Overcoming Hyperkalaemia to Optimise Heart Failure Therapy: The Emerging Role of Novel Potassium Binders

Abstract

Hyperkalaemia is common in patients with heart failure. It limits the initiation, optimisation and continuation of guideline-directed medical therapy, particularly mineralocorticoid receptor antagonists. Two potassium binders, patiromer and sodium zirconium cyclosilicate (SZC), have emerged as strategies to address this barrier. SZC is an inorganic crystalline compound that binds potassium in exchange for sodium and hydrogen throughout the gastrointestinal tract, resulting in rapid potassium lowering, whereas patiromer is a non-absorbed organic polymer that exchanges potassium for calcium in the colon and has a slower onset of action. Both agents have demonstrated efficacy in maintaining normokalaemia and enabling the continuation of renin–angiotensin–aldosterone system inhibitor therapy in heart failure. Differences in electrolyte effects and tolerability have clinical implications: patiromer is associated with hypomagnesaemia, while SZC delivers a sodium load that may predispose patients to fluid retention. However, no head-to-head randomised trials are available and evidence for improvement in heart failure morbidity or mortality remains limited, underscoring the need for adequately powered outcome studies.

Heart failure (HF) remains a major cause of morbidity and mortality worldwide. Advances in pharmacotherapy, including angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), angiotensin receptor–neprilysin inhibitors (ARNI), β-blockers, mineralocorticoid receptor antagonists (MRAs), sodium–glucose cotransporter-2 inhibitors and device therapies are the cornerstone of HF therapy and have significantly improved outcomes. Among these therapies, MRAs have been shown to reduce mortality and hospitalisations in patients with HF with reduced ejection fraction (HFrEF).

However, the presence of hyperkalaemia often limits the initiation, maintenance or up-titration of MRAs (and other renin–angiotensin–aldosterone system inhibitors [RAASIs]) in patients with HF, particularly those with concomitant renal dysfunction. Potassium abnormalities are also common during hospitalisation for acute or worsening HF. In the EVEREST trial, dynamic changes in serum potassium levels during hospitalisation were frequently observed and were associated with adverse clinical outcomes in patients with HFrEF.1 Hyperkalaemia may lead to treatment interruption, dose reduction or complete avoidance of these therapies, thereby undermining prognosis. Hyperkalaemia has been consistently reported in major randomised controlled trials evaluating MRAs in HF. In the RALES trial, hyperkalaemia occurred in 13.5% of patients treated with spironolactone compared with 9.9% receiving placebo.2 Similarly, in the EMPHASIS-HF trial, hyperkalaemia occurred in 11.8% of patients receiving eplerenone versus 7.2% in the placebo group.3 More recently, in the FINEARTS-HF trial, hyperkalaemia was reported in 14.3% of patients treated with finerenone compared with 6.9% receiving placebo, underscoring the persistent challenge of potassium management during the optimisation of MRA therapy.4 Recent advances in mineralocorticoid receptor antagonism have focused on the development of non-steroidal agents with improved selectivity and safety profiles. The newer agents, such as finerenone, demonstrate more targeted receptor binding and reduced off-target effects compared with traditional steroidal MRAs. Importantly, emerging evidence suggests that these agents may be associated with a comparatively lower risk of clinically significant hyperkalaemia, potentially expanding the safe use of aldosterone blockade in patients with HF and concomitant renal dysfunction.5

Potassium binders, such as sodium polystyrene sulfonate, have long been used to manage hyperkalaemia, but have limitations including safety, tolerability, slow onset and limited data in HF.6 In recent years, novel potassium binders such as patiromer and sodium zirconium cyclosilicate (SZC) have emerged, offering more favourable pharmacological and safety profiles.7

This review aims to evaluate the mechanisms of action, clinical evidence and therapeutic implications of patiromer and SZC in HF, along with placing their use within the broader context of hyperkalaemia management to enable optimisation of guideline-directed therapy.

Hyperkalaemia in Heart Failure: The Scope of the Problem

Hyperkalaemia is a common and clinically significant complication in patients HF, particularly in those with HFrEF, and its prevalence increases with advancing disease severity. Patients with cardiorenal comorbidities, including chronic kidney disease, HF and diabetes, are at particularly high risk of hyperkalaemia (Figure 1). A major contributor to hyperkalaemia in HF is the widespread use of RAASIs, including ACEis, ARBs, ARNIs and MRAs, which are cornerstone, life-saving therapies but impair renal potassium excretion.8 Hyperkalaemia is commonly categorised according to serum potassium concentration: mild hyperkalaemia (5.1–5.5 mmol/l), moderate hyperkalaemia (5.6–6.0 mmol/l) and severe hyperkalaemia (>6.0 mmol/l). These thresholds are widely used in clinical trials and clinical practice to guide monitoring and therapeutic interventions in patients with HF.7 Importantly, observational studies have demonstrated a U-shaped relationship between serum potassium concentration and mortality in HF.7 Some recent real-world cohort work has also demonstrated that hyperkalaemia is associated with higher rates of HF hospitalisations, arrhythmias and mortality.9 As a result, hyperkalaemia represents a key barrier to the initiation, optimisation and maintenance of guideline-directed medical therapy (GDMT) in HF. Thus, a therapeutic strategy that can safely and reliably control potassium is of great interest in the HF domain.

Figure 1: Prevalence of Hyperkalaemia across Patient Populations.

Prevalence ranges reflect estimates derived from observational cohorts and guideline documents; reported values vary according to hyperkalaemia definition, renal function and background pharmacotherapy.7,33,34 HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction.

Comparison of Novel Potassium Binders: Sodium Zirconium Cyclosilicate and Patiromer

In recent years, two novel potassium binders – patiromer and SZC – have expanded the therapeutic options for the management of hyperkalaemia. While both agents effectively lower serum potassium and enable the continuation of RAASIs, they differ in physicochemical properties, onset of action and safety considerations.10,11

SZC is an inorganic, crystalline compound with a highly selective pore structure that preferentially binds potassium ions in exchange for sodium and hydrogen throughout the gastrointestinal tract, including the small intestine. This results in a relatively rapid onset of potassium lowering, with measurable reductions observed within 1 hour of administration. In contrast, patiromer is a non-absorbed organic polymer that exchanges potassium for calcium and acts primarily in the colon, leading to a slower onset of action.

From a safety perspective, patiromer is associated with hypomagnesaemia and requires magnesium monitoring, whereas SZC does not significantly affect serum magnesium or calcium levels, but delivers a sodium load that may predispose susceptible patients to fluid retention and oedema. Consequently, SZC may be preferred when rapid potassium reduction is required, whereas patiromer may be more suitable for chronic potassium control in stable patients in whom sodium load is a concern. Importantly, no head-to-head randomised trials directly comparing the two agents are currently available. Table 1 summarises the key differences between SZC and patiromer.

Table 1: Mechanistic and Pharmacological Differences Between Novel Potassium Binders Used for Hyperkalaemia Management.

Feature	Sodium Zirconium Cyclosilicate	Patiromer
Chemical nature	Inorganic crystalline compound	Organic polymer
Ion exchange	Exchanges K+ for Na+ and H+	Exchanges K+ for Ca2+
Site of action	Entire gastrointestinal tract (including small intestine)	Primarily colon
Onset of action	Rapid (within 1 h)	Slower (4–7 h)
Selectivity	Highly selective for K+ (approximately 3 Å pore size)	Less selective
Effect on magnesium	Neutral	Can cause hypomagnesaemia
Sodium load	Yes (clinically relevant oedema concern)	No sodium load

Patiromer: Clinical Trials and Evidence

Patiromer is a non-absorbed organic polymer potassium binder that exchanges potassium for calcium ions primarily in the distal colon, leading to increased faecal potassium excretion. Its site of action and mechanism account for a slower onset of potassium lowering compared with SZC, but it has demonstrated consistent efficacy for chronic potassium control and prevention of recurrent hyperkalaemia.

Early evidence for patiromer was established in OPAL-HK, a Phase III study that demonstrated effective potassium lowering and prevention of recurrent hyperkalaemia in patients with chronic kidney disease receiving RAASIs. In OPAL-HK, patiromer significantly reduced serum potassium during an initial treatment phase and maintained normokalaemia during a randomised withdrawal period, with recurrence of hyperkalaemia observed following treatment discontinuation.12 Although HF was not the primary focus, the high prevalence of RAASI use and cardiorenal comorbidity in OPAL-HK provides important context for the subsequent evaluation of patiromer in HF-specific populations.

Early Heart Failure Evidence: PEARL-HF

The PEARL-HF trial was the first randomised, double-blind, placebo-controlled study to evaluate patiromer in patients with chronic HF at increased risk of hyperkalaemia receiving MRA therapy. In this study, 105 patients with chronic HF and either chronic kidney disease or a prior history of hyperkalaemia were randomised to patiromer (RLY5016) or placebo for 4 weeks while receiving spironolactone therapy (starting at 25 mg/day with planned uptitration).8 The primary endpoint was the between-group difference in serum potassium concentration at week 4. Patiromer (30 g/day) significantly reduced mean serum potassium compared with placebo and markedly lowered the incidence of hyperkalaemia (defined as serum potassium ≥5.5 mmol/l), allowing a greater proportion of patients to continue spironolactone without treatment interruption. Although the trial was not powered to assess clinical outcomes, PEARL-HF provided proof of concept that potassium-binding therapy could enable safer use of MRAs in HF populations vulnerable to potassium elevation.

Cardiorenal Populations and Mineralocorticoid Receptor Antagonist Enablement: AMBER

The AMBER trial further evaluated patiromer in patients with advanced chronic kidney disease and resistant hypertension, a population with substantial clinical overlap with HF. In this randomised, double-blind, placebo-controlled trial, 295 patients with an estimated glomerular filtration rate of 25–45 ml/min/1.73 m² were randomised to patiromer or placebo during initiation of spironolactone therapy, with the primary endpoint being the proportion of patients remaining on spironolactone at 12 weeks.13 Patiromer significantly increased spironolactone persistence by reducing hyperkalaemia-related discontinuation. Prespecified subgroup analyses, including patients with HF at baseline, demonstrated consistent potassium-lowering efficacy and similar treatment effects, supporting the role of patiromer in maintaining RAASI therapy in patients with cardiorenal comorbidity. While HF-specific outcomes were not assessed, the AMBER trial reinforced the utility of patiromer as a strategy to prevent hyperkalaemia-related interruption of MRA therapy.

Contemporary HFrEF Evidence: The DIAMOND Trial

The DIAMOND trial represents the most comprehensive evaluation of patiromer in HFrEF. DIAMOND was a multicentre, randomised, double-blind, placebo-controlled, randomised-withdrawal trial that enrolled patients with symptomatic HFrEF receiving GDMT who had current or prior hyperkalaemia limiting optimisation of RAASIs.14 During an initial run-in phase, patiromer was administered to correct hyperkalaemia and enable optimisation of background therapy, including MRAs. Patients who achieved normokalaemia were subsequently randomised to continue patiromer or switch to placebo.

The primary endpoint was the between-group difference in serum potassium-adjusted area under the curve during the randomised withdrawal phase. Patiromer significantly reduced recurrent hyperkalaemia compared with placebo and was associated with fewer dose reductions or discontinuations of RAASIs, including MRAs. Patients randomised to patiromer were more likely to maintain optimised background therapy without hyperkalaemia-related interruption. Although the trial was not powered to evaluate mortality or HF hospitalisation, DIAMOND demonstrated that patiromer effectively supports long-term potassium control and sustained use and optimisation of disease-modifying therapy in HFrEF.

Summary of Evidence for Patiromer in Heart Failure

Available evidence supports patiromer as an effective agent for chronic potassium control and prevention of recurrent hyperkalaemia in patients with HF, particularly those requiring sustained use of MRAs and other RAASIs. Randomised trials demonstrate that patiromer facilitates initiation, continuation and the optimisation of GDMT by reducing hyperkalaemia-related treatment interruptions (Table 2). Patiromer was generally well tolerated in these studies, with gastrointestinal adverse events and hypomagnesaemia being the most commonly reported safety considerations. However, similar to SZC, no trial has yet demonstrated a direct reduction in HF morbidity or mortality.

Table 2: Evidence for Patiromer in Heart Failure and Cardiorenal Populations.

Study	Design	Population	Primary/Key Outcome	Key Findings	Limitations
PEARL-HF 20118	Randomised, double-blind, placebo-controlled trial	Chronic HF with history of hyperkalaemia or CKD receiving spironolactone; n=105	Difference in serum potassium at week 4	Patiromer significantly reduced serum potassium and decreased the incidence of hyperkalaemia (7% versus 25% with placebo)	Small sample size; short follow-up; not powered for clinical outcomes
AMBER (HF subgroup) 201913	Randomised, double-blind, placebo-controlled trial	CKD (eGFR 25–45 ml/min/1.73 m²) with resistant hypertension; HF subgroup present (~45%); n=295 total	Persistence of spironolactone therapy at 12 weeks	Patiromer reduced hyperkalaemia and enabled greater continuation of spironolactone therapy	HF findings based on subgroup analysis; primary population CKD
DIAMOND 202214	Multicentre, randomised, double-blind, placebo-controlled withdrawal trial	Symptomatic HFrEF with current or prior hyperkalaemia receiving RAASI therapy; n=878 randomised	Serum potassium-adjusted area under the curve during randomised phase	Patiromer reduced recurrent hyperkalaemia and lowered RAASI dose reduction or discontinuation, allowing sustained optimisation of GDMT	Not powered for mortality or HF hospitalisation outcomes

CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; GDMT = guideline-directed medical therapy; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; RAASI = renin–angiotensin–aldosterone system inhibitor.

Sodium Zirconium Cyclosilicate: Clinical Trials and Evidence

SZC is a non-absorbed, inorganic, crystalline potassium binder with a highly selective microporous structure that exchanges potassium and ammonium ions for sodium and hydrogen ions throughout the gastrointestinal tract, including the small intestine.15 This physicochemical selectivity allows preferential binding of potassium over divalent cations and results in relatively rapid reductions in serum potassium, with measurable effects observed within 1 hour of administration and sustained normokalaemia during maintenance therapy.16 SZC is administered orally, typically at 10 g three times daily for up to 48 hours for initial correction, followed by individualised 5–10 g once-daily maintenance dosing to maintain potassium control.17 Because SZC is not systemically absorbed, it does not significantly affect serum calcium or magnesium concentrations; however, its sodium content may predispose susceptible patients, particularly those with HF or advanced kidney disease, to fluid retention and peripheral oedema, necessitating careful monitoring ofvolume status and serum potassium during therapy.18 The most common adverse effects reported include oedema, which is dose-related and probably related to the sodium content of the drug (each 5 g contains ~400 mg sodium), as well as gastrointestinal adverse effects such as constipation; hypokalaemia and nasopharyngitis have also been observed but typically resolve with dose adjustment or temporary discontinuation. SZC is not intended for emergency treatment of life-threatening hyperkalaemia, given its relatively delayed onset compared with IV therapies.19

Robust evidence supports the efficacy of SZC in the management of hyperkalaemia across diverse patient populations. The ZS-002 Phase 2 trial established the initial proof-of-concept for the safety and potassium-lowering efficacy of sodium zirconium cyclosilicate (ZS-9) in patients with chronic kidney disease.20 In the pivotal Phase III randomised controlled trial by Packham et al. (ZS-003), which enrolled patients with serum potassium levels between 5.0 and 6.5 mmol/l, SZC produced rapid, dose-dependent reductions in serum potassium during a 48-hour correction phase, with up to 86% of patients achieving normokalaemia with the 10 g three-times-daily regimen compared with 48% receiving placebo. Normokalaemia was subsequently maintained during a short-term maintenance phase, establishing SZC’s efficacy for both acute correction and early maintenance of hyperkalaemia.21

Owing to its relatively rapid onset of potassium-lowering action, SZC may be particularly useful in hospitalised patients with acute decompensated HF who develop hyperkalaemia during initiation or intensification of GDMT. The HARMONIZE (ZS-004) trial extended these findings by demonstrating that, following initial potassium correction, once-daily SZC effectively maintained normokalaemia over 28 days in outpatients with hyperkalaemia.22 Sustained potassium control was further confirmed in the 11-month open-label extension study (ZS-004E), which demonstrated durable efficacy and acceptable tolerability with long-term maintenance dosing.23 Importantly, across these studies, potassium-lowering efficacy was consistent among key subgroups, including patients with chronic kidney disease, diabetes mellitus, HF and those receiving RAASIs.

Additional Phase III studies further reinforced the generalisability and durability of SZC therapy. The HARMONIZE-Global trial replicated the efficacy and safety of SZC across geographically and ethnically diverse populations, supporting its applicability in routine clinical practice worldwide.24 Long-term open-label data from ZS-005 demonstrated sustained normokalaemia for up to 12 months with flexible maintenance dosing, providing important evidence for chronic use in predominantly cardiorenal populations.25

A subsequent meta-analysis of potassium-binding agents, including SZC, confirmed its efficacy in lowering serum potassium and supported a favourable overall safety profile across heterogeneous patient populations.10 These studies established SZC as an effective option for both acute potassium correction and long-term maintenance therapy in general hyperkalaemia, forming the evidentiaryfoundation forsubsequent evaluation in HF-specific populations. The clinical development of SZC from early dose-finding studies to large Phase III and HF-focused trials is summarised in Figure 2.

Figure 2: Clinical Development Timeline of Sodium Zirconium Cyclosilicate in Heart Failure and Chronic Kidney Disease.

MRA = mineralocorticoid receptor antagonist; RAASI = renin–angiotensin–aldosterone system inhibitors.

Sodium Zirconium Cyclosilicate in Heart Failure: Evidence from Clinical Trials

PRIORITIZE-HF Trial

The PRIORITIZE-HF trial was designed to evaluate whether treatment with SZC could facilitate the initiation and safe up-titration of RAASIs, particularly MRAs, without inducing clinically significant hyperkalaemia in patients with HFrEF who were under-treated due to concerns regarding potassium elevation.26 This international, multicentre, randomised, double-blind, placebo-controlled Phase II study enrolled patients with symptomatic HFrEF (left ventricular ejection fraction [LVEF] ≤40%) who were at increased risk of hyperkalaemia, as defined by estimated glomerular filtration rate and baseline serum potassium criteria. Participants were randomised to receive SZC 5 g or placebo once daily for 12 weeks, during which optimisation of RAASI therapy was actively encouraged.26

The trial was prematurely terminated because of operational challenges related to the COVID-19 pandemic, leading to the randomisation of 182 patients, substantially fewer than the planned sample size of 280. The primary endpoint – the distribution of patients across four predefined RAASI treatment categories at 12 weeks – did not differ significantly between treatment groups (p=0.43). Nevertheless, several secondary and exploratory findings suggested potential clinical benefit with SZC. A numerically greater proportion of patients in the SZC group achieved target MRA doses compared with placebo (56.4% versus 47.0%) and mean serum potassium concentrations during treatment were lower with SZC (4.65 mmol/l at the end of treatment) than with placebo (4.90 mmol/l). A prespecified subgroup analysis indicated a larger treatment effect among patients randomised earlier in the trial, prior to 12 June 2019, with target MRA dose achievement observed in 58.6% of SZC-treated patients versus 30.4% in the placebo group.

Exploratory patient-reported outcomes also demonstrated numerical improvements favouring SZC, including higher Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores and a greater proportion of patients reporting improvement on the Patient Global Impression of Change scale.

Key Clinical Trial: REALIZE-K

The most direct randomised evidence supporting the use of SZC to facilitate MRA therapy in HFrEF is provided by the REALIZE-K trial, reported by Kosiborod et al. in 2025.27 REALIZE-K was a prospective, double-blind, randomised-withdrawal trial enrolling patients with symptomatic HFrEF (New York Heart Association class II–IV; LVEF ≤40%) receiving GDMT, excluding MRAs and with prevalent or incident MRA-associated hyperkalaemia (Figure 3).

Figure 3: Trial Design and Key Outcomes of the REALIZE-K Study.

LVEF = left ventricular ejection fraction; MRA = mineralocorticoid receptor antagonist.

During an open-label run-in phase, spironolactone was initiated and titrated to a target dose of 50 mg/day; patients who developed hyperkalaemia received open-label SZC. Participants who subsequently achieved normokalaemia while receiving SZC in combination with spironolactone at a dose of ≥25 mg/day were randomised to continued SZC or placebo for 6 months.

A total of 203 participants underwent randomisation (SZC, n=102; placebo, n=101). The primary endpoint – optimal treatment response, defined as maintenance of normokalaemia while receiving spironolactone ≥25 mg/ day without rescue therapy – was achieved in 71% of patients in the SZC group compared with 36% in the placebo group (OR 4.45; 95% CI [2.89–6.86]; p<0.001). Secondary endpoints consistently favoured SZC, including maintenance of normokalaemia at target spironolactone dose, receipt of spironolactone ≥25 mg/day 81 versus 50%, prolonged time to recurrent hyperkalaemia (HR 0.51) and longer time to spironolactone dose reduction or discontinuation (HR 0.37). Overall adverse event rates were comparable between groups (64% versus 63%).

Although the trial was not powered for clinical outcomes, the composite of cardiovascular death or worsening HF occurred more frequently in the SZC group than in the placebo group (11% versus 3%; nominal p=0.034). This imbalance may reflect chance variation, selection effects inherent to the randomised-withdrawal design, or unmeasured confounding rather than a causal relationship.

REALIZE-K demonstrates that SZC significantly improves the ability to initiate and maintain spironolactone therapy at guideline-recommended doses in patients with HFrEF complicated by hyperkalaemia. These findings highlight the need for adequately powered outcome trials to clarify its impact on HF morbidity and mortality.

Real-world and Observational Evidence

Observational studies provide complementary but heterogeneous evidence regarding the use of SZC in HF populations. In a retrospective cohort study of patients with systolic HF (LVEF <50%) and baseline hyperkalaemia, Hida et al. reported that long-term SZC continuation (≥2 years) was associated with sustained normokalaemia, increased use and dosing of renin–angiotensin system inhibitors and MRAs, improvement in LVEF and a non-significant trend toward reduced all-cause mortality or hospital readmission (29% versus 47%; p=0.079).28

In contrast, a comparative effectiveness analysis by Shimada et al. evaluating patients with HF initiating potassium-binding therapy found that, after inverse probability of treatment weighting, SZC use was associated with a higher risk of HF hospitalisation compared with calcium polystyrene sulfonate (HR 1.36; 95% CI [1.06–1.75]), despite superior MRA continuation rates (70.1 versus 59.0%).29 Similarly, Desai et al. observed an increased incidence of HF-related hospitalisations and oedema events among patients with chronic kidney disease and HF treated with SZC.30

Taken together, real-world data suggest that while SZC may facilitate optimisation and persistence of MRA therapy, its effects on volume status and HF hospitalisation require careful consideration, particularly in patients with advanced HF or concomitant chronic kidney disease.

Summary of Evidence of Sodium Zirconium Cyclosilicate in Heart Failure

The evidence supporting the use of SZC in HF is strongest for its ability to correct hyperkalaemia and facilitate the initiation and maintenance of MRA therapy (Table 3). In the randomised REALIZE-K trial, SZC significantly increased the proportion of patients with HFrEF who maintained normokalaemia while receiving guideline-relevant doses ofspironolactone, compared with placebo, although the study was not powered to assess clinical outcomes. Observational studies suggest that SZC may enable greater persistence and up-titration of RAASIs but provide inconsistent signals regarding HF hospitalisation and volume-related adverse events, particularly in patients with advanced HF or concomitant chronic kidney disease. An exploratory analysis in REALIZE-K observed a numerically higher incidence of cardiovascular death or worsening HF in the SZC arm compared with placebo.27 This finding should be interpreted cautiously because the trial was not powered to evaluate clinical outcomes and the number of events was small. Several potential explanations have been proposed. First, the randomised-withdrawal design and relatively small sample size may have resulted in chance imbalance between treatment groups. Second, the sodium content of SZC may contribute to fluid retention and worsening congestion in susceptible patients with advanced HF, particularly those with impaired renal function or baseline volume overload. Third, differences in patient characteristics at randomisation may have influenced event rates. Consequently, the observed imbalance should not be interpreted as evidence of harm but rather as a signal requiring confirmation in larger outcome-driven trials. Collectively, available data support SZC as an effective strategy to enable GDMT in the setting of hyperkalaemia, while highlighting the need for adequately powered outcome-driven trials to define its long-term safety and impact on HF morbidity and mortality.

Table 3: Evidence for Sodium Zirconium Cyclosilicate in Heart Failure: Randomised and Observational Data.

Study	Design	Population	Primary/key Outcome	Key Findings	Limitations
REALIZE-K 202527	Randomised, double-blind, randomised-withdrawal trial	HFrEF (NYHA II–IV, LVEF ≤40%) with prevalent or incident MRA-associated hyperkalaemia; n=203	Optimal treatment response: normokalaemia while receiving spironolactone ≥25 mg/day without rescue therapy	Achieved in 71% with SZC versus 36% with placebo (OR 4.45; 95% CI [2.89–6.86]; p<0.001)	Not powered for clinical outcomes; exploratory analysis showed numerically higher HF events in SZC arm
Hida et al. 202528	Retrospective cohort study	Systolic HF (LVEF <50%) with baseline hyperkalaemia; n=61	Composite of all-cause mortality or HF readmission at 2 years	Lower event rate with long-term SZC continuation (29% versus 47%; p=0.079)	Small sample; observational design; non-significant trend
Shimada et al. 202529	Retrospective comparative effectiveness study (IPTW-adjusted)	HF patients initiating potassium-binding therapy; n=12,918	HF hospitalisation; MRA continuation	SZC associated with higher HF hospitalisation risk versus CPS (HR 1.36; 95% CI [1.06–1.75]) and higher MRA continuation (70.1% versus 59.0%)	Residual confounding likely; CPS comparator limits generalisability

CPS = calcium polystyrene sulfonate; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; IPTW = inverse probability of treatment weighting; LVEF = left ventricular ejection fraction; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association; SZC = sodium zirconium cyclosilicate.

Safety, Tolerability and Considerations in Heart Failure Settings

Both patiromer and SZC are non-absorbed agents and have demonstrated favourable overall safety profiles in clinical trials of hyperkalaemia, with adverse event rates generally comparable to placebo and no evidence of major systemic toxicity. Patiromer is primarily associated with gastrointestinal adverse effects and hypomagnesaemia, reflecting non-selective binding of magnesium in the gastrointestinal tract and necessitating periodic monitoring of serum magnesium during long-term therapy. SZC does not significantly affect serum magnesium or calcium concentrations, but exchanges potassium for sodium and hydrogen ions, raising considerations regarding sodium load and volume status.

In clinical studies, SZC has been generally well tolerated in both short- and long-term use, with commonly reported adverse events including peripheral oedema, hypokalaemia and gastrointestinal symptoms, such as constipation, most of which are dose-related and reversible with dose adjustment or temporary interruption. Hypersensitivity reactions, including angio-oedema, have been reported rarely. In HF-specific studies, including the REALIZE-K trial, overall and serious adverse event rates were comparable between SZC- and placebo-treated patients and no new safety signals were identified; however, the available trials were not powered to detect infrequent adverse events or long-term clinical outcomes.

In patients with HF, careful monitoring is required when initiating or up-titrating potassium binders. For SZC, attention to volume status is particularly important, as the associated sodium load may contribute to fluid retention and peripheral oedema, especially in patients with advanced HF, pre-existing congestion, or concomitant chronic kidney disease. Body weight, clinical signs of congestion and diuretic requirements should therefore be assessed regularly. Serum potassium concentrations should be monitored closely with either agent, as overcorrection may result in hypokalaemia, which is associated with an increased risk of ventricular arrhythmias and adverse outcomes in HF. Renal function and electrolyte balance should be monitored in accordance with guideline recommendations, particularly during initiation and dose adjustments of background RAASI therapy.

Potential drug–drug interactions should also be considered, as both patiromer and SZC may bind concomitant oral medications in the gastrointestinal tract; separation of administration times is recommended to minimise this risk. From a practical perspective, pharmacological differences between patiromer and SZC may influence agent selection in HF. Because patiromer exchanges potassium for calcium and does not add sodium load, it may be preferable in patients with advanced HF or congestion. In contrast, SZC has a more rapid onset of action and may be advantageous when prompt potassium reduction is required, such as during hospitalisation or GDMT up-titration. Thus, potassium binders may be considered in selected patients with HF in whom hyperkalaemia limits implementation or optimisation of GDMT, with agent selection individualised according to clinical context, urgency of potassium control, volume status, renal function, tolerability, cost, reimbursement and local availability.

Guideline Recommendations

Current international HF guidelines recognise hyperkalaemia as an important barrier to optimisation of RAASI therapy. The 2021 European Society of Cardiology HF guidelines acknowledge that newer potassium binders such as patiromer and SZC can effectively reduce serum potassium and may facilitate the continuation of RAASIs in patients who develop hyperkalaemia.31 Similarly, the 2022 American Heart Association/ American College of Cardiology/Heart Failure Society of America HF guidelines note that potassium binders may enable continuation of GDMT in patients with hyperkalaemia, although evidence demonstrating improvement in cardiovascular outcomes remains limited.32 In clinical practice, these recommendations highlight the potential role of potassium binders as adjunctive therapies to support optimisation of disease-modifying HF treatments while maintaining safe potassium levels. A practical clinical algorithm for the management of hyperkalaemia during optimisation of GDMT in HF is shown in Figure 4.

Figure 4: Practical Algorithm for Management of Hyperkalaemia during Optimisation of Guideline-directed Medical Therapy in Patients with Heart Failure.

ACEi = angiotensin-converting enzyme inhibitor; AKI = acute kidney injury; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor–neprilysin inhibitor; CKD = chronic kidney disease; GDMT = guideline-directed medical therapy; MRA = mineralocorticoid receptor antagonist; NSAID = non-steroidal anti-inflammatory drug; RAASI = renin–angiotensin–aldosterone system inhibitor.

Limitations of Current Evidence

HF-specific data for both patiromer and SZC are largely derived from small, randomised studies, randomised-withdrawal designs, or observational cohorts with limited event numbers and follow-up, restricting causal inference. For patiromer, evidence is primarily derived from trials focused on potassium control and treatment persistence, including randomised-withdrawal designs such as DIAMOND, rather than hard clinical outcomes. For SZC, although the REALIZE-K trial demonstrated improved maintenance of MRA therapy, it was not powered for clinical endpoints and the exploratory imbalance in HF events warrants cautious interpretation. To date, no large, long-term randomised trial has demonstrated a reduction in mortality or HF hospitalisations with potassium-binder therapy. The real-world implementation, cost-effectiveness and applicability across diverse HF phenotypes and populations remain incompletely characterised. In addition, randomised controlled trials evaluating potassium binders specifically in patients with acute or hospitalised HF are currently lacking, limiting the ability to draw firm conclusions regarding their safety and efficacy in this high-risk clinical setting.

Future Perspectives

Key gaps in the evidence base highlight several priorities for future research. Adequately powered randomised controlled trials are needed in both HF with reduced and preserved ejection fraction to determine whether potassium binder-enabled optimisation of GDMT, including with patiromer and SZC, translates into reductions in mortality and HF hospitalisation. Such studies should incorporate stratification by renal function and hyperkalaemia risk and include health-economic analyses to inform real-world implementation.

Implementation studies evaluating multidisciplinary potassium-management pathways are also required to define how novel potassium binders can be optimally integrated into routine HF care during initiation and up-titration of disease-modifying therapies. The mechanistic and biomarker-driven studies should assess whether sustained potassium control and therapy optimisation are associated with reverse remodelling and identify patient subgroups most likely to benefit. Finally, longer-term real-world safety, comparative effectiveness and cost-effectiveness data – particularly in resource-limited settings – are needed to inform sustainable and targeted use of potassium binders in HF.

Conclusion

Novel potassium binders such as SZC and patiromer are important adjunctive therapies for patients with HF in whom hyperkalaemia limits the implementation of GDMT. Differences in mechanism and onset of action between patiromer and SZC may influence clinical use, with each agent offering distinct advantages for optimising guideline-directed HF therapy. While current evidence supports effective potassium control and treatment optimisation, definitive data demonstrating improvements in HF morbidity or mortality are lacking. Until such outcomes data are available, potassium binders should be used selectively, with careful monitoring of electrolyte balance, renal function and volume status, as part of a comprehensive strategy to maximise evidence-based HF therapy.

Clinical Perspective

• Hyperkalaemia is a frequent and clinically important barrier to the initiation, up-titration and maintenance of guideline-directed medical therapy in patients with heart failure, particularly mineralocorticoid receptor antagonists in those with concomitant renal dysfunction.

• Novel potassium binders, including patiromer and sodium zirconium cyclosilicate, provide effective strategies to maintain normokalaemia and enable continuation or optimisation of renin–angiotensin–aldosterone system inhibitor therapy in selected heart failure populations.

• While current evidence supports their role in facilitating guideline-recommended therapy, definitive data demonstrating improvements in heart failure morbidity or mortality are lacking, underscoring the need for outcome-driven trials and careful patient selection in clinical practice.