Sodium Zirconium Cyclosilicate, Hyperkalaemia, and Spironolactone Optimization in Heart Failure with Reduced Ejection Fraction: The REALIZE-K Open-Label Run-in Phase

In heart failure with reduced ejection fraction (HFrEF), mineralocorticoid receptor antagonists (MRAs) reduce mortality and HF hospitalizations, and are one of the key cornerstones of guideline-directed medical therapy.1-4 Hyperkalaemia (or fear of hyperkalaemia) is a major reason for their underuse.5 In the randomized-withdrawal phase of the REALIZE-K trial, of patients with HFrEF and prevalent hyperkalaemia or at risk of hyperkalaemia, continued use of the potassium (K+) binder sodium zirconium cyclosilicate (SZC) led to large increases in the number of participants on optimal-dose spironolactone with normokalaemia, and reduced the risk of hyperkalaemia and down-titration/discontinuation of spironolactone compared with withdrawal to placebo.6 Prior to the placebo-controlled, randomized-withdrawal phase of REALIZE-K, there was a run-in phase in which SZC was used to manage hyperkalaemia and spironolactone dose was optimized.7 This analysis evaluated the efficacy of SZC in lowering serum (s)K+ and enabling SZC titration during the run-in phase among those with prevalent hyperkalaemia on no or low-dose (12.5 mg) spironolactone; and in those identified as at high risk of hyperkalaemia on no or low-dose spironolactone, to evaluate the incidence of hyperkalaemia during spironolactone dose titration during the run-in phase and use of SZC to lower sK+ and enable maintenance of spironolactone. This was a post-hoc analysis of REALIZE-K, which was a prospective phase 4, double-blind, placebo-controlled, randomized-withdrawal trial evaluating the role of SZC in enabling MRA therapy in patients with HFrEF and hyperkalaemia.7 Patient eligibility criteria have been reported previously.7 Briefly, trial participants were required to have a left ventricular ejection fraction ≤40% and to be on a stable dose of angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor–neprilysin inhibitor, as well as a beta-blocker. Patients had to be either untreated with, or on a low dose of, MRA (<25 mg daily of spironolactone or eplerenone) because of either: prevalent hyperkalaemia (Cohort 1), defined as sK+ 5.1–5.9 mEq/L at screening and estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73 m2; or at high risk of hyperkalaemia (Cohort 2), defined as either documented history of hyperkalaemia (sK+ >5.0 mEq/L) in the previous 36 months and eGFR ≥30 ml/min/1.73 m2, or sK+ 4.5–5.0 mEq/L, and either eGFR 30–60 ml/min/1.73 m2 or aged >75 years. Participants who fulfilled the eligibility criteria entered the open-label run-in phase. This analysis included all participants who entered the open-label period and received at least one dose of SZC or spironolactone. In Cohort 1 (prevalent hyperkalaemia at screening), this was a 4-week period during which patients were initiated on SZC on day 1 at a dose of 10 g three times daily for 48 h until sK+ was normalized (3.5–5.0 mEq/L). After sK+ normalization, SZC was down-titrated or up-titrated between 5 g every other day and 15 g daily to maintain sK+ 3.5–5.0 mEq/L as per protocol-mandated instructions.7 Spironolactone was either initiated or up-titrated to a target dose of 50 mg daily, as tolerated, per protocol-mandated instructions.7 In Cohort 2 (high risk of hyperkalaemia), the open-label run-in phase could be extended up to 6 weeks. Spironolactone was initiated or up-titrated on day 1 and was systematically up-titrated to a target dose of 50 mg daily, as tolerated per protocol-mandated instructions.7 Patients who experienced hyperkalaemia (sK+ >5.0 mEq/L) during the first 4 weeks of the run-in phase were started on SZC 10 g three times daily for ≤48 h until sK+ normalized (3.5–5.0 mEq/L). Those who achieved normokalaemia were maintained on SZC 10 g daily, which could be down- or up-titrated between 5 g every other day and 15 g daily to maintain normokalaemia per protocol-mandated instructions.7 In the REALIZE-K run-in phase, 95 patients with prevalent hyperkalaemia (Cohort 1) and 271 at high risk of hyperkalaemia (Cohort 2) were enrolled. Ninety-four in Cohort 1 and 268 in Cohort 2 received at least one dose of spironolactone. Ninety-four in Cohort 1 and 147 in Cohort 2 received at least one dose of SZC. In Cohort 1, mean age was 70.5 years, mean K+ was 5.3 (± 0.4), 31.6% had type 2 diabetes, and mean eGFR was 56.4 ml/min/1.73 m2. SZC resulted in reduction of sK+ to ≤5.0 mEq/L within 48 h in 79.8% of patients (Figure 1). In those who achieved normokalaemia, 77.0% achieved titration to 50 mg of spironolactone, 2.7% to 37.5 mg, 18.9% to 25 mg, and 1.4% to 12.5 mg over the subsequent 4 weeks. At the end of the open-label phase, 11.6% of patients remained hyperkalaemic (sK+ >5.0 mEq/L) despite SZC titration; 1.1% had experienced an oedema-related adverse event. In Cohort 2, mean age was 69.9 years, mean K+ was 4.7 (± 0.4), 21.5% had type 2 diabetes, and mean eGFR was 59.3 ml/min/1.73 m2. Over 6 weeks, MRA dose titration to 50 mg once daily resulted in hyperkalaemia (sK+ >5.0 mEq/L) in 77.8% of patients (in 20.5%, MRA titration resulted in sK+ >5.5 mEq/L and in 1.8%, sK+ was >6.0 mEq/L). Those who did versus did not develop hyperkalaemia were more likely to have had atrial fibrillation, have a lower baseline eGFR, and a higher baseline sK+ and N-terminal pro-B-type natriuretic peptide (Table 1). In 73.5% of those who developed hyperkalaemia, SZC treatment resulted in resolution of hyperkalaemia (sK+ ≤5.0 mEq/L) within 48 h. Over the 6 weeks, 77.3% achieved titration to 50 mg of spironolactone, 2.3% to 37.5 mg, 19.5% to 25 mg, and 0.8% to 12.5 mg. At the end of the open-label phase, 12.2% remained hyperkalaemic (sK+ >5.0 mEq/L) despite addition of SZC and 1.9% experienced an oedema-related adverse event. In the run-in phase of REALIZE-K, SZC reduced sK+ to ≤5.0 mEq/L in 80% of those with prevalent hyperkalaemia within 48 h, and over the next 4 weeks enabled 80% of these patients to tolerate doses of spironolactone ≥25 mg. Among those defined as being at high risk of hyperkalaemia (based on prior history of hyperkalaemia or risk factors such as age or advanced chronic kidney disease), 78% developed hyperkalaemia during spironolactone up-titration. Among these patients, SZC resulted in reduction of sK+ to ≤5.0 mEq/L in 73.5% of patients within 48 h of incident hyperkalaemia and enabled 87% to tolerate doses of spironolactone ≥25 mg. There is ongoing uncertainty and debate about which definition of hyperkalaemia is optimal in terms of identifying risk of clinical events. This issue is of major relevance for many novel therapies in recently completed, ongoing and upcoming clinical trials to both treat and prevent heart failure. These novel therapies include non-steroidal MRAs and aldosterone synthase inhibitors. Hyperkalaemia occurs frequently in higher-risk patients undergoing spironolactone up-titration, suggesting that rechallenge with MRAs in this population should be undertaken with caution and careful laboratory surveillance. In most patients with prevalent hyperkalaemia or those at high risk of hyperkalaemia, use of SZC rapidly corrects sK+ to the normal range and allows initiation and titration of spironolactone to optimal doses without recurrent hyperkalaemia. The authors thank the participants, their families, and all investigators involved in this study. The authors thank Alejandra Silva, MD, for her review of the data and manuscript drafts. The first and subsequent drafts were written by the author group, but administrative support (for manuscript styling and formatting) was provided by Jess Fawcett, BSc, of Core (a division of Prime, London, UK), supported by AstraZeneca according to Good Publication Practice guidelines. Data underlying the findings described in this paper may be requested in accordance with AstraZeneca's data sharing policy. AstraZeneca Group of Companies allows researchers to submit a request to access anonymized patient-level clinical data, aggregate clinical or genomics data (when available), and anonymized clinical study reports through the Vivli web-based data request platform. This work was supported by AstraZeneca. Conflicts of interest: M.C.P. has received research grants or contracts from AstraZeneca, Amgen, 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, 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 for AstraZeneca, Moderna, and Teikoku. D.Z.I.C. 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, GSK, 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. A.S.D. has received institutional research grants from Abbott, Alnylam, AstraZeneca, Bayer, DevPro Biopharma, Novartis, and Pfizer; and has received personal consulting fees from Abbott, Alnylam, AstraZeneca, Avidity Biopharma, Axon Therapeutics, Bayer, Biofourmis, Boston Scientific, Endotronix, GSK, Medpace, Medtronic, Merck, New Amsterdam, Novartis, Parexel, Porter Health, Regeneron, River2Renal, Roche, scPharmaceuticals, Verily, and Zydus. J.M.T. has received research funding in the form of grants to institutions from AstraZeneca and/or consulting fees for AstraZeneca. S.V. 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. K.C. has received grants and/or research support and/or speaking honoraria from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, HLS Therapeutics, Humber River Health, Janssen, Merck, Novartis, Novo Nordisk, and Pfizer. D.D. is an employee of Fortrea, which received a consultancy fee for the conduct of the current study from AstraZeneca. S.P. has received research grants and consulting fees from AstraZeneca. M.D., J.M.E., L.F., and M.O. are employees of and hold (or may hold) stock in AstraZeneca. M.O.A. has received research grants and/or consulting fees from AstraZeneca. K.A.C. is supported by the Keenan Chair in research leadership; and has received research grants and/or consulting fees from AstraZeneca. L.K. has received lecture fees from Boehringer Ingelheim, Novartis, and Richter. A.L. has received research grants and/or consulting fees from AstraZeneca. M.L. has received honoraria for lectures from AstraZeneca, Bayer, Novartis, and Viatris. M.C.M. has received honoraria for lectures or advisory boards from AstraZeneca, Boehringer Ingelheim, Bayer, Novartis, Novo Nordisk, Rovi, and Vifor CSL. B.M. has received lecture fees from Abbott, AstraZeneca, Biotronik, Boehringer Ingelheim, CSL-Behring, Daiichi-Sankyo, Medtronic, and Novartis. J.N.V. has received honoraria for lectures or advisory boards from Alleviant, AstraZeneca, Boehringer Ingelheim, Bayer, Novartis, Novo Nordisk, Pfizer, Roche, Rovi, and Vifor CSL. I.S. 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. J.V. has received speaker or consultancy fees from Abbvie, Amgen, AOP Health, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, ProMed, Servier, Swixx BioPharma, and Zentiva. J.W. has received research grants and/or consulting fees from AstraZeneca. M.N.K. became an AstraZeneca employee (Senior Vice President for Late Stage Cardiovascular, Renal and Metabolic Disease) on 6 January 2025, with oversight of the development of several compounds, including SZC. During the trial, M.N.K. acted as the Primary Investigator for an independent academic research organization, and was not an AstraZeneca employee. M.N.K. received research grants from AstraZeneca, Boehringer Ingelheim, and Pfizer; has received consultant/advisory board fees 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, Novo Nordisk, Pfizer, Pharmacosmos, Regeneron, Roche, Sanofi, scPharmaceuticals, Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca and Vifor Pharma; has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and owns stock options in Artera Health and Saghmos Therapeutics. All other authors have nothing to disclose.

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