Pivotal clinical trials, meta-analyses and current guidelines in the treatment of hyperkalemia Free

Abstract

Hyperkalemia (HK) is the most common electrolyte disturbance observed in patients with advanced stages of chronic kidney disease (CKD), is a potentially life-threatening clinical condition due to an increased risk of fatal arrhythmias, and strongly impacts the quality of life and prognosis of CKD patients. Moreover, while renin–angiotensin–aldosterone system inhibitors (RAASIs) represent the most cardio-nephro-protective drugs used in clinical practice, the treatment with these drugs per se increases serum potassium (sK) values, particularly when heart failure and diabetes mellitus coexist. In fact, the onset or recurrence of HK is frequently associated with not starting, down-titrating or withdrawing RAASIs, and is an indication to begin renal replacement treatment in end-stage renal disease. Current strategies aimed at preventing and treating chronic HK are still unsatisfactory, as evidenced by the relatively high prevalence of HK also in patients under stable nephrology care, and even in the ideal setting of randomized clinical trials. Indeed, dietary potassium restriction, the use of sodium bicarbonate or diuretics, the withdrawal or down-titration of RAASIs, or the administration of old potassium binders, namely sodium polystyrene sulphonate and calcium polystyrene sulphonate, have limited efficacy and are poorly tolerated; therefore, these strategies are not suitable for long-term control of sK. As such, there is an important unmet need for novel therapeutic options for the chronic management of patients at risk for HK. The development of new potassium binders may change the treatment landscape in the near future. This review summarizes the current evidence on the treatment of chronic HK in cardio-renal patients.

INTRODUCTION

Hyperkalemia (HK) is a common finding in patients with advanced stages of chronic kidney disease (CKD), particularly when heart failure (HF) and diabetes mellitus (DM) coexist. HK remarkably increases the risk of sudden death due to fatal arrhythmias [1, 2], strongly impacts upon the quality of life and prognosis [3], and acts as a major driver to start renal replacement treatment (RRT) in end-stage renal disease (ESRD) [4, 5].

Moreover, HK hinders the use of renin–angiotensin–aldosterone system inhibitors (RAASIs) in patients with CKD and HF, in whom RAASIs have been shown to effectively improve renal and cardiovascular outcomes, but also to compound the risk of HK [6, 7]. In fact, while the fear of HK leads to sub-optimal use of RAASIs in current clinical practice [8], submaximal doses or treatment withdrawal in patients with CKD or HF, or a combination of these two clinical conditions (‘cardio-renal patients’), is associated with significantly worse outcomes compared with patients on recommended doses [6, 9]. On the contrary, although HK has been reported as an infrequent complication of RAASIs treatment in randomized clinical trials (RCTs), results coming from real-world observational studies suggest that HK rates are alarmingly higher [10–12]. Consequently, RAASIs are widely underutilized in patients who would otherwise derive the greatest benefits from therapy, and HK represents the main obstacle to the initiation or sustained treatment with these drugs [13, 14].

Whilst effective therapeutic options are available for the acute management of HK, current strategies for the treatment of chronic HK have limited efficacy. Diuretic therapy and the use of the old potassium (K) binders, namely sodium polystyrene sulphonate (SPS) and calcium polystyrene sulphonate (CPS), are generally not well tolerated or are potentially harmful, and are anyway not suitable for the use in the long term. As regards a restriction of dietary K intake, a recent comprehensive review has suggested an intake of 4.7 g/day in the early stages of CKD without risk of HK, while dietary K restriction down to 2–3 g/day is recommended in CKD patients with serum K (sK) >5.3 mmol/L [15]. Correct dietary counselling and intervention are therefore crucial in CKD patients in order to limit dietary K load in the case of chronic or recurrent HK. Careful recall of K intake may focus the dietary intervention and prevent excessive K load, leading to a reduction in sK. Unfortunately, education for a dietary approach to limiting K-rich foods is uncommon during clinician visits. Studies on the effectiveness of K dietary management in patients with advanced CKD are needed because, up to now, the efficacy of dietary counselling in the prevention or treatment of chronic HK remains to be demonstrated (Table 1).

Thus, there is an important unmet need for a well-tolerated therapy to control sK both in patients with CKD or HF requiring treatment with RAASIs, and in those who need to start RRT due to the development of HK not responsive to medical treatment.

For decades, SPS has represented the cornerstone of the treatment of chronic HK. However, SPS long-term efficacy and safety have not been evaluated in large-scale RCTs and many adverse effects such as constipation, diarrhoea, sodium loading, hypomagnesemia, hypocalcemia and even life-threatening colonic necrosis have limited its use in current clinical practice. Moreover, SPS has been typically used in hospitals and less frequently in the outpatient setting due to low tolerability [16, 17]. It is noteworthy that there are country-specific differences in the use of ‘old’ K binders because of different views among nephrologists concerning the benefit-to-risk ratio in treating chronic HK. In fact, an analysis performed on data from the Dialysis Outcomes and Practice Patterns Study showed that >40% of dialysis patients were prescribed SPS in France, compared with 25% in Sweden, 14% in Belgium, 13% in Italy and 5% in Canada. In the USA, Australia, New Zealand and Germany, only 1–3% of patients were prescribed SPS, and <1% of dialysis patients had SPS prescribed in the UK, Spain and Japan [18]. The very low rate of prescription of SPS in some countries (e.g. the USA) may arise from concerns over the risk of colonic necrosis during treatment with the resin mixed with 70% sorbitol, also given the Food and Drug Administration (FDA) black box warning, while most European nephrologists appear more strongly persuaded of the effectiveness of SPS in lowering sK than they are concerned about the drug safety.

CPS has an advantage over SPS, as it binds K in the distal colon in exchange for calcium and consequently does not cause sodium retention. However, besides being less used in clinical practice, it shares with SPS a paucity of data on long-term efficacy and tolerability.

Two new K binders, namely patiromer and sodium zirconium cyclosilicate (SZC), have been approved in the USA and Europe, and SZC also in Canada, based on the results of several large-scale RCTs in patients with CKD and HF, showing that these drugs allow a long-term effective control of sK and the maintenance of RAASIs at effective doses with limited adverse effects [19] (Table 2). Furthermore, these drugs may hopefully reduce the number of patients with advanced CKD who need to start RRT because of the development of HK [20]. In this review, we will discuss the pivotal clinical trials, current guidelines and meta-analyses available to date on the treatment of HK in the cardio-renal patient.

PIVOTAL CLINICAL TRIALS ON THE TREATMENT OF HK IN CARDIO-RENAL PATIENTS

Patiromer

Patiromer is a non-systemically absorbed polymer that binds K in exchange for calcium predominantly in the distal colon. The net result is an increase in the fecal excretion of K, with ensuing decreased sK. It has been studied in a variety of populations, but primarily in patients with CKD and/or HF [21].

OPAL-HK (A Two-Part, Single-Blind, Phase 3 Study Evaluating the Efficacy and Safety of Patiromer for the Treatment of Hyperkalemia) was a multicentre, prospective Phase 3 study enrolling high-risk patients with CKD Stage 3 or 4 and HK (sK 5.1–6.5 mmol/L), on RAASIs treatment. More than 50% of the patients had DM, 46% an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² and 42% a history of HF. In the first 4-week single-blind phase, 243 patients received patiromer 4.2 or 8.4 g twice daily, depending on baseline sK range. After 4 weeks, sK decreased significantly (−1.01 ± 0.03 mmol/L; P < 0.001), with greater reduction being observed in patients with higher baseline sK. In the second 8-week randomized withdrawal phase of the study, 107 patients whose sK decreased to 3.8–5.1 mmol/L at the end of the initial phase were randomized to continue patiromer at the previous dose or switched to placebo. A statistically significant difference (0.72 mmol/L, 95% confidence interval 0.46–0.99; P < 0.001) in sK change was observed between the group switched to placebo versus the group remaining on patiromer. Interestingly, 94% of patients on patiromer with sK >5.5 mmol/L at baseline were able to remain on RAASIs, compared with 44% of those switched to placebo. Patiromer was well tolerated throughout the study, with constipation being the only adverse events with a reported frequency >3% [22].

AMETHYST-DN (Patiromer in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy) was a long-term Phase 2, multicentre, open-label, dose-ranging RCT in DM patients with mild-to-moderate HK and Stages 3–4 CKD. Patiromer (starting doses of 4.2–16.8 g twice daily) significantly lowered sK and reduced the recurrence of HK in patients treated with RAASIs from Week 4 through Week 52. It is also noteworthy that patients treated with patiromer experienced a significant reduction in mean systolic and diastolic blood pressure. A significant blood pressure-lowering effect of patiromer, in association with decreasing aldosterone levels, has been confirmed by the OPAL-HK study [23]. Hypomagnesemia was the most common treatment-related adverse event (7.2%), but no patient developed severe hypomagnesemia. Worsening of CKD was the most frequently reported adverse event leading to drug discontinuation. Most of these events occurred during the long-term maintenance phase, suggesting that the progression of underlying CKD was the main contributory factor. Consistent with this observation was the finding that the proportion of patients with more severe CKD at baseline was higher among those who were withdrawn (32.3%) from, than among those who completed (19.9%), the study [24].

PEARL-HF (Evaluation of Patiromer in Heart Failure Patients) was a multicentre, double-blind RCT enrolling HF patients with a history of discontinuation of RAASIs because of the development of HK or eGFR <60 mL/min/1.73 m². Patiromer, compared with placebo, significantly lowered sK levels (−0.45 mEq/L; P < 0.001) and allowed a higher proportion of patients (91% versus 74%; P = 0.019) to remain on treatment with spironolactone at recommended therapeutic dose [25].

To determine the onset of action of patiromer in patients with CKD receiving at least one RAASI, in a separate Phase 1, open-label, single-arm study [26] 27 hyperkalemic patients (sK 5.5–6.4 mmol/L) received patiromer 8.4 g twice daily, after a 3-day potassium-and-sodium restricted diet. Patiromer reduced significantly sK at 7 h after the first dose; sK did not increase either prior to the next dose or within 24 h since the last dose. Overall, patiromer was well tolerated, without serious adverse events and with no withdrawals.

SZC

SZC is an inorganic crystal that is not systemically adsorbed, acting throughout the length of the gastrointestinal tract where it binds K with a strong selectivity in exchange for hydrogen and sodium cations (∼8% sodium by total weight) and providing both targeted and rapid onset of action [27]. SZC has been evaluated in four RCTs (ZS-002, ZS-003, ZS-004, ZS-004E), one of which (ZS-004E) included an open-label extension trial, and one open-label, long-term study (ZS-005). A brief summary of the main results of these studies follows.

ZS-002 was a Phase 2, prospective RCT investigating the safety, tolerability, efficacy and pharmacodynamics of SZC in patients with Stage 3 CKD and HK (sK 5.0–6.0 mmol/L). Ninety patients were randomized to receive SZC 0.3, 3 or 10 g thrice daily, or placebo. The primary efficacy endpoint (rate of sK decline in the first 48 h) was reached in the 3 g (P = 0.048) and 10 g (P < 0.0001) dose groups versus placebo, with SZC showing a dose-dependent sK decrease [28].

ZS-003 was a Phase 3, prospective RCT investigating the safety and efficacy of SZC in patients with HK (sK 5.0–6.5 mmol/L). A total of 753 patients were randomly assigned to either SZC 1.25, 2.5, 5 or 10 g thrice daily, or placebo, for 48 h (initial phase). Patients with normokalemia at 48 h were then randomly assigned to either SZC once daily or placebo for 12 days (maintenance phase) without K dietary restrictions. During the maintenance phase, both SZC 5 and 10 g were significantly superior to placebo in maintaining normokalemia (P = 0.008 and P < 0.001, respectively). HK recurred in patients assigned to placebo who had received SZC 5 or 10 g during the initial phase [29].

ZS-004 (Hyperkalemia Randomized Intervention Multidose ZS-9 Maintenance (HARMONIZE)) was a Phase 3, prospective RCT study of safety and efficacy of SZC in patients with HK (sK ≥5.1 mmol/L). Two hundred fifty-eight patients received open-label SZC 10 g thrice daily for 48 h (initial phase). Patients who achieved normokalemia (N = 237) were randomized to receive SZC 5, 10 or 15g once daily or placebo for 28 days (double-blind maintenance phase) without K dietary restrictions. During the initial 48 h, SZC 10 g thrice daily induced a significant reduction of sK reduction as early as at 1 h. Mean sK was significantly reduced in all SZC groups compared with placebo during the initial and maintenance phase across all prespecified subgroups (CKD, HF, DM and patients on RAASIs), with numerically lower sK being achieved in the higher dose groups. No serious drug-related adverse events were reported in any study group. In the maintenance phase, there was a higher incidence of oedema (generalized and peripheral) in the SZC 15 g group (14.3%) compared with all other study groups, with similar rates being reported in the 5 and 10 g dose groups (2.2% and 5.9%, respectively) and the placebo group (2.4%) [30].

ZS-004E was an open-label extension of the HARMONIZE trial that investigated the safety and efficacy of SZC in patients with HK who completed ZS-004, or who discontinued ZS-004 due to hypokalemia or HK in the maintenance phase and had a mean i-STAT^® K between 3.5 and 6.2 mmol/L, inclusive. One hundred and twenty-three patients from HARMONIZE received an additional open-label treatment with SZC 10 g once daily as an initial dose. SZC dose was titrated in 5 g once daily increments or decrements (maximum 15 g once daily; minimum SZC 5 g once every other day) for up to 11 months. The primary efficacy endpoint was the proportion of patients with average sK ≤5.1 mmol/L during the extended dosing phase. SZC was shown to be effective in maintaining normokalemia for up to 11 months. The proportions of patients with sK ≤5.1 mmol/L and sK ≤5.5 mmol/L ranged from 81.2% to 93.5% and from 97.0% to 100%, respectively, across the extended dosing phase [32].

ZS-005 was a 12-month, prospective, open-label, single-arm Phase 3 study investigating the efficacy and safety of SZC for the long-term management of HK. A total of 751 outpatients with HK (i-STAT K ≥5.1 mmol/L) were enrolled across 56 sites. No dietary restrictions or changes in RAASIs therapy were required. Patients were initiated with SZC 10 g thrice daily for 24 to 72 h (correction phase). Patients who achieved normokalemia (i-STAT K 3.5–5.0 mmol/L) at any point during the correction phase immediately qualified to enter the maintenance phase with a starting dose of SZC 5 g once daily. Modification of SZC dose, in increments/decrements of 5 g once daily up to a maximum of 15 g once daily or a minimum of 5 g every other day, was allowed based on i-STAT K measurements. Primary efficacy endpoints included the proportions of patients who achieved sK 3.5–5.0 mmol/L during the correction phase and who maintained mean sK ≤5.1 and ≤5.5 mmol/L over months 3–12. In the correction phase, the proportions of patients achieving sK 3.5–5.0 and 3.5–5.5 mmol/L were 78% and 99%, respectively. Across the maintenance phase, 88% of patients had a mean sK of ≤5.1 mmol/L, and 99% had a mean sK ≤5.5 mmol/L. There was a mean reduction of 0.9 mmol/L (−15%) in sK from correction phase baseline to maintenance phase baseline. Maintenance of normokalemia between maintenance phase days was also observed across subpopulations, including patients on RAASIs and those with CKD or HF. Throughout the maintenance phase, mean sK levels remained within the normal range, but were seen to increase at the end of study, following discontinuation of SZC (7 days after the last dose). Over the 12-month maintenance phase, peripheral oedema was reported in 113 patients (15%), which was rated as mild-to-moderate in 90% of patients. However, oedema was considered related to SZC in 18 patients (2%) [33].

Additionally, oedema or peripheral oedema, most of which was defined as mild, was reported in 63/468 (13.5%) patients with DM and in 24/278 (8.6%) non-DM patients during the maintenance phase of ZS-005 [31].

While SZC contains ∼800 mg of sodium in a 10 g dose [27], and this may theoretically be a reason for caution in patients with HF, the clinical significance of this adverse effect seems modest according to published data [28–33].

It should be underscored that no specific definition of oedema was provided in published trials with SZC, nor were changes reported for urinary sodium excretion or body weight. From a pathophysiological standpoint, an increase in sK directly inhibits sodium chloride (NaCl) reabsorption by Na-Cl co-transporter (NCC) in the distal convoluted tubule via depolarization of the plasma membrane, increase in intracellular chloride concentration and ensuing inhibition of the with-no-lysine kinase-dependent NCC phosphorylation. Hypokalemia produces the reverse effects, especially in the presence of hypovolemia and increased levels of angiotensin II. Thus, on theoretical grounds, a marked reduction in sK obtained with K binders may favour NaCl reabsorption increasing the risk of fluid retention, especially with SPS and SZC that exchange K for sodium [34].

The characteristics of the ongoing clinical trials on both patiromer and SZC are summarized in Table 3.

META-ANALYSES OF STUDIES ON THE CLINICAL USE OF PATIROMER AND SZC IN CARDIO-RENAL PATIENTS

Two systematic reviews and meta-analyses have evaluated the evidence concerning the efficacy and safety of treatment with patiromer and SZC in patients with CKD, HF and DM.

Meaney et al. performed a qualitative review including eight completed studies and a random-effects meta-analysis including six studies with 654 patients on patiromer and 1102 patients on SZC [19]. Mean age, sK and eGFR of patients at baseline were similar in patiromer and SZC trials (65.8 years versus 65.7 years, 5.31 mmol/L versus 5.35 mmol/L, and 45.1 mL/min/1.73 m² versus 45.8 mL/min/1.73 m², respectively). However, the overall prevalence of CKD, HF and DM was lower in the SZC than in the patiromer trials (66% versus 93%, 39% versus 48%, and 61% versus 73%, respectively); also, the overall proportion of patients treated with RAASIs was lower in the SZC than in the patiromer trials (67% versus 86%).

For patiromer, the mean change in sK at Week 4 was −0.70 mmol/L; the mean change in sK at Day 3 was −0.36 mmol/L. Of the patients, 93% could continue, start or titrate RAASIs during the maintenance phase of the trials. For SZC, the mean change in sK at 48 h was −0.67 mmol/L; the mean change in sK at 1 h was −0.17 mmol/L. None of the included trials reported the proportion of patients that could continue, start or titrate RAASIs. A subgroup analysis of 45 patients with baseline sK ranging from 6.1 to 7.2 mEq/L had a mean −0.4 mmol/L decrease in sK at 1 h after 10 g SZC administration.

As for safety issues, overall 7.6% of the patients in patiromer studies experienced constipation and 7.1% experienced hypomagnesemia (P < 0.05; compared with placebo), while 1.1% of the patients in SZC studies experienced urinary tract infections and 0.9% experienced oedema.

Das et al. published a systematic review and meta-analysis on the efficacy and safety of patiromer in hyperkalemic patients [35]. These investigators included the OPAL-HK [22], the AMETHYST-DN [24] and the PEARL-HF trials [25] in their systematic review, but limited their meta-analysis to the PEARL-HF and the Part B of the OPAL-HK trials, with the aim of evaluating hard outcomes (i.e. all-cause mortality, frequency and duration of hospitalizations, all reported cardiovascular or gastrointestinal adverse events, episodes of hypokalemia or HK during the treatment period) as primary endpoints. Serial changes in sK during the treatment period and after drug discontinuation, and all other adverse reactions during the treatment period were evaluated as secondary endpoints.

In the patients treated with patiromer compared with placebo, the investigators found a non-significant decrease in all-cause mortality and a non-significant increase in all serious cardiovascular events. The risk of non-serious gastrointestinal events was significantly lower with placebo compared with patiromer. However, the frequency of all serious adverse events was non-significantly lower in patients treated with patiromer than in patients that received placebo. No data on the frequency of hospitalization or hypokalemia were available during the treatment period investigated.

As for efficacy, the proportion of patients with HK at the end of treatment was lower in those treated with patiromer than in those allocated to placebo, both in the PEARL-HF trial (7.3% versus 24.5%) and in Part A of the OPAL-HK trial (15% versus 60%).

As for a lower (8.4–25.2 g/day) compared with a higher (16.8–33.6 g/day) patiromer dose, the patients receiving a lower dose had a non-significantly lower risk of all-cause mortality, all serious cardiovascular adverse events, all serious gastrointestinal events, all other cardiovascular adverse events and all other gastrointestinal adverse events. The lower dose of patiromer significantly reduced the risk of all non-serious miscellaneous (pruritus, fatigue and headache) events compared with the higher dose. The reduction in the risk of serious renal adverse events with a lower compared with a higher dose was significant in the AMETHYST-DN trial, but not in the OPAL-HK Part B trial. Overall, the reduction of all other renal adverse events with the lower dose was non-significant. No data on the frequency of hospitalization were available, nor was the frequency of hypokalemia or HK investigated with respect to different patiromer dose. As for efficacy, the mean change in sK at the end of the trials or at the first drug dose titration was greater with a higher compared with a lower dose of patiromer. To date, there is no clear-cut evidence supporting a dose-dependent effect of patiromer or SZC on hard cardiovascular endpoints or on all-cause mortality.

GUIDELINES ON THE TREATMENT OF HK IN CARDIO-RENAL PATIENTS

Recommendations by international guidelines with reference to the monitoring and management of HK in cardio-renal patients are largely indirect, and pertain to indications to the starting and titration of RAASIs, with special attention being devoted to mineralocorticoid receptor antagonists (MRAs), according to sK at baseline and during treatment. In fact, even the recommendations provided by published guidelines differ slightly as to the level of sK (e.g. >5.0 versus >5.5 mmol/L) at which the dose of RAASI should be decreased or the treatment with these drugs should be stopped, and a K-lowering agent should be started. However, both retrospective studies conducted in patients with CKD, Type 2 DM or HF, or various combinations of these separate conditions suggest that the lowest mortality occurs in these patients at sK values ∼4.0–4.5 mmol/L, increasing significantly at sK >5.0 mmol/L or <4.0 mmol/L.

The 2016 European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of acute and chronic HF [6] indicate that MRAs should be started at low dose, and subsequently uptitrated, in all patients with HF with reduced ejection fraction and sK <5.0 mmol/L if symptoms persist despite optimal doses of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). However, if sK increases to >5.5 mmol/L during treatment, MRA dose should be halved and sK should be monitored frequently; if sK increases to >6.0 mmol/L, ESC guidelines recommend that MRAs be stopped immediately. As a general rule, it is suggested that sK and serum creatinine be monitored at 1 and 4 weeks after starting/increasing dose and at 8 and 12 weeks, 6, 9, and 12 months, and 4-monthly thereafter. Furthermore, the advocated sK threshold for seeking specialist advice is as low as >5.0 mmol/L during treatment with ACEI or ARB, and it is recommended that treatment with these agents be stopped if sK increases to >5.5 mmol/L. These recommendations, based mainly on epidemiological evidence [3], are in line with those of a partial update of the National Institute for Health and Care Excellence Guidelines on CKD issued in 2014, stating that RAASIs should not be routinely offered in patients with CKD if pre-treatment sK exceeds 5.0 mmol/L, and that treatment should be stopped if sK is >6.0 mmol/L notwithstanding the discontinuation of other drugs that may promote HK [36]. As all current guidelines recommend treatment with RAASI in CKD, Type 2 DM and HF, and the risk of HK is significantly increased by this treatment, a prudent choice of the lowest threshold of sK >5.0 mEq/L has been made for the definition of HK in most of the interventional trials with the new K-binding drugs, for safety reasons.

A recent consensus document issued by the Working Group on Cardiovascular Pharmacotherapy of the ESC has further elaborated on the recommendations by the 2016 ESC guidelines, on the grounds that RAASIs treatment, particularly MRAs, are frequently down-titrated or stopped when HK develops, and these agents are not reinstituted when sK has decreased to safe values [37]. As the prevalence of CKD and DM is elevated among patients with HF, the substantial risk of developing potentially dangerous HK in these patients exposes them to undertreatment with RAASIs, and deprives them of proven benefits in terms of reduction of the risk of death and hospitalization for worsening HF. In this perspective, published guidelines recommend that appropriate dietary prescriptions be provided to patients with CKD to reduce K daily intake that concomitant drugs known to induce HK be withdrawn, and that non-K sparing diuretic be started or uptitrated [6, 36, 38, 39]. Moreover, expert consensus suggests that treatment with an approved K-lowering agent (i.e. K-binding drugs) be initiated as soon as sK rises above 5.0 mmol/L in patients on at-target doses of RAASIs to allow the prosecution of treatment. An approved K-binding drug may also be started early, when sK is still <5.0 mmol/L, to facilitate uptitration of RAASIs to optimal doses. Levels of sK should be monitored closely, and RAASIs should be stopped if sK increases to >6.5 mmol/L. As SPS has a low though definite risk of colonic necrosis and is not suitable for chronic treatment, it has been suggested that patiromer or SZC may be preferable options to prevent or treat HK and allow the prosecution of adequate RAASIs treatment in patients with HF [37]. On the contrary, no data from clinical trials are available on the efficacy and safety of the treatment with new K-binding drugs for >12 months.

Recently, the sK threshold to down-titrate or stop treatment with MRAs in patients with HF has been debated [40, 41]. In fact, on one hand, data obtained from large patient populations with HF, especially when CKD and/or DM coexist, indicate a U-shape relationship between sK and mortality, and suggest that the risk of death increases significantly for sK >5.0 or <4.0 mmol/L [3, 42, 43]; on the other hand, secondary analyses of the Randomized Aldactone Evaluation Study and EMPHASIS-HF studies have shown that the beneficial effects of MRAs on cardiovascular outcomes were detectable also in patients with sK >5.5 mmol/L [44, 45], and high–normal sK (5.0–5.5 mmol/L) values in another large published cohort of patients with chronic HF were associated with favourable outcomes [46]. However, it should be noted that pivotal trials on MRAs in HF have excluded patients with baseline sK >5.0 mmol/L and serum creatinine >2.5 mg/dL or eGFR <30 mL/min/1.73 m²; thus, there is a substantial risk of development of severe HK in real-world patients with HF and advanced CKD. In this respect, a position paper issued by the Italian Society of Nephrology has advocated that sK ≥5.0 mmol/L be considered abnormal in CKD, and require careful follow-up and implementation of preventive and therapeutic strategies aimed at maintaining sK in the optimal clinical range (4.0–4.5 mmol/L). Specifically, it is suggested that adequate treatment and nutritional approach be adopted to offset chronic HK in patients with CKD and HF, and that the use of new oral K binders be considered to allow the prosecution of optimal RAASIs doses [47].

CONCLUSIONS

HK is a common and challenging problem for clinicians caring for patients with CKD and/or HF. The therapeutic options for treating chronic HK have remained unchanged over recent decades, with discontinuation of RAASIs being the main strategy to prevent the onset or recurrence of HK.

Actually, other approaches to prevent or treat chronic HK have been proved to be unsatisfactory, due to a low rate of patient adherence (K dietary restriction), unfavourable efficacy and safety profile (SPS), and potentially adverse effects (intensive diuretic treatment). Therefore, there is an important unmet need for new therapeutic options for the chronic management of patients with or at risk for HK, and indeed the potential availability of new therapies may change the treatment landscape in the near future.

Patiromer and SZC appear as effective and well-tolerated medications to reduce sK consistently and safely over the long term. These K binders could allow the adoption of a wider use of RAASIs at recommended doses in patients with CKD and HF and, hopefully, could enable a delay the start of RRT due to the development of HK in patients with ESRD.

ACKNOWLEDGEMENTS

This article was published as part of a supplement financially supported with an educational grant from Vifor Fresenius Medical Care Renal Pharma and AstraZeneca with no influence on its content.

CONFLICT OF INTEREST STATEMENT

S.B. has no conflict of interest to declare. G.R. has received lecture fees from AstraZeneca and Otsuka. The authors declare that this manuscript has not been published previously in whole or in part.

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