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Sodium Zirconium Cyclosilicate in HFrEF and Hyperkalemia: REALIZE-K Design and Baseline Characteristics

MN. Kosiborod, D. Cherney, K. Connelly, AS. Desai, PO. Guimarães, L. Kuthi, A. Lala, V. Madrini, B. Merkely, JN. Villota, I. Squire, JM. Testani, J. Vaclavik, S. Verma, J. Wranicz, M. Dahl, JM. Eudicone, L. Friberg, MC. Petrie

. 2024 ; 12 (10) : 1707-1716. [pub] 20240513

Language English Country United States

Document type Journal Article, Randomized Controlled Trial, Multicenter Study

Persistent link   https://www.medvik.cz/link/bmc25004066

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).

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$a Kosiborod, Mikhail N $u Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, Missouri, USA. Electronic address: mkosiborod@saint-lukes.org
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$a Sodium Zirconium Cyclosilicate in HFrEF and Hyperkalemia: REALIZE-K Design and Baseline Characteristics / $c MN. Kosiborod, D. Cherney, K. Connelly, AS. Desai, PO. Guimarães, L. Kuthi, A. Lala, V. Madrini, B. Merkely, JN. Villota, I. Squire, JM. Testani, J. Vaclavik, S. Verma, J. Wranicz, M. Dahl, JM. Eudicone, L. Friberg, MC. Petrie
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$a 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).
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$a Cherney, David $u University Health Network and Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada
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$a Connelly, Kim $u St. Michael's Hospital, Toronto, Ontario, Canada
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$a Desai, Akshay S $u Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA. Electronic address: https://twitter.com/akshaydesaimd
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$a Guimarães, Patrícia O $u Cardiovascular Clinical Trials Academic Research Organization, Hospital Albert Einstein, São Paulo, Brazil
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$a Kuthi, Luca $u Semmelweis University, Budapest, Hungary
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$a Lala, Anuradha $u The Mount Sinai Hospital, New York, New York, USA
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$a Madrini, Vagner $u Hospital Israelita Albert Einstein, São Paulo, Brazil
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$a Merkely, Bela $u Semmelweis Egyetem, Budapest, Hungary
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$a Villota, Julio Nuñez $u Hospital Clinico Universitario de Valencia, Valencia, Spain
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$a Squire, Iain $u University Hospitals of Leicester NHS Trust - Glenfield Hospital, Leicester, United Kingdom
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$a Testani, Jeffrey M $u Section of Cardiovascular Medicine, Yale University, Guilford, Connecticut, USA
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$a Vaclavik, Jan $u University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Czech Republic
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$a Verma, Subodh $u Institute of Unity Health Toronto and University of Toronto, Toronto, Ontario, Canada
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$a Wranicz, Jerzy $u Department of Electrocardiology, Medical University of Lodz, Łódź, Poland
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$a Dahl, Magnus $u BioPharmaceuticals Medical, AstraZeneca, Gothenburg, Sweden
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$a Eudicone, James M $u BioPharmaceuticals Medical (Evidence), AstraZeneca, Wilmington, Delaware, USA
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$a Friberg, Lovisa $u BioPharmaceuticals Medical, AstraZeneca, Gothenburg, Sweden
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$a Petrie, Mark C $u Institute of Cardiovascular and Medical Sciences, University of Glasgow, and Glasgow Royal Infirmary, Glasgow, United Kingdom. Electronic address: https://twitter.com/markcpetrie20
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