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Managing Hyperkalemia in High-Risk Patients in Long-Term Care
Rajeev Kumar, MD, FACP; Leo Kanev, MD; Steven D. Woods, PharmD; Melanie Brenner, PharmD; and Bernie Smith, RPh, MBA, MHA

Managing Hyperkalemia in High-Risk Patients in Long-Term Care

Rajeev Kumar, MD, FACP; Leo Kanev, MD; Steven D. Woods, PharmD; Melanie Brenner, PharmD; and Bernie Smith, RPh, MBA, MHA
Zirconium Cyclosilicate
Sodium zirconium cyclosilicate (ZS-9) is an inorganic cation-exchange crystal currently undergoing clinical evaluation as a potential treatment for hyperkalemia. It is an orally administered compound composed of zirconium and silicate that exchanges sodium and hydrogen for K+ and ammonium as it moves through the GI tract.92-94 Based on recovery of zirconium in feces of ZS-9-treated rats, the drug appears to not be systemically absorbed.93 The silicate compound is administered as a powder mixed in 240 mL (approximately one cup) of water with each dose.95

Clinical Efficacy, Safety, and Tolerability of ZS-9 in the Treatment of Hyperkalemia
In randomized, double-blind, placebo-controlled trials, ZS-9 was effective in reducing serum K+ levels in hyperkalemic patients with CKD, HF, and/or diabetes.94,95 Starting doses in clinical trials ranged from 0.3 to 10 g three times daily (TID), with maintenance doses between 1.25 and 15 g once daily.93-95 In the phase 3 study by Packham and colleagues,94 754 patients with a serum K+ level of 5.0 to 6.5 mEq/L at baseline were treated with 1.25 to 10 g of ZS-9 TID or placebo for 48 hours; those achieving serum K+ level between 3.5 and 4.9 mEq/L were then randomized to receive ZS-9 1.25 to 10 g once daily or placebo from day 3 through day 14. The primary end point (exponential rate of change in serum K+ level during the first 48 hours) showed reductions of 0.11% to 0.30% per hour across ZS-9 dose groups versus 0.09% per hour for placebo (P <.001 for the comparison with the 3 highest dose groups). During the maintenance phase, the 5 g and 10 g doses were significantly better than placebo at maintaining normal K+ levels.

In a phase 3 study evaluating the safety and efficacy of ZS-9 for 4 weeks in outpatients with hyperkalemia (serum K+ level ≥5.1 mEq/L), 258 patients received 10 g of ZS-9 TID for 2 days.95 Those achieving normokalemia (n = 237) were then randomized to ZS-9 (5, 10, or 15 g) or placebo once daily for 28 days.95 The primary end point (mean K+ level in each dose group vs placebo during days 8-29) was met, with significantly lower serum K+ levels in all 3 dose groups (4.8 mEq/L [95% CI, 4.6-4.9], 4.5 mEq/L [4.4-4.6], and 4.4 mEq/L [4.3-4.5] for 5 g, 10 g, and 15 g doses, respectively, vs 5.1 mEq/L [5.0-5.2] for placebo; P <.001 for all comparisons; Figure 495).95

Studies reported in the literature to date have followed patients for up to 28 days of maintenance therapy with ZS-9,93-95 although a recent congress abstract reported data in 421 patients treated with ZS-9 for up to 24 weeks and 149 patients treated for up to 52 weeks in the open-label extension phase of the 28-day maintenance study.96 Mean serum K+ level was 4.7 mEq/L for patients treated for at least 24 weeks, and 89% of patients had a mean serum K+ level of 5.1 mEq/L or less between week 12 and week 52.96

Regarding the safety and tolerability of ZS-9, in the 28-day maintenance phase of the study by Kosiborod and colleagues, 45% to 53% of patients given ZS-9 reported at least 1 AE versus 32% of patients given placebo.95 Edema was the most common AE with ZS-9, with rates increasing with dose (2.2% with 5 g, 5.9% with 10 g, and 14.3% with 15 g).95 Hypokalemia was observed in 10.7% of patients treated with 15 g ZS-9. Across all patients given ZS-9 in the long-term extension, AEs of worsening of hypertension were reported in 8.2%, peripheral edema in 7.6%, and constipation in 5.0%.96

The New Drug Application for ZS-9 was first submitted to the FDA in May 2015 and resubmitted in 2016.97,98 An FDA response to the resubmission is expected in the first half of 2017.

Effects of New K+ Binders on Serum Aldosterone and Blood Pressure
While K+ contributes to regulation of aldosterone synthesis and secretion,99 the relationship between serum K+ levels and aldosterone response is complex.100 In a prespecified exploratory analysis of OPAL-HK, it was reported that mean serum aldosterone levels decreased significantly (−1.99 ± 0.51 [SE] ng/dL; P = .0001) and concordantly with serum K+ levels in the intital patiromer treatment phase.101 In the randomized withdrawal phase, the initial decrease in aldosterone levels was sustained (+0.23 ± 1.07 ng/dL) in patients continuing with patiromer, whereas levels increased significantly (+2.78 ± 1.25 ng/dL; P ≤.03) in those given placebo.101 Because aldosterone activates mineralocorticoid receptors, the decreased aldosterone levels associated with patiromer treatment could represent an additional benefit of the drug.101

With regard to blood pressure, in OPAL-HK, mean systolic and diastolic blood pressures decreased significantly in the initial treatment phase, and during the randomized withdrawal phase in patients receiving patiromer.101 Although AMETHYST-DN was not designed to study the effect of patiromer on blood pressure, mean systolic and diastolic blood pressures decreased considerably.91 The reductions in blood pressure were observed at day 3 (first postbaseline visit) and continued through week 52 of treatment.91 Data presented in an abstract suggest that ZS-9 does not produce any clinically meaningful changes in blood pressure,102 although other preliminary data suggest that ZS-9 is associated with a reduction in aldosterone levels.103

Conclusion
Elderly patients in the long-term care setting characteristically have several disease states and take multiple medications. These patients typically have long-standing hypertension, reduced renal function, and/or HF that puts them at a much greater risk for medication-induced changes in potassium homeostasis. The overactivity of the RAAS plays a major role in the development of end-organ damage and these chronic conditions, so it is logical to target this system. Over the years, the use of RAASIs has been shown to improve clinical outcomes in patients with hypertension, CKD with or without diabetes, and HF, but these benefits come with the risk of hyperkalemia. Physicians practicing in the long-term care setting may be reluctant to add or increase the dose of a guideline-recommended RAASIs because of this risk.

New therapies for the treatment of hyperkalemia will provide clinicians with more options to address this potentially life-threatening electrolyte abnormality. Beyond the treatment of hyperkalemia, these agents may also enable more patients to be maintained on or add guideline-recommended RAASI therapy. New K+ binders could also be appropriate for the older patients with stage 5 CKD who may not be suitable for or refuse dialysis.16,18,19 Hyperkalemia is and continues to be a challenging clinical problem in the elderly patient. A much-needed paradigm shift from the periodic management of hyperkalemia to preventative measures aimed at avoiding these episodes and enabling the continued use of standard of care medications seems to be in sight. 

Acknowledgment: Editorial assistance was provided by Narender Dhingra, MBBS, PhD, of AlphaBioCom, LLC, and funded by Relypsa, Inc.
Author affiliations: Opko Health, Miami, FL (MB); Northwest Suburban Physicians, Arlington Heights, IL (LK) Midwest Geriatrics LLC, Burr Ridge, IL (RK); Remedy Senior Care, Waxhaw, NC (BS); Relypsa, Inc, Redwood City, CA (SDW).
Funding source: This publication was sponsored by Relypsa, Inc.
Author disclosure: Dr Brenner reports previous employment with Relypsa, Inc (August 2015-October 2016), and previous ownership of Relypsa, Inc, stock. Drs Kumar and Kanev report receipt of honoraria from Relypsa, Inc, for participating in an advisory board on hyperkalemia management. Mr Smith reports no relationships or financial interests with any entity that would pose a conflict of interest with the subject matter of this supplement. Dr Woods reports employment with Relypsa, Inc, and previous ownership of Relypsa stock.
Authorship information: Concept and design (RK, SDW); acquisition of data (SDW); analysis and interpretation of data (MB, LK, RK, BS, SDW); drafting of the manuscript (MB, LK, RK, SDW); critical revision of the manuscript for important intellectual content (MB, LK, RK, BS, SDW); administrative, technical, or logistic support (SDW); and supervision (RK).
Address correspondence to: Rajeev Kumar, MD, Midwest Geriatrics LLC, 6101 S County Line Rd, Burr Ridge, IL 60527. E-mail: rkumar@midwestgeriatrics.com.
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