terminal pro B-type natriuretic peptide (median 1,136 pg/mL), and high HFrEF therapy use (64% sacubitril/valsartan, 96% beta-blocker, 42% sodium glucose co-transporter 2 inhibitor). At randomization, 78% were receiving spironolactone 50 mg daily. CONCLUSIONS: REALIZE-K is the first trial to evaluate whether SZC can enable rapid and safe MRA optimization and long-term continuation in patients with HFrEF and prevalent/high risk of hyperkalemia. (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients with Symptomatic HFrEF Receiving Spironolactone [REALIZE-K]; NCT04676646).

BioPharmaceuticals Medical AstraZeneca Gothenburg Sweden

BioPharmaceuticals Medical AstraZeneca Wilmington Delaware USA

Cardiovascular Clinical Trials Academic Research Organization Hospital Albert Einstein São Paulo Brazil

Cardiovascular Division Brigham and Women's Hospital Boston Massachusetts USA https twitter com akshaydesaimd

Department of Electrocardiology Medical University of Lodz Łódź Poland

Hospital Clinico Universitario de Valencia Valencia Spain

Hospital Israelita Albert Einstein São Paulo Brazil

Institute of Cardiovascular and Medical Sciences University of Glasgow and Glasgow Royal Infirmary Glasgow United Kingdom https twitter com markcpetrie20

Institute of Unity Health Toronto and University of Toronto Toronto Ontario Canada

Saint Luke's Mid America Heart Institute and University of Missouri Kansas City Kansas City Missouri USA

Section of Cardiovascular Medicine Yale University Guilford Connecticut USA

Semmelweis Egyetem Budapest Hungary

Semmelweis University Budapest Hungary

St Michael's Hospital Toronto Ontario Canada

The Mount Sinai Hospital New York New York USA

University Health Network and Mount Sinai Hospital and University of Toronto Toronto Ontario Canada

University Hospital Ostrava and Faculty of Medicine University of Ostrava Czech Republic

University Hospitals of Leicester NHS Trust Glenfield Hospital Leicester United Kingdom

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ClinicalTrials.gov
NCT04676646