Background: Mineralocorticoid receptor antagonists (MRA) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF) but are underused in clinical practice. Observational data suggest that hyperkalemia is the leading obstacle for the suboptimal use of MRA., Objectives: This study sought to evaluate the effects of sodium zirconium cyclosilicate (SZC) in optimizing use of spironolactone among participants with HFrEF and hyperkalemia., Methods: REALIZE-K (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients With Symptomatic HFrEF Receiving Spironolactone) was a prospective, double-blind, randomized- withdrawal trial in participants with HFrEF (NYHA functional class II-IV; left ventricular ejection fraction ≤40%), optimal guideline-directed therapy (except MRA), and prevalent or incident MRA-induced hyperkalemia. During open-label run-in, participants underwent spironolactone titration (target: 50 mg/day); those with hyperkalemia started SZC. Participants with normokalemia (potassium: 3.5-5.0 mEq/L) on SZC and spironolactone ≥25 mg/day were randomized to continued SZC or placebo for 6 months. The primary endpoint was optimal treatment response (normokalemia on spironolactone ≥25 mg/day without rescue therapy for hyperkalemia [months 1-6]). The 5 secondary endpoints were tested hierarchically. Exploratory endpoints included a composite of adjudicated cardiovascular death or worsening heart failure (HF) events (hospitalizations and urgent visits)., Results: Overall, 203 participants were randomized (SZC: 102; placebo: 101). Higher percentage of SZC- vs placebo-treated participants had optimal response (71% vs 36%; OR: 4.45; 95% CI: 2.89-6.86; P < 0.001). SZC (vs placebo) improved the first 4 secondary endpoints: normokalemia on randomization dose of spironolactone and without rescue therapy (58% vs 23%; OR: 4.58; 95% CI: 2.78-7.55; P < 0.001); receiving spironolactone ≥25 mg/day (81% vs 50%; OR: 4.33; 95% CI: 2.50-7.52; P < 0.001); time to hyperkalemia (HR: 0.51; 95% CI: 0.37-0.71; P < 0.001); and time to decrease/discontinuation of spironolactone due to hyperkalemia (HR: 0.37; 95% CI: 0.17-0.73; P = 0.006). There was no between-group difference in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score at 6 months (-1.01 points; 95% CI: -6.64 to 4.63; P = 0.72). Adverse events (64% vs 63%) and serious adverse events (23% vs 22%) were balanced between SZC and placebo, respectively. Composite of cardiovascular (CV) death or worsening HF occurred in 11 (11%) participants in the SZC group (1 with CV death, 10 with HF events) and 3 (3%) participants in the placebo group (1 with CV death, 2 with HF events; log-rank nominal P = 0.034)., Conclusions: 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 hyperkalemia 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. (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients With Symptomatic HFrEF Receiving Spironolactone; NCT04676646)., Competing Interests: Funding Support and Author Disclosures The REALIZE-K trial was funded by AstraZeneca. Dr Kosiborod will become an AstraZeneca BioPharmaceuticals Research and Development Employee as Senior Vice President for Late Stage Cardiovascular, Renal and Metabolic Disease, effective January 6, 2025; this role entails development oversight for several compounds, including SZC. During conduction of the trial, Dr Kosiborod acted as the Primary Investigator from an independent academic research organization; he was not an employee of AstraZeneca during the design or conduction of the REALIZE-K trial or at the time of manuscript submission; has received research grants (payment to institution) from AstraZeneca, Boehringer Ingelheim, and Pfizer; has received consultant/advisory board fees (payment to institution) from 35Pharma, Alnylam, Amgen, Applied Therapeutics, Arrowhead Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Corcept Therapeutics, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon Pharmaceuticals, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pfizer, Pharmacosmos, Regeneron, Roche, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support (payment to institution) from AstraZeneca and Vifor Pharma; has received honoraria (payment to institution) from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and owns stock options in Artera Health and Saghmos Therapeutics. Dr Cherney has received honoraria from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, Abbvie, Janssen, AMGEN, Bayer, Prometic, Bristol Myers Squibb, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon, Inversago, GlaxoSmithKline, and Novo Nordisk; and has received operational funding for clinical trials from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring, Novo Nordisk, and Bayer. Dr Desai has received institutional research grants from Abbott, Alnylam, AstraZeneca, Bayer, DevPro Biopharma, Novartis, Pfizer; and has received personal consulting fees from Abbott, Alnylam, AstraZeneca, Avidity Biopharma, Axon Therapeutics, Bayer, Biofourmis, Boston Scientific, Endotronix, GlaxoSmithKline, Medpace, Medtronic, Merck, New Amsterdam, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, scPharmaceuticals, Verily, and Zydus. Dr Testani has received research funding in the form of grants to institutions from AstraZeneca and/or consulting for AstraZeneca. Dr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery; and has received grants and/or research support and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Humber River Health, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, S&L Solutions Event Management Inc, Sanofi, and Sun Pharmaceuticals; and is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Dr Chinnakondepalli has received research funding in the form of grants to institutions from AstraZeneca and/or consulting for AstraZeneca. Dr Dolling is an employee of Fortrea, which received a consultancy fee for the conduct of the current study from AstraZeneca. Dr Patel has received research funding in the form of grants to institutions from AstraZeneca and/or consulting for AstraZeneca. Mr Dahl, Mr Eudicone, Ms Friberg, and Dr Ouwens are employees of and hold or may hold stock in AstraZeneca. Dr Antunes has received research funding in the form of grants to institutions from AstraZeneca and/or consulting for AstraZeneca. Dr Connelly is supported by the Keenan Chair in research leadership; and has received research funding in the form of grants and/or consulting for AstraZeneca. Dr Kuthi has received lecture fees from Boehringer, Novartis, and Richter (outside of the submitted work). Dr Lala has received research funding in the form of grants to institutions from AstraZeneca and/or consulting for AstraZeneca. Dr Lorenzo has received honoraria for lectures from AstraZeneca, Bayer, Novartis, and Viatris (outside of the submitted work). Dr Marcos has received honoraria for lectures or advisory boards from AstraZeneca, Boehringer Ingelheim, Bayer, Novartis, Novo Nordisk, Rovi, and Vifor CSL (outside of the submitted work). Dr Nuñez has received honoraria for lectures or advisory boards from Alleviant, AstraZeneca, Boehringer Ingelheim, Bayer, Novartis, Novo Nordisk, Pfizer, Roche, Rovi, and Vifor CSL (outside of the submitted work). Dr Merkely has received lecture fees from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, CSL-Behring, Daiichi-Sankyo, Medtronik, and Novartis. Dr Squire has received speaker fees from PharmaCosmos; and his research department has received funding for research from Novartis, AstraZeneca, Boehringer Ingelheim, PharmaCosmos, the British Heart Foundation, and the National Institute for Health Research. Dr Wranicz has received research funding in the form of grants to institutions from AstraZeneca and/or consulting for AstraZeneca. Dr Petrie has received research grants or contracts from AstraZeneca, Boehringer Ingelheim, Boston Scientific, Medtronic, Novartis, Novo Nordisk, Pharmacosmos, Roche, SQ Innovations, and 3R LifeSciences; has received consulting fees or honoraria from Abbvie, Abott, Akero, Applied Therapeutics, Amgen, AnaCardio, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Cardiorentis, Corteria, Corvia, Eli Lilly, FIRE 1, Foundry, Horizon Therapeutics, LIB Therapeutics, Moderna, New Amsterdam, Novartis, Novo Nordisk, Pharmacosmos, Regeneron, Reprieve, Siemens, Takeda, Teikoku, Vifor, and 3R Lifesciences; and has participated on Data and Safety Monitoring Boards from AstraZeneca, Moderna, and Teikoku. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. 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