Novel potassium binders: a clinical update

Hyperkalaemia in heart failure

HK is a potentially life-threatening electrolyte abnormality. There is no universal definition of HK; however, a serum level greater than 5.0–5.5 mmol/L is generally regarded as abnormal.⁴ The Swedish heart failure registry showed an increased mortality associated with abnormal serum potassium.⁵ Hypokalaemia is associated with increased long-term mortality, as opposed to HK’s association with increased short-term mortality.⁵

The incidence of HK in heart failure remains highly variable.^4,6,7 In PARADIGM-HF, enalapril was compared with the combination drug sacubitril/valsartan. The latter had a hazard ratio of 0.80 (95% confidence interval [CI] 0.73 to 0.87), but both were associated with significant risk of HK. Mild HK (>5.5 mmol/L) was seen in 17.3% and 16.1% of patients receiving enalapril and sacubitril/valsartan, respectively, and a smaller proportion of patients (5.6% vs. 4.3%, respectively) had severe HK (>6.0 mmol/L).⁸

The PROTECT trial investigated the association of HK during acute heart failure and changes in RAAS inhibitors, and showed HK patients were often on mineralocorticoid antagonists (MRAs) prior to admission. However, dose reduction of MRAs was independently associated with increased 180-day mortality (hazard ratio 1.73, 95%CI 1.15 to 2.60).⁹

Similarly, in patients with cardiorenal syndrome (CRS), the presence of both heart failure and reduced kidney function represents a common risk factor for HK. RAAS inhibitors are both cardio- and reno-protective, yet HK limits application in these patients.¹⁰ The difficulty in prescribing therapeutic doses of RAAS inhibitors because of HK sequelae highlights the practical challenge of effective heart failure management, and the need for a long-term reliable and tolerable potassium-lowering agent.

Patiromer

Patiromer (Veltassa^®, VIfor Pharma) is a new generation of potassium-lowering agent, which was first approved by the Food and Drug Administration (FDA) in 2015. It is an oral suspension that is insoluble, non-absorbed and organic. It comprises the patiromer anion and the calcium sorbitol counter-ion. The active moiety patiromer is a carboxylic acid compound with a relatively low molecular weight, enabling a high binding capacity for cations.¹¹ The polymer works primarily in the distal colon,¹² binding to potassium, and consequently reducing luminal absorption. A summary of trials is provided in tables 1 and 2.^13-15

Efficacy

PEARL-HF

(Evaluation of the Efficacy and Safety of Patiromer, a Polymeric Potassium Binder, in a Double-Blind, Placebo-Controlled Study in Patients with Chronic Heart Failure)

Unique to PEARL-HF, all patients had chronic heart failure (defined as ejection fraction of ~40%, NYHA class II or III) with a mean duration of over four years. In addition, patients were required to have either CKD (defined as estimated glomerular filtration rate [eGFR] <60 ml/min), and were receiving at least one RAAS inhibitor; or previous history of HK leading to RAAS inhibitor or beta blocker being discontinued six months prior.

Primary outcome (measured at four weeks) showed reduced incidence of HK with patiromer (7.3% vs. 24.5% in placebo, p=0.015), and enabled greater scope for uptitration of spironolactone to 50 mg (secondary outcome, 91% vs. 74% in placebo, p=0.019). The treatment group’s potassium level was 0.45 mmol/L lower (p=0.015) compared with the control. In the subgroup analysis, CKD patients experienced a greater reduction of mean serum potassium with patiromer than those without CKD (mean difference in serum potassium between treatment groups –0.52 ± 0.23 mmol/L, p=0.031 vs. –0.35 ± 0.10 mmol/L, p=0.001 in those with eGFR ≥60 ml/min), and a reduced incidence of HK (6.7% vs. 38.5% with placebo, p=0.041).¹⁵

OPAL-HK

(Patiromer in Patients with Kidney Disease and Hyperkalaemia Receiving RAAS inhibitors)

Patients with CKD III/IV (defined as eGFR 15–-60 ml/min/1.73 m²) on at least one RAAS with baseline HK (defined as 5.1–6.5 mmol/L) entered a four-week, single-blinded treatment phase, receiving 4.2 g of patiromer twice daily in mild HK (5.1–5.5 mmol/L), and higher dose of 8.4 g twice daily in moderate-to-severe HK (5.6–6.5 mmol/L).

During phase I, the primary outcome was defined as the mean change in serum potassium from baseline to week four, and the secondary outcome as the proportion of patients achieving the target potassium range. The mean change in potassium was –1.01 ± 0.03 mmol/L (95%CI –1.07 to –0.95 mmol/L, p<0.001), with a more apparent reduction in the moderate-to-severe cohort (–1.23 ± 0.04 mmol/L vs. –0.65 ± 0.05 mmol/L). The majority of patients (76%) achieved target potassium range at week four, with little difference between mild and moderate-to-severe HK patients (74% vs. 77%).

During phase II, 52 patients switched to placebo, and 55 continued to receive patiromer. The estimated median change in the potassium level was 0.72 mmol/L and 0 mmol/L in the placebo and treatment group, respectively. In the treatment group, 15% of patients had at least one episode of HK, 16% required an intervention for HK, and 94% continued RAAS inhibitors. In contrast, 60% in the placebo group had at least one episode of HK, 62% required an intervention for HK, and only 44% were able to continue with RAAS inhibitors.¹⁴

AMETHYST-DN

(Effect of Patiromer on Serum Potassium Level in Patients with Hyperkalaemia and Diabetic Kidney Disease)

This study evaluated the efficacy of patiromer in patients with type 2 diabetes, and CKD (defined as eGFR 15-60 ml/min) with or without hypertension. All patients had hypertension, 87% had CKD III/IV, and 35% had heart failure. All participants had to receive an angiotensin-converting enzyme (ACE) inhibitor, angiotensin-receptor blocker (ARB), or both for ≥28 days.

The primary outcome was the mean reduction in serum potassium level at week four, or prior to initiation of dose titration. Patiromer was associated with a reduction of serum potassium levels at week four (and up to week 52) regardless of severity of baseline HK, and other baseline comorbidities (p<0.001 across all starting doses). Target mean serum potassium level was achieved within 48 hours in mild HK, and week one in moderate HK. During the maintenance phase, 83.1–92.7% and 77.4–95.1% of patients in the mild and moderate HK group, respectively, remained in their target range. However, a significant rise in serum potassium was reported on day three (for mild HK +0.25 mmol/L; for moderate HK +0.33 mmol/L), and day 28 (for mild HK +0.39 mmol/L; for moderate HK +0.48 mmol/L) upon discontinuation of patiromer.¹³

Safety profile

Patiromer is generally a safe and well-tolerated drug. The most common adverse effects are hypomagnesaemia and gastrointestinal disorders with the most frequently reported being constipation, diarrhoea, abdominal pain and flatulence. Most symptoms resolved spontaneously, with only 6–9.2% cases leading to discontinuation of patiromer.^13-15

In AMETHYST-DN, the mean serum magnesium level remained in the normal range throughout the treatment period, with a mean reduction of 0.10 to 0.20 mg/dL and 0.10 to 0.30 mg/dL in the mild and moderate HK groups, respectively.¹³ There was a potential dose-response relationship between higher starting doses and the percentage of hypomagnesaemia. In OPAL-HK, mean serum magnesium was also within the normal range, but 4% of patients were initiated on magnesium replacement.¹⁴ PEARL-HF reported the highest percentage of hypomagnesaemia, and it occurred in two of three (67%) hypokalaemic patients.¹⁵

All studies evaluated hypokalaemia (serum potassium <3.5 mmol/L) as part of safety studies; 3% of patients in OPAL-HK experienced hypokalaemia, 5.6% in AMETHYST-DN, and 6% in PEARL-HF. In all three studies, no patients had a serum potassium of less than 3.0 mmol/L, or serious adverse events as a result. In PEARL-HF, patients were given the highest standardised dose of patiromer from day one, but did not appear to have a higher incidence of hypokalaemia. In contrast, the incidence of hypomagnesaemia was much higher.¹⁵

Current UK practice – patiromer

In February 2020, NICE published guidance on patiromer for treating HK. The recommendations are as follows:²

1. For acute HK alongside standard care.
2. For patients with persistent HK and stage IIIb to V CKD or heart failure, if they have confirmed HK (>6.0 mmol/L), and unable to tolerate RAAS inhibitor as a result, and are not on dialysis.

NICE states patiromer would not replace intravenous insulin and dextrose in the acute setting, but may replace calcium resonium.

There is no evidence supporting the direct effect of patiromer on mortality or progression of CKD in patients with persistent HK.¹⁴ Its perceived benefit is based on the assumption that patients on patiromer would be able to optimise RAAS inhibition therapy.

Sodium zirconium cyclosilicate (SZC)

SZC (Lokelma^®, AstraZeneca) was approved by the FDA in 2018 for the treatment of HK. SZC is an inorganic non-absorbed polymer of zirconium silicate, which selectively traps monovalent cations (potassium and ammonium) over divalent cations (magnesium and calcium cations), and exchanges them for sodium and hydrogen counter-ions. Similar to patiromer, SZC lowers intraluminal potassium ions available for absorption, and increases potassium excretion throughout the GI tract. A summary of trials is provided in table 3.^16-18

Efficacy

HARMONIZE-Global

(Efficacy and Safety of Sodium Zirconium Cyclosilicate for Hyperkalaemia: the Randomized, Placebo-Controlled Trial)

This phase III prospective study recruited outpatients with HK (≥5.1 mmol/L) in the context of diabetes, heart failure, and CKD. Eligible candidates entered a 48-hour open-label correction phase, receiving 10 g of SZC three times a day. The mean reduction of serum potassium was 0.81 mmol/L (95%CI –0.86 to –0.76, p<0.001) and 1.28 mmol/L (95%CI –1.34 to –1.22, p<0.001) at 24 and 48 hours, respectively. Response to SZC was recorded as early as one-hour post-administration; 63.3% (95%CI 57.2% to 69.1%) and 89.1% (95%CI 84.8% to 92.6%) achieved normokalaemia by 24 hours and 48 hours, respectively.

Patients were randomised into the 28-day maintenance phase receiving either SZC 5 g four times daily, 10 g four times daily or placebo. HK recurrence followed a first-order kinetics with 58.6% and 77.3% remaining normokalaemic in the 5 g and 10 g four times daily groups, respectively. In contrast, only 24% of the placebo group maintained normokalaemia.

An 11-month open-label extension (OLE) of HARMONIZE

Inclusion criteria for the OLE included participants with a serum potassium of 3.5–6.2 mmol/L upon completion of the HARMONIZE 28-day maintenance phase, and those who discontinued SZC due to hypo- or hyperkalaemia with normal serum potassium level on day one of the OLE. HK subjects entered the extension correction phase, receiving SZC 10 g three times daily for 24 to 48 hours until serum potassium was corrected. The remaining (normokalaemic) participants entered directly into the extension maintenance phase, commencing on 10 g SZC once daily. There was no salt/diet restriction, and medications such as RAAS inhibitors and diuretics were permitted. At baseline, mean potassium was 4.8 mmol/L, 68.1% of participants were on at least one RAAS inhibition therapy; 64.5%, 13.2%, and 66.5% had CKD, heart failure, and diabetes, respectively.

The primary end point (potassium ≤5.1 mmol/L) was achieved in 92.8% of patients (adjusted 95%CI 84.7% to 96.8%). There were 90.3% of patients able to continue or uptitrate RAAS therapies, and 3.6% discontinued them. Overall, 66.7% reported adverse events, mostly related to GI symptoms. Oedema was reported in 16 patients (13%), and 11 of those had risk factors at baseline predisposing to fluid retention. Diuretics were required in 64.7% of patients with oedema, but none had to discontinue SZC. An observation of note was an improvement in blood pressure at the end of the study, as well as serum bicarbonate, which may be relevant in the context of secondary prevention for CKD.

SZC among individuals with hyperkalaemia – a 12-month phase III study

This outpatient, open-label study included 746 HK adults (K⁺ ≥5.1 mmol/L) entering a 24- to 72-hour correction phase with SZC 10 g three times daily. Once potassium was in range (3.5–5.0 mmol/L), the dose was adjusted to a maintenance dose of 5 g once daily (with uptitration permitted according to a pre-specified algorithm).

Initial mean serum potassium was 5.6 mmol/L, 65% and 15% had CKD and heart failure, respectively, and 65% of patients were on at least one RAAS inhibitor. Upon completion of the correction phase, 78% and 98% achieved serum potassium values of 3.5–5.0 and 3.5–5.5 mmol/L, respectively (primary study end point). Over 3–12 months, 88% and 99% of participants had mean serum potassium of ≤5.1 and ≤5.5 mmol/L, respectively.

The same RAAS inhibition was continued from baseline in 74%, 13% had doses uptitrated, 14% had doses reduced, and 11% had RAAS therapy discontinued. RAAS inhibition was initiated in 14% of naïve participants. Bicarbonate increased by 0.8–1.2 mmol/L and 1% of patients took sodium bicarbonate.

Safety profile

The most common adverse effects of SZC are hypokalaemia and oedema-related events. Owing to the sodium content of SZC, oedema is an important safety concern. Oedema developed in 113 (15%) participants, but only 18 (2%) were thought to be related to SZC. Those who developed oedema were likely to be more advanced in age with worse heart failure, renal function, HK, and used a calcium channel blocker or diuretic at baseline. In view of the multiple comorbidities and absence of placebo control, more studies would be required to determine the risk of SZC-related oedema.

Current UK practice – SZC

In September 2019, NICE published guidance on SZC for treating HK. The recommendations are as follows:³

1. In emergency care for acute life-threatening HK alongside standard care.
2. For patients with persistent HK and stage IIIb to V CKD or heart failure, if they have confirmed HK (>6.0 mmol/L), and unable to tolerate RAAS inhibitor as a result, and are not on dialysis.

NICE state that there is no clinical evidence that SZC extends life or improves quality of life. SZC may allow people to stay on RAAS inhibitors (drugs used to treat heart failure and kidney disease) for longer. Staying on these drugs may extend life and improve quality of life.

Discussion

Both patiromer and SZC demonstrated favourable efficacy and safety in maintaining normokalaemia from available data. A comparison of the two products is provided in table 4. The management of acute life-threatening HK is an established practice in the UK,¹⁹ and NICE stated that the use of either potassium-lowering agent may have a role alongside usual care.^2,3 Evidence suggests SZC has a quicker onset of action, and, therefore, may be more preferable in the acute setting.²⁰ A dose-dependent onset of effect can be seen within the first hour, lowering serum potassium by 0.11 to 0.2 mmol/L, and 0.73 to 1.1 mmol/L by hour 48.^21,22 In contrast, patiromer only demonstrated a reduction of 0.21 mmol/L seven hours after administration, owing to its longer onset of action.²³

A meta-analysis of phase II and phase III clinical trials comparing the two agents shows a higher overall percentage of gastrointestinal adverse events, as well as electrolytes abnormalities in the patiromer group.²⁰ The most apparent differences in adverse events were constipation (7.6% vs. 1.1%) and diarrhoea (4.5% vs. 1.6%), likely due to the osmotic effect of calcium sorbitol. The comparatively higher rate of hypokalaemia and hypomagnesaemia observed could be explained by patiromer’s non-specific cation binding nature. There is a potential dose-response effect of SZC, with patients on the higher dose three-times more likely to develop oedema compared with the lower dose (15.2% vs. 5.1%).²¹ However, only 2.0% and 1.0% of respective patients were thought to have treatment-related oedema. A similar proportion (0.9%) was reported in a meta-analysis, but risk of oedema must be considered in at-risk groups, such as heart failure and CKD.

SZC was not reported to have any drug-to-drug interaction, but can transiently increase gastric pH. It is recommended that other oral medications should be administered at least two hours before and after SZC.²⁴ Patiromer demonstrates significant binding to multiple drugs, and requires medications to be spaced three hours apart,²⁵ but has the advantage of being a once-daily preparation. In practice, commencement of either drug would require patient education to alter the administration time of other medications, as well as dose titration.

There were insufficient data for the long-term use of either agent regarding mortality related to heart failure or CKD. OPAL-HK showed more patients (taking patiromer) stayed on RAAS inhibitors than those taking placebo (94% vs. 44%).¹⁴ The perceived benefit of RAAS inhibition therapy assumes that stopping or reducing treatment is associated with increased mortality. The DIAMOND trial (posted in April 2019) is a phase IIIb, double-blind, placebo-controlled, randomised, and parallel-group study to determine if patiromer will result in continued use of RAAS inhibitors in the context of hyperkalaemia in heart failure. The most important primary outcome would include time to first occurrence of cardiovascular death or cardiovascular hospitalisation compared with the placebo group. This would be the first study to answer if the use of patiromer in optimising RAAS inhibitors would improve cardiovascular outcomes. The estimated primary completion date is March 2020. Similarly, PRIORITIZE-HF (posted in May 2018) is a phase II, double-blind, placebo-controlled, randomised, and parallel-group study to evaluate the efficacy and safety of SZC to initiate and uptitrate RAAS inhibitors. The primary measures include proportion of participants achieving RAAS inhibitors at target dose in comparison with the placebo group. The study was unfortunately stopped due to the COVID-19 pandemic.

Conclusion

Overall, patiromer appears to be a well-tolerated potassium binder with an acceptable adverse event profile. It has a role in the chronic management of HK, and is efficacious in CKD and heart failure patients. The addition of patiromer may allow a higher proportion of patients to continue RAAS inhibitors, but the benefit in long-term clinical outcome has yet to be proven.

SZC may be preferable in the acute setting due its quicker onset of action and achievement of normokalaemia. With fewer drug interactions, patients may find this more tolerable. However, its adverse event of oedema may exacerbate an already present problem in heart failure and CKD patients.

As with patiromer, long-term studies need to demonstrate improvement in mortality and morbidity, however, both these agents may promote more effective management of heart failure.

Key messages

• Both patiromer and sodium zirconium cyclosilicate (SZC) are well tolerated, and may allow patients to continue on optimal renin–angiotensin–aldosterone system (RAAS) therapy
• Long-term mortality data for both agents would be required to demonstrate survival benefits
• SZC may complement insulin and dextrose in the management of acute hyperkalaemia

Conflicts of interest

None declared.

Funding

None.

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