Sodium zirconium cyclosilicate for treating hyperkalaemia

Patients in the NHS with serum potassium levels above the normal range do not always need treatment to lower potassium

3.1 Hyperkalaemia is a high level of potassium in the blood. The company defined high serum potassium values as above 5.0 mmol/litre, and the European Resuscitation Council classifies hyperkalaemia as mild (serum potassium level of 5.5 mmol/litre to 5.9 mmol/litre), moderate (6.0 mmol/litre to 6.4 mmol/litre) or severe (6.5 mmol/litre and above). The committee understood that tests of serum potassium values may incorrectly identify hyperkalaemia, and often need to be confirmed before hyperkalaemia is treated. Hyperkalaemia occurs most commonly in people with chronic kidney disease (stages 4 and 5), heart failure, liver disease, metabolic acidosis, and adrenal insufficiency. It can also occur after treatments for high blood pressure, chronic kidney disease, proteinuria (protein in the urine) and heart failure; these treatments include potassium-sparing diuretics or renin-angiotensin-aldosterone system (RAAS) inhibitors. RAAS inhibitors include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) and aldosterone receptor antagonists. Serum potassium levels in people with chronic kidney disease and in people having RAAS inhibitors are routinely monitored. The clinical experts present at the second committee meeting explained that people with heart failure may have treatment for hyperkalaemia at serum potassium levels above 5.5 mmol/litre, whereas people with chronic kidney disease may have treatment at serum potassium levels above 6.0 mmol/litre. They explained that the reason treatment for people with heart failure is considered at a lower serum potassium level than for people with chronic kidney disease is because they are at higher risk from arrythmias, which a sudden change in serum potassium can induce. The committee heard that some people, often those with renal disease, can accommodate high but stable potassium levels. It understood that, once the diagnosis of hyperkalaemia is confirmed, the decision to use a treatment that actively lowers serum potassium takes into account whether the rise in serum potassium is acute and changes on electrocardiogram (ECG). The committee concluded that the company's clinical definition of hyperkalaemia as serum potassium levels above 5.0 mmol/litre was not widely accepted. It also concluded that, unless they need emergency treatment, few patients in the NHS with serum potassium levels above 5.0 mmol/litre have treatment to lower potassium.

The treatment of life-threatening acute hyperkalaemia and chronic hyperkalaemia differs

3.2 The need for, and type of, treatment for hyperkalaemia depends on its severity. Life-threatening acute hyperkalaemia needs emergency treatment in hospital. NICE-accredited clinical practice guidelines for the treatment of acute hyperkalaemia from the UK Renal Association state that the risk of cardiac arrhythmias increases with serum potassium levels above 6.5 mmol/litre. Small rises in serum potassium above this can cause changes on ECG. To lower the risk of cardiac arrest, physicians treat with active potassium-lowering treatments, then identify and remove the cause of hyperkalaemia. The guidelines include the following treatments:

People with chronic hyperkalaemia would welcome an alternative to stopping RAAS inhibitors

3.3 The company proposed that people with chronic hyperkalaemia who take sodium zirconium cyclosilicate would be less likely to stop RAAS inhibitors, so would live longer and have a lower risk of their kidney disease or heart failure getting worse. It did not provide any clinical evidence for this (see section 3.14). NICE's clinical guideline on chronic kidney disease in adults: assessment and management states that RAAS inhibitors should not be 'routinely' started in people with serum potassium levels of 5.0 mmol/litre and above, and should be stopped in people with levels of 6.0 mmol/litre and above. NICE's clinical guideline on chronic heart failure in adults: assessment and management states that serum potassium levels should be monitored before and after starting a RAAS inhibitor or changing RAAS inhibitor dose, but does not specify serum potassium levels at which RAAS inhibitors should be avoided or stopped. The committee and the clinical experts present at both committee meetings agreed that RAAS inhibitors would be used in the NHS for some people with serum potassium levels 5.0 mmol/litre and above and would be stopped when serum potassium levels are 6.0 mmol/litre and above. At levels of serum potassium below 6.0 mmol/litre, the RAAS inhibitor dose would be more likely to be reduced, rather than stopped. This is because the perceived benefits of being on treatment outweigh the risks of having a serum potassium level of between 5.0 mmol/litre and 6.0 mmol/litre. The committee noted that some people stop RAAS inhibitors for reasons other than hyperkalaemia. The committee concluded that patients and clinicians are keen for new treatments that would allow them to continue RAAS inhibitors.

The long-term benefit of continuing RAAS inhibitors on quality of life and survival in people with hyperkalaemia may vary between patient subgroups

3.4 The clinical expert at the first committee meeting explained that the benefit, or potential harm, of being on RAAS inhibitor treatment depended on: the underlying condition; the class of RAAS inhibitor (ACE inhibitors, ARBs, aldosterone receptor antagonists); and outcome (for example, cardiovascular disease, worsening of renal disease, death). The committee was aware that an NIHR-funded trial is evaluating the potential benefit of withdrawing ACE inhibitors and ARBs in people with stage 4 or 5 chronic kidney disease. The British Society for Heart Failure's response to consultation and a clinical expert present at the second meeting both noted that RAAS inhibitors may be of greater benefit in people with heart failure with reduced ejection fraction compared with people with preserved ejection fraction. The committee acknowledged that, rather than stopping RAAS inhibitor treatment, the dose may be reduced for some people with hyperkalaemia (see section 3.3). It also acknowledged that, for people on more than 1 RAAS inhibitor, it may not be necessary to stop more than 1 to resolve hyperkalaemia. The committee concluded that the harms and benefits of stopping RAAS inhibitors because of hyperkalaemia compared with standard care could be affected by the:

Sodium zirconium cyclosilicate is unlikely to replace a low-potassium diet

3.5 The patient experts noted that maintaining a low-potassium diet is challenging because so many foods contain potassium. The clinical experts explained that they consider the diet worth trying, that it is recommended by NICE, and that it lowers serum potassium compared with an unrestricted diet. They added that a new treatment option would not replace dietary advice but complement it, and may mean that the diet need not be so strict. The committee concluded that sodium zirconium cyclosilicate is unlikely to replace a low-potassium diet.

The company proposes using sodium zirconium cyclosilicate in a population narrower than that in the marketing authorisation

3.6 The marketing authorisation indication for sodium zirconium cyclosilicate specifies 'treatment for hyperkalaemia'. It was based on the trials presented by the company in which people with serum potassium levels above 5.0 mmol/litre were recruited and had treatment (see section 3.8). The company focused its submission on people with chronic kidney disease (stages 3 to 5, excluding those on dialysis) or heart failure. The committee was aware that some people in the trial may have had both chronic kidney disease and heart failure. It noted that the population in the company's submission is narrower than the marketing authorisation because the marketing authorisation also includes people with other conditions and milder hyperkalaemia (see section 3.1). The committee concluded that, given the evidence the company chose to present, it would appraise sodium zirconium cyclosilicate within the population the company proposed, which was narrower than the marketing authorisation.

The company proposes that sodium zirconium cyclosilicate will be used in emergency care for acute, or outpatient care for chronic, hyperkalaemia

3.7 The marketing authorisation for sodium zirconium cyclosilicate covers using it as a corrective treatment for lowering serum potassium levels followed by using it as a maintenance treatment (at a lower dose) for people whose serum potassium levels normalise after the corrective treatment. The maintenance dose aims to avoid repeat hyperkalaemia. The committee noted that the marketing authorisation does not specify whether sodium zirconium cyclosilicate should be used to treat life-threatening hyperkalaemia needing emergency treatment, or persistent hyperkalaemia treated in the outpatient setting. It also noted that it does not specify the level of serum potassium at which treatment should be started. The company proposed that sodium zirconium cyclosilicate would be used:

Trial evidence does not show whether sodium zirconium cyclosilicate is more clinically effective than NHS standard care

3.8 The clinical-effectiveness evidence for sodium zirconium cyclosilicate came from the ZS004 and ZS005 trials. The trials were done in the outpatient setting, and included some people who would not have treatment in the NHS (because they had lower serum potassium levels than would be treated in the NHS). In its consultation response, the company presented results for 8 patients in ZS004 with serum potassium levels of 6.5 mmol/litre and above, arguing that these patients are likely to have emergency treatment in the NHS. However, the committee noted that, like all the other patients in that trial, they had had treatment as outpatients. Both trials had 2 phases. The first 'correction' phase was single arm (everyone had treatment to lower their serum potassium levels; there was no control group) in patients with serum potassium levels of 5.1 mmol/litre and above. In response to the appraisal consultation document, the company presented data from a third trial, ZS003, which included a placebo-control arm in the 2‑day correction phase. The second phase of all 3 trials measured how well sodium zirconium cyclosilicate maintained serum potassium levels in people whose serum potassium levels had responded in the 'correction' phase and were between 3.5 mmol/litre and 5.0 mmol/litre. In ZS004, 'responders' were randomised to placebo or to continue sodium zirconium cyclosilicate or placebo for 28 days. In ZS005, all 'responders' had sodium zirconium cyclosilicate for 52 weeks. The committee appreciated that the primary outcome measure in all the trials was serum potassium levels. The single-arm maintenance part of ZS005 measured changing use of RAAS inhibitors as an exploratory endpoint. However, the single-arm design of this trial meant that there were no data on whether, compared with standard care, sodium zirconium cyclosilicate allowed a higher proportion of patients to maintain RAAS inhibitors, a key potential benefit suggested by the company (see section 3.3). The committee concluded that the company had not provided any data comparing sodium zirconium cyclosilicate with treatments currently used in the NHS to correct hyperkalaemia and maintain normal serum potassium levels in the outpatient setting (that is, a low-potassium diet and management of RAAS inhibitors). Also, the trials did not reflect treatment of acute hyperkalaemia in hospital. Without these data, it could not determine whether sodium zirconium cyclosilicate is more clinically effective than current standard care in the NHS in either an emergency care or outpatient setting.

Sodium zirconium cyclosilicate could be beneficial in treating acute life-threatening hyperkalaemia

3.9 The committee noted that treating acute life-threatening hyperkalaemia in hospital is established clinical practice. It agreed that lowering potassium levels for patients needing emergency care was a life-saving intervention. The committee therefore concluded that randomised evidence was not needed to show that treating hyperkalaemia in the emergency care setting prolonged life. As such, the uncontrolled evidence showing that sodium zirconium cyclosilicate reduces serum potassium (see section 3.8) is sufficient to conclude that it could be a useful intervention in people with hyperkalaemia needing treatment in the emergency care setting.

It is not clear whether lowering serum potassium is beneficial in chronic hyperkalaemia

3.10 In the correction phase of ZS003, sodium zirconium cyclosilicate was associated with a greater reduction in serum potassium than placebo. The committee was aware that around three-quarters of people in this trial had serum potassium levels below 5.5 mmol/litre, outside the range that would be treated in the NHS. In the correction phases of ZS004 and ZS005, sodium zirconium cyclosilicate was associated with reduced serum potassium levels from above 5.0 mmol/litre to within the normal range of 3.5 mmol/litre to 5.0 mmol/litre in around 70% of patients. In the subgroup of people with serum potassium levels of 6.5 mmol/litre and above, all patients had serum potassium in the normal range after 48 hours of treatment. The average serum potassium in patients in ZS004, over the 28 days after the correction phase, was 5.1 mmol/litre in the placebo group, and 4.8 mmol/litre and 4.5 mmol/litre in the 5 g and 10 g daily doses of sodium zirconium cyclosilicate groups respectively. These all fell within a range that would not be treated further in the NHS. In response to consultation, the company provided a post-hoc analysis of the subgroups of patients in ZS004 and ZS005 who had baseline serum potassium levels of 6.0 mmol/litre and above and 5.5 mmol/litre and above, the threshold at which RAAS inhibitors are likely to be stopped in chronic kidney disease and heart failure respectively. Most patients had a serum potassium under the threshold after the correction phase and maintained this level during the correction phase. The committee noted:

Sodium zirconium cyclosilicate is associated with adverse effects

3.11 The company presented data showing that treatment with sodium zirconium cyclosilicate was associated with hypokalaemia, that is low serum potassium. The committee understood that hypokalaemia, like hyperkalaemia, is associated with life-threatening arrhythmias. The committee also noted the wording from the European Medicines Agency that the risk of intestinal perforation is currently unknown but has been reported with polymers that act in the gastrointestinal tract. The committee concluded that sodium zirconium cyclosilicate is associated with adverse effects.

There is insufficient evidence to prove a causal link between lowering serum potassium levels and improving long-term outcomes

3.12 Data were not collected in trials ZS003, ZS004 and ZS005 on the effect of sodium zirconium cyclosilicate on long-term outcomes such as progression of chronic kidney disease or mortality. However, the company proposed in its model that people with hyperkalaemia who have sodium zirconium cyclosilicate live longer than people who do not. This was based on a systematic review of evidence for both chronic kidney disease and heart failure. The company presented evidence from observational cohort studies which showed a higher risk of death, hospitalisation and major adverse cardiovascular events associated with high, but also with lower than normal, serum potassium levels. Using these data, the company assumed that, because patients with higher serum potassium compared with normal values have a higher risk of death, sodium zirconium cyclosilicate prolongs life because it lowers serum potassium. The committee noted that the observational data did not guarantee an independent association between high serum potassium levels and death. It also noted that the observational data did not provide evidence that lowering serum potassium extends life. The committee was aware that these studies could adjust only for known, measured confounders. It also noted that the studies may have been affected by time-dependent confounding, for example, because increasing serum potassium levels affects RAAS inhibitor use, which in turn affects subsequent serum potassium levels and long-term outcomes. Therefore, RAAS inhibitor use is a time-dependent confounder. The committee was aware that using standard regression adjustment is not appropriate when attempting to estimate causal effects from observational data affected by time-dependent confounding, and noted that the company was unable to show that alternative appropriate methods had been used. It also noted that the authors of a company-supported observational study used in the model cautioned against assuming a causal effect, and acknowledged the possibility of residual confounding. It agreed that a relationship between lowering serum potassium to a normal range and fewer adverse outcomes was biologically plausible for a subset of endpoints. While the company claimed that a randomised trial showed that lowering potassium prolonged survival in people with heart failure, the committee recognised this was a post-hoc observational analysis of a trial cohort. The company did not otherwise provide randomised evidence that lowering serum potassium prolongs life in the outpatient setting. The committee concluded that there was insufficient evidence to prove definitively that lowering serum potassium levels in the outpatient setting leads to improved outcomes.

Stopping RAAS inhibitors likely increases the risk of death, hospitalisation and disease progression

3.13 In addition to proposing clinical benefit because of lowering serum potassium levels (see section 3.12), the company also proposed that people having treatment with sodium zirconium cyclosilicate would live longer and have a better quality of life than people not on treatment. This was because treatment with sodium zirconium cyclosilicate would allow them to maintain or restart treatment with RAAS inhibitors. Based on targeted reviews for chronic kidney disease and heart failure, the company presented data from a network meta-analysis of randomised controlled trials and several observational studies. It assumed that, because these studies showed that starting a RAAS inhibitor is associated with living longer, people who stop a RAAS inhibitor would have shortened lives. It also presented evidence that RAAS inhibitors are associated with delayed disease progression, and therefore improved quality of life. The committee noted that it would have preferred to have seen a systematic review of the literature. It also noted that it was unclear whether the company had considered in its analyses the factors that may affect the balance of harms and benefits of continuing RAAS inhibitors in people with hyperkalaemia. The committee noted evidence from the clinical experts and from responses to consultation that the benefits of RAAS inhibitors were well established for certain people. It concluded that, in the population being considered, stopping RAAS inhibitors would generally be associated with an increased risk of adverse outcomes and disease progression. The committee concluded that starting RAAS inhibitors prolongs life for many people, so stopping RAAS inhibitors for people who benefit from them would likely shorten life.

There is no evidence that sodium zirconium cyclosilicate prolongs survival in people having treatment for chronic hyperkalaemia

3.14 The committee recalled that serum potassium levels outside the normal range (but below the threshold needing treatment as an emergency in hospital) may increase the risk of mortality (see section 3.12). However, the committee noted that there was no comparative evidence from a randomised trial showing that lowering serum potassium in such people prolonged survival. Stopping RAAS inhibitors may also increase the risk of mortality (see section 3.13). The committee noted that there was also no comparative evidence from clinical trials that RAAS inhibitor use differed between people having sodium zirconium cyclosilicate and people having standard care in the NHS. Therefore, the committee concluded that there was no direct evidence that sodium zirconium cyclosilicate improves survival in people having treatment for chronic hyperkalaemia.

The company's patient-level simulation model is appropriate

3.15 The company modelled the cost effectiveness of sodium zirconium cyclosilicate using a patient-level simulation model. The model generated a serum potassium trajectory for each patient over time. The proportion of patients who entered the model on RAAS inhibitors was based on the ZS005 clinical trial. Thereafter, RAAS inhibitor use was determined by the patient's serum potassium trajectory. The company chose to model sodium zirconium cyclosilicate as prolonging life in 2 ways: by level of serum potassium (in which treatment led to the full benefit seen in epidemiological studies) and by whether the patient was on a RAAS inhibitor (see sections 3.12 and 3.13). Therefore, patients in the model with normal levels of serum potassium and on RAAS inhibitors on average lived longer and had a better quality of life than patients with higher levels of serum potassium not on RAAS inhibitors. The committee noted that the company modelled 2 settings:

It is not appropriate to assume that lowering serum potassium in people with chronic hyperkalaemia prolongs life, based only on observational studies

3.16 The company modelled an association between serum potassium levels and the risks of mortality, hospitalisation and major adverse cardiovascular events using observational studies. The committee recalled that the observational studies supporting this assumption did not establish a direct causal link between lowering serum potassium and improved outcomes (or low serum potassium levels and worse outcomes). Also, it was aware that the underlying causes of hyperkalaemia may have led to poor outcomes rather than the hyperkalaemia itself, and that it was unclear whether results from the observational studies had been appropriately adjusted to account for time-dependent confounders (see section 3.12). The committee noted that the company chose a single, company sponsored, study (Luo et al., 2016) rather than a meta-analysis, and that this was a US study rather than a UK study. The ERG assumed no direct effect of potassium levels on outcomes in an exploratory analysis. The committee agreed that this could be conservative for some endpoints but agreed that this was reasonable without better evidence. It noted that the company had done scenario analysis individually, reducing the increased risk of mortality, hospitalisation or adverse events assumed to be caused by abnormal potassium levels to 80% of the modelled benefit in the company's base case. However, the committee would have preferred to have seen a wider range of scenarios, including its preferred scenario of no benefit, to understand the uncertainty around these parameters. It concluded that it is not appropriate to assume that lowering serum potassium prolongs life in people with chronic hyperkalaemia, based only on observational studies. It would have preferred to have seen how sensitive the estimates of cost effectiveness were to this assumption. Given the uncertainty, the committee concluded that it would like to have seen that sodium zirconium cyclosilicate was cost effective in the absence of an association between serum potassium and adverse outcomes, including death.

The company's approach to modelling the association between RAAS inhibitor use and outcomes is appropriate

3.17 The company modelled an association between use of RAAS inhibitors and the risks of mortality, hospitalisation and major adverse cardiovascular events based on odds ratios from a network meta-analysis of clinical trials of starting RAAS inhibitors (Xie et al., 2016). The committee recalled and accepted evidence from the clinical and patient experts that maintaining RAAS inhibitor therapy is likely to be beneficial for certain patients (see section 3.13). It noted that the company did scenario analyses using alternative data sources and assuming that RAAS inhibitor use had no effect on outcomes. The committee concluded that the company's approach to modelling the association between RAAS inhibitor use and outcomes was appropriate.

The number of people who stop, down-titrate or restart RAAS inhibitors is a source of uncertainty in the model

3.18 The proportion of patients in the model who stopped or down-titrated RAAS inhibitors at specific serum potassium levels, or who restarted RAAS inhibitor therapy, were mostly based on clinical expert opinion and differed between sodium zirconium cyclosilicate and standard care. The committee questioned why the company had not provided more robust data for UK practice, and was concerned about the potential conflicts of interests of the experts consulted by the company. It also recalled that it had not seen evidence that the use of RAAS inhibitors would differ depending on whether patients had sodium zirconium cyclosilicate or standard of care (see section 3.13). It therefore preferred the ERG's assumption that rates of stopping, down-titrating or restarting RAAS inhibitors were the same for all patients. It would also have preferred to have seen evidence for the proportion of patients who stop or down-titrate RAAS inhibitors based on UK studies instead of expert opinion.

The costs of sodium zirconium cyclosilicate would be higher in the NHS in the outpatient setting than is assumed by the company

3.19 The committee recalled that the company assumed that in the outpatient setting, patients would have treatment for up to 1 year, and then sodium zirconium cyclosilicate would be stopped (see section 3.15). It noted that this did not align with the expected use in clinical practice, where treatment would continue indefinitely if there was clinical benefit. It would have preferred to have seen a scenario analysis in which the costs and benefits of sodium zirconium cyclosilicate were modelled beyond 52 weeks. The committee concluded that the company's model underestimated the treatment costs in the outpatient setting. The analyses considered by the committee used the list price for sodium zirconium cyclosilicate. However, the committee noted that, because the drug would only be prescribed in secondary care, then it would be eligible for a patient access scheme discount.

The ERG's exploratory base case is more closely aligned to committee's preferred assumptions

3.20 The committee noted that the ERG's exploratory base case was more closely aligned to its preferred assumptions, including:

Sodium zirconium cyclosilicate is recommended as an option for people who need emergency treatment of hyperkalaemia in hospital

3.21 The committee considered the cost-effectiveness results in the emergency care setting. It recalled that randomised evidence was not needed to show that treating hyperkalaemia in the emergency care setting prolonged life, and that such treatment was standard clinical practice (see section 3.9). It also agreed that sodium zirconium cyclosilicate reduced serum potassium levels quickly so was a suitable treatment option in this setting. It noted that the drug was associated with lower costs and improved quality of life in both the company's and ERG's base cases and all scenario analyses. It recalled that these results were subject to some uncertainty because there was limited clinical evidence of sodium zirconium cyclosilicate's use in the emergency care setting (see section 3.8) and the gain in quality-adjusted life years (QALYs) was very small. It also recalled that the model used a short time horizon in the emergency care setting so any long-term benefits of sodium zirconium cyclosilicate (such as enabling patients to restart RAAS inhibitors) may have been underestimated. The committee agreed that people with hyperkalaemia would value the option of an alternative treatment to lower serum potassium levels that was better tolerated than calcium resonium (see section 3.2). It therefore concluded that it could recommend sodium zirconium cyclosilicate as an option for people who need treatment for hyperkalaemia in an emergency care setting.

Sodium zirconium cyclosilicate is not recommended as a treatment option in the outpatient setting

3.22 The committee then considered the cost-effectiveness results in the outpatient setting. In recalled that the ERG's alternative base case was more closely aligned to its preferred assumptions (see section 3.20), but that including life extension based on epidemiological studies was not in line with the committee's preferences. The committee noted that the ERG's base case for chronic kidney disease used an odds ratio for RAAS inhibitor outcomes compared with active control (see section 3.20), and that removing this assumption in line with committee's preferences would likely reduce the incremental cost-effectiveness ratio (ICER) by around £1,500 per QALY gained. It noted that the results were highly uncertain because:

The committee recalled its conclusion that a link between lowering serum potassium levels and improved long-term outcomes was plausible for some outcomes, but unproven (see section 3.16). It agreed that an ICER for decision making would lie near the ERG's scenario analysis removing the association between serum potassium levels and outcomes. The committee would have preferred to have seen evidence that sodium zirconium cyclosilicate was cost effective when this assumption was used. The committee could not determine a most plausible ICER for the outpatient setting because it had not seen scenario analyses that reflected its preferred assumptions. It would also have liked to have seen cost-effectiveness scatter plots to help determine the effect of the uncertainty in the modelled parameters on the cost-effectiveness estimates. The committee also recalled its conclusion that treatment with RAAS inhibitors would improve outcomes but noted that uncertainties around the assumptions of how many patients would down-titrate or restart RAAS inhibitors had not been fully addressed in the company's model (see section 3.17). The committee concluded that, because the modelling assumptions were unsupported by robust evidence, it could not recommend sodium zirconium cyclosilicate for people with chronic hyperkalaemia in the outpatient setting.

The company has not shown that sodium zirconium cyclosilicate is innovative

3.23 The company proposed several benefits of sodium zirconium cyclosilicate, including preventing the need to modify RAAS inhibitor treatment and avoiding a restrictive low-potassium diet. The committee recalled that people would still need to avoid dietary potassium. The patient experts stated that, if the company had shown evidence for these benefits, then sodium zirconium cyclosilicate would be innovative. The committee was aware that other gastrointestinal potassium binders exist and, although these are not well tolerated, sodium zirconium cyclosilicate does not represent a step-change in treatment. The committee concluded, sodium zirconium cyclosilicate could not be considered innovative.