Patients with CKD and HF tend to have recurrent hyperkalemia episodes with successively shorter time between each subsequent episode. In a large population cohort study (n = 157,766) conducted in Denmark between 2000 and 2012, it was shown that among people with CKD that had a first HK event, 42.96% had a second event, with a median time between events of 7.7 months. Patient proportions who experienced a third (57.07%) or fourth (60.10%) hyperkalemia event after previous events were even greater. Similar observations were made among HF patients¹[Thomsen 2018, p. 1614/fig.2].

Reference:

1. Thomsen RW, Nicolaisen SK, Hasvold P, et al. Elevated potassium levels in patients with chronic kidney disease: occurrence, risk factors and clinical outcomes-a Danish population-based cohort study. Nephrol Dial Transplant. 2018 Sep 1;33(9):1610-1620. doi: 10.1093/ndt/gfx312.

Ambulatory care sensitive conditions (ACSCs) are health conditions for which good outpatient care can likely prevent the need for hospitalization and are recognized internationally as a measure of adequacy of ambulatory and primary health care performance. A Canadian retrospective study identified CKD patients at being at high risk of an ACSC-related hospital encounter: Almost one in four hospitalized patients with CKD could have a CKD–related ACSC encounter¹[Ronksley 2016,p.2028/pg.2], most notably for heart failure or hyperkalemia²[Ronskley 2017, p.311/fig.3] .

References:

1. Ronksley PE, Hemmelgarn BR, Manns BJ, et al. Potentially Preventable Hospitalization among Patients with CKD and High Inpatient Use. Clin J Am Soc Nephrol. 2016 Nov 7;11(11):2022-2031. doi: 10.2215/CJN.04690416. Epub 2016 Oct 6.
2. Ronksley PE, Hemmelgarn BR, Manns BJ, et al. Potentially Preventable Hospitalization among Patients with CKD and High Inpatient Use. Clin J Am Soc Nephrol. 2016;11(11):2022-2031. doi:10.2215/CJN.04690416

RAASi (ACEi, MRAs and ARBs) are commonly used to treat CKD. The fact that these drugs are intrinsically associated with serum potassium elevation, and that they are used in populations already at risk for hyperkalemia, create an important clinical dilemma. Downtitration or discontinuation of these agents is one of the strategies that can be used to help correct serum potassium levels; however suboptimal dosing of RAASi therapy is also associated with an increased mortality in CKD patients. Modification of RAASi regimens as a strategy to lower serum potassium should therefore be employed with caution and in accordance with existing guidelines.

Reference:

1. Epstein M, Reaven NL, Funk SE, McGaughey KJ, Oestreicher N, Knispel J. Evaluation of the treatment gap between clinical guidelines and the utilization of renin-angiotensin-aldosterone system inhibitors. Am J Manag Care. 2015;21(11 Suppl):S212-S220.

There is only one randomized clinical trial which studied the efficacy and safety of SPS in mild hyperkalemia. This study, which followed 33 patients for approximately a week, suggest a numerical, but not statistically significant increase in patients achieving normokalaemia in the SPS group vs. the placebo group (73% vs. 38%, P = 0.07). A trend towards higher electrolytic disturbances and an increase in GI adverse events was also observed in the SPS group.  The authors concluded that, despite SPS apparent efficacy, the GI symptoms associated with its use remain a concern, and that additional randomized clinical trials would be needed to appropriately evaluate SPS¹[Lepage 2015, p.2136/pg.1]. 

Reference:

1. Lepage L, Dufour AC, Doiron J, et al. Randomized Clinical Trial of Sodium Polystyrene Sulfonate for the Treatment of Mild Hyperkalemia in CKD. Clin J Am Soc Nephrol. 2015;10(12):2136-2142. doi:10.2215/CJN.03640415

The product monograph indicates that SPS may cause some degree of gastric irritation, and that anorexia, nausea, vomiting, constipation, and diarrhea may also occur¹[Sanofi-Aventis Canada 2018, p. 11].

A recently published Canadian retrospective study analysed the incidence of GI adverse events in over 20,000 adult SPS users. Results indicate that SPS use is associated with a higher risk of adverse GI event over 30 days than non-use (incidence rate = 22.97 per 1000 person-years vs. 11.01 per 1000 person-years)²[Noel 2019, p.1025/pg.1]. These results suggest caution should be exercised with the prolonged use of SPS.

References:

1. Kayexalate® Product Monograph. Sanofi-Aventis Canada Inc. 2018.
2. Noel JA, Bota SE, Petrcich W, et al. Risk of Hospitalization for Serious Adverse Gastrointestinal Events Associated With Sodium Polystyrene Sulfonate Use in Patients of Advanced Age [published correction appears in JAMA Intern Med. 2020 Feb 24;:]. JAMA Intern Med. 2019;179(8):1025-1033. doi:10.1001/jamainternmed.2019.0631

Patiromer Sorbitex Calcium (PSC) and Sodium Zirconium Cyclosilicate (SZC) both act by binding K+ in the gastrointestinal lumen to increase fecal K+ excretion. This results in a reduction of free potassium in the GI tract, leading to a reduction of serum potassium levels. Both agents are not systematically absorbed¹ [Vifor Fresenius Medical Care Renal Pharma Ltd. 2020/p.13-14]²[AstraZeneca Canada Inc., 2020/p.14].

PSC is a cation exchange polymer that exchanges Ca2+ for K+ absorbed 1[Vifor Fresenius Medical Care Renal Pharma Ltd. 2020/p.13]; SZC is a non-polymer inorganic powder that preferentially exchanges H+ and Na2+ for K+²[AstraZeneca Canada Inc., 2020/p.14].

References:

1. VELTASSA® Product Monograph. Vifor Fresenius Medical Care Renal Pharma Ltd. 2020.
2. LOKELMA® Product Monograph. AstraZeneca Canada Inc., 2020.

Several phase 3 randomized clinical trials have already been completed and provide compelling evidence on the efficacy of novel binders for the correction of HK and the maintenance of hyperkalemia.

In the OPAL-HK study, it was shown that PSC can efficiently correct hyperkalemia in patients with CKD in an initial phase of treatment (Mean ( ± SE) change in serum K over 4 weeks: −1.01 ± 0.03 mmol/L (95% CI, −1.07 to −0.95; P<0.001), and that this reduction could be maintained for up to 8 weeks³[Weir 2015, p.211/pg.1].

The efficacy of SZC has been evaluated in three randomized clinical trials. In the ZS-003 trial, which included ambulatory outpatients with HK, with was shown that HK could be rapidly corrected (48 hours) and that normokalemia could be maintained in a stable fashion over a 3-week period⁴[Packham 2015, p.1571/pg.1]. This rapid correction was similarly observed in the HARMONIZE trial, maintenance of normokalemia was observed for a period of up to a year in the extension study⁷[AstraZeneca Inc. 2020, p.23/pg.1] ⁸[Kosiborod 2015, p.2223/pg.1]. In the DIALIZE study, maintenance of normokalemia over 4 weeks was achieved in a significant proportion of patients undergoing chronic hemodialysis¹⁰[Fishbane 2019, p. 1723/pg.1].

References:

1. Pitt B, Anker SD, Bushinsky DA, et al. Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial. Eur Heart J. 2011;32(7):820-828. doi:10.1093/eurheartj/ehq502
2. Bakris GL, Pitt B, Weir MR, et al. Effect of Patiromer on Serum Potassium Level in Patients With Hyperkalemia and Diabetic Kidney Disease: The AMETHYST-DN Randomized Clinical Trial. JAMA. 2015;314(2):151–161. doi:10.1001/jama.2015.7446
3. Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015;372(3):211-221. doi:10.1056/NEJMoa1410853
4. Packham DK, Rasmussen HS, Singh B. New agents for hyperkalemia. N Engl J Med. 2015;372(16):1571-1572. doi:10.1056/NEJMc1501933
5. Ash SR, Singh B, Lavin PT, Stavros F, Rasmussen HS. A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient. Kidney Int. 2015;88(2):404-411. doi:10.1038/ki.2014.382
6. Spinowitz BS, Fishbane S, Pergola PE, et al. Sodium Zirconium Cyclosilicate among Individuals with Hyperkalemia: A 12-Month Phase 3 Study. Clin J Am Soc Nephrol. 2019;14(6):798-809. doi:10.2215/CJN.12651018
7. LOKELMA® Product Monograph. AstraZeneca Canada Inc., 2020.
8. Kosiborod M, Rasmussen HS, Lavin P, et al. Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial [published correction appears in JAMA. 2015 Feb 3;313(5):526. Dosage error in text]. JAMA. 2014;312(21):2223-2233. doi:10.1001/jama.2014.15688
9. Anker SD, Kosiborod M, Zannad F, Piña IL, McCullough PA, Filippatos G, van der Meer P, Ponikowski P, Rasmussen HS, Lavin PT, Singh B, Yang A, Deedwania P. Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients: results from a phase 3 randomized, double-blind, placebo-controlled trial. Eur J Heart Fail. 2015 Oct;17(10):1050-6. doi: 10.1002/ejhf.300. Epub 2015 Jun 16. PMID: 26011677; PMCID: PMC5033065.
10. Fishbane S, Ford M, Fukagawa M, et al. A Phase 3b, Randomized, Double-Blind, Placebo-Controlled Study of Sodium Zirconium Cyclosilicate for Reducing the Incidence of Predialysis Hyperkalemia. J Am Soc Nephrol. 2019;30(9):1723-1733. doi:10.1681/ASN.2019050450

Numerous studies, which evaluated the efficacy and safety of novel potassium binders, have been published in the last few years. Given this wealth of information, systematic reviews and meta-analyses have been conducted in an attempt to better evaluate the outcomes associated with these agents.

In a qualitative review and random-effects meta-analysis, Meaney et al. have included 14 studies comprising 654 patients treated with PSC and 1102 patients who received SZC. Among the selected studies were 2 phase II and 1 phase III trials for PSC; a single phase II and 2 phase III trials evaluated SZC.

The authors concluded that novel potassium binders represent a significant advancement in the armamentarium for HK management, especially with respect to SPS. They identified the time to onset of effect, adverse event profiles and drug interactions to be the more notable differences between PSC and SZC¹[Meaney 2017, p.401/pg.1].

Reference:

1. Meaney CJ, Beccari MV, Yang Y, Zhao J. Systematic Review and Meta-Analysis of Patiromer and Sodium Zirconium Cyclosilicate: A New Armamentarium for the Treatment of Hyperkalemia. Pharmacotherapy. 2017 Apr;37(4):401-411. doi: 10.1002/phar.1906. Epub 2017 Mar 10. PMID: 28122118; PMCID: PMC5388568.

In all pivotal trials, PSC and ZSC have proven to be well tolerated overall, and for periods of up to 1 year, with generally mild to moderate adverse events that resolved spontaneously.

The most commonly reported AEs with PSC were GI disorders (constipation: 6.2%, diarrhea: 3.0%, abdominal pain, 2.9%, flatulence, 1.8%), hypomagnesemia (5.3%) and hypokalemia (1.5%)¹[Vifor Fresenius Medical Care Renal Pharma Ltd. 2020, p.9/tb.2].

For SZC, the most commonly reported AEs were edema (5.7%) and hypokalemia (4.1%). In patients receiving chronic hemodialysis, the most common AEs were constipation (4%) and diarrhea (4%) and hypokalemia (5.2%)²[AstraZeneca Canada Inc., 2020, p.11/tb.5, p.12/tb.7].

References:

1. VELTASSA® Product Monograph. Vifor Fresenius Medical Care Renal Pharma Ltd. 2020.
2. LOKELMA® Product Monograph. AstraZeneca Canada Inc., 2020.

Patients with end-stage renal disease who receive hemodialysis will often present with HK, especially in-between treatments. While dialysis itself plays a role in maintaining normokalemia in these patients, other approaches to manage HK in predialysis are limited with regards to efficacy and safety. Novel potassium binders could therefore represent an option for the management of HK in this setting.

The DIALIZE study is the first randomized, placebo-controlled study to evaluate the efficacy and safety of a novel binder in the management of HK for hemodialysis patients, more specifically during the long interdialytic interval. In this trial, which included 196 patients, 41.2% of patients who received SZC were deemed responders (i.e. maintained a serum potassium of 4.0-5.0 mmol/L) as opposed to 1.0% of the placebo group. The safety profile of SZC appeared similar to what was previously observed in non-dialysis patients1[Fishbane 2019, p.1723/pg.1].

Reference:

1. Fishbane S, Ford M, Fukagawa M, et al. A Phase 3b, Randomized, Double-Blind, Placebo-Controlled Study of Sodium Zirconium Cyclosilicate for Reducing the Incidence of Predialysis Hyperkalemia. J Am Soc Nephrol. 2019;30(9):1723-1733. doi:10.1681/ASN.2019050450