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Literature Review: Hyperkalemia


New Treatment for Hyperkalemia

Current therapy options are limited and there is an increased risk of drug–drug interactions when patients take >1 potassium increasing drug. Hyperkalemia is defined as elevated serum

potassium concentrations (>5.0 mEq/L).


Greater degrees of hyperkalemia—potassium levels of 6.0 to 7.0 mEq/L (moderate hyperkalemia) and >7.0 mEq/L (marked hyperkalemia)—may lead to life-threatening cardiac arrhythmias and cardiac arrest, with increased mortality. Patients at the highest risk for hyperkalemia are those with chronic kidney disease (CKD), with or without diabetes or heart failure.1,2 Therapy for CKD and heart failure often includes medications that interrupt the renin–angiotensin–aldosterone system (RAAS), but these drugs may compound the hyperkalemia risk. Furthermore, the risk is magnified when the drugs are used in combination with other therapies such as angiotensin-converting enzyme (ACE) inhibitors.


 Managing hyperkalemia is challenging because current treatment options are limited. Also, there is greater risk of drugdrug interactions (DDIs) when patients are taking combinations of potassium-increasing drugs. Two oral agents—patiromer and sodium zirconium cyclosilicate (ZS-9)—may offer clinicians new treatment options for patients with hyperkalemia. Both medicines are currently under FDA review.


Efficacy and tolerability, patient comorbidities, and DDIs are important when considering treatment; First Report Managed Care identified 3 studies that examined these criteria. One study reviewed the clinical problem of hyperkalemia and the emerging treatment options in development.3 A second study evaluated patiromer in patients with CKD taking RAAS inhibitors.4 The final study identified patient- and physician-related risk factors for hyperkalemia associated with potassium-increasing DDIs.5 This article provides an overview of these studies.


 Options for the management of hyperkalemia include discontinuation or reduced doses of RAAS inhibitors, loop diuretics, restriction of dietary potassium, or sodium polystyrene sulfonate. None of these approaches are optimal because they require withholding life-saving or kidney preserving therapy, have low rate of patient adherence, or have an unfavorable adverse effect profile and low toler­ability, according to Pitt et al.3  


In a recent study, the researchers identified predictors of hyperkalemia with comorbid conditions (Table 1) and reviewed new treatments that may change the landscape of pharmacologic options. Patiromer and ZS-9 act to re­move potassium by exchanging cations (calcium and sodium for patiromer and ZS-9, respectively) for potassium in the distal colon, binding potassium, and increasing its fecal excretion. Patiromer is an organic, nonabsorbed polymer, while ZS-9 is an inorganic polymer.3



Patiromer has been studied in pa­tients with heart failure, type 2 diabetes and CKD. The PEARL-HF (Evaluation of RLY5016 in Heart Failure Patients) study, for example, was a multicenter, randomized, double-blind, placebo-controlled, parallel group, multidose study to evaluate patiromer in 120 pa­tients with chronic heart failure who were treated with standard background therapy and had an indication for spironolactone. For inclusion, patients were re­quired to have a serum potassium between 4.3 and 5.1 mEq/L at screening, an estimated glomerular filtration (eGFR) rate of <60 mL/min, or a documented history of RAAS inhibitor discontinuation due to hyperkalemia within 6 months.3


Patients were randomized to double-blind patiromer 15 g twice daily or placebo for 4 weeks; spironolac­tone 25 mg once daily was also initiated in the cohort with plans to increase the dose to 50 mg once daily after 2 weeks if serum potassium was >3.5 to ≤5.1 mEq/L. The primary end point was mean change in serum potassium from baseline to day 28. Serum potassium was significantly lower in the patiromer group compared with placebo, regardless of eGFR. A lower incidence of hyperkalemia was observed in the patiromer group versus the placebo group (7% vs 25%, respectively; P=.015); and more patiromer-treated patients had serum potassium of <3.5 mEq/L compared with placebo, but the difference was not significant (6% vs 0%, respectively). Adverse events (AEs) were mainly gastrointestinal (GI), and mild or moderate in severity.3



Two studies have assessed the safety and efficacy of ZS-9 in a variety of di­agnoses associated with hyperkalemia. In a multicenter, 2-stage, double-blind, phase 3 trial, 753 patients with hyper­kalemia were randomly assigned to receive to receive ZS-9 (at a dose of 1.25 g, 2.5 g, 5 g, or 10 g) or placebo 3 times daily for 48 hours. Patients with normokalemia (serum potassium level, 3.5-4.9 mmol/L) at 48 hours were ran­domly assigned to receive either ZS-9 or placebo once daily on days 3 to 14. The primary outcome was the exponential rate of change in mean serum potas­sium levels at 48 hours. The patient population reflected patients with risk factors for hyperkalemia, including CKD (61%), heart failure (42%), diabetes mellitus (61%), and RAAS inhibitor use (64%).3


The mean serum potassium decreased from 5.3 mmol/L at baseline to 4.9 mmol/L, 4.8 mmol/L, and 4.6 mmol/L at 48 hours in the 2.5-g, 5-g, and 0-g ZS-9 groups, respectively, compared with a rate of 5.1 mmol/L at 48 hours in the group who received 1.25 g of the drug and the placebo group. The pa­tients who received 5 g and 10 g maintained serum potassium levels at 4.7 mmol/L and 4.5 mmol/L, respectively, during the maintenance phase, com­pared with more than 5.0 mmol/L in the placebo group. Rates of AEs were similar in the ZS-9 and placebo groups, with GI side effects being the most common complication in the 2 study groups.3


Both agents have the potential to offer advantages over existing management options based on clinical trials demonstrating their tolerability and safety for patients with hyperkalemia, said the researchers. It is also possible that patiromer and ZS-9 might enable more patients to be started or maintained on guideline-recommended RAAS inhibitors.3



Hyperkalemia increases the risk of death and limits the use of RAAS inhibitors in high-risk patients. The OPAL-HK (A Two-Part, Single-Blind, Phase 3 Study Evaluating the Safety and Efficacy of Patiromer for the Treatment of Hyperkalemia) trial was a multinational, single-blind, 2 phase study, which assessed the efficacy and safety of patiromer in patients with stage 3 or 4 CKD who were taking at least 1 RAAS inhibitor and had a serum potassium of 5.1 to <6.5 mmol/L.4


In the initial single-blind treatment phase, 243 patients were enrolled and received patiromer (at an initial dose of 4.2 g or 8.4 g twice a day) for 4 weeks; the primary end point was the mean change in the serum potassium level from baseline to week 4. A total of 76% of the patients had normal potassium levels (3.5-<5.1 mmol/L) at the end of this phase; 107 of these patients entered an 8-week, placebo-controlled, randomized, withdrawal phase, in which patients were assigned to patiromer (n=55) or switched to placebo (n=52). The primary end point was the between-group difference in the median change in the serum potassium level over the first 4 weeks of that phase. Hyperkalemia (potassium level, ≥5.5 mmol/L) recurred in 60% of the patients who were switched to placebo versus only 15% in the patiromer treatment arm through week 8.4


During the initial treatment phase and through its follow-up period, AEs were reported in 47% of the patients overall. Mild-to moderate constipation was the most common AE; hypokalemia occurred in 3%. The most common AEs are shown in Table 2. Three patients experienced ≥1 serious AE, which were considered by investigators to be unrelated to patiromer treatment.4


“Among patients with chronic kidney disease who were taking RAAS inhibitors and who had hyperkalemia, treatment with patiromer was associated with reductions in serum potassium levels and maintenance of normal potassium levels,” concluded the researchers.



Potassium-increasing DDIs are among the most common DDIs, occurring in up to 10% of hospitalized patients; these DDIs may induce hyperkalemia and life-threatening cardiac arrhythmias. New data from Eschmann et al5 identified patient- and physician-rated risk factors for the development of hyperkalemia among 76,447 patients hospitalized in the University Hospital in Zurich, Sweden between December 1, 2009, and December 31, 2011.

The researchers looked at the risk factors and the clinical outcomes among the patient cohort prescribed 8413 potentially severe potassium-increasing DDIs. They considered the following drugs to be potassium increasing: ACE inhibitors, angiotensin-receptor blockers, direct renin inhibitors, immunosuppressive agents (calcineurin inhibitors), potassium-sparing diuretics (aldosterone-receptor antagonists and epithelial sodium channel blockers), potassium supplements, and trimethoprim. The researchers also examined patient risk factors (eg, age and duration of therapy) and physician-related factors that might affect risk (eg, serum potassium monitoring).5

Table 3 lists the risk factors for hyperkalemia DDIs found in the study. Among patient-related characteristics associated with the risk of hyperkalemia, pulmonary allograft was highest with a relative risk (RR) of 5.1, probably due to the number of potassium-increasing drugs they received (eg, immunosuppressive agents, trimethoprim, and ACE inhibitors). Impaired renal function with creatinine clearance <60 mL/min (RR, 2.7) also significantly increased risk, followed by diabetes mellitus (RR, 1.6) and female gender (RR 1.5). Medication also affected the risk for hyperkalemia.


As expected, the risk of hyperkalemia increased with the number of concurrently administered potassium-increasing drugs (RR, 3.3 per additional drug), and with longer duration of the DDI (RR, 4.9 for duration ≥6 days). Physician-related factors for hyperkalemia were undetermined or elevated serum potassium level before treatment initiation (RR, 2.2) and infrequent monitoring of serum potassium during a DDI (interval >48 hours; RR, 1.6).5


Patient- and physician-related factors should be considered to reduce the risk of hyperkalemia during potassium-increasing DDIs, concluded the researchers. Additionally, systematic measuring of potassium levels before drug therapies involving potassium-increasing DDIs and periodic monitoring are essential.5 —Eileen Koutnik-Fotopoulos



1. Ingelfinger JR. A new era for the treatment of hyperkalemia. N Engl J Med. 2015;372(3):275-277.

2. Sarafidis PA, Georgianos PI, Bakris GL. Advances in treatment of hyperkalemia in chronic kidney disease. Expert Opin Pharmacother. 2015;16(4):2205-2215.

3. Pitt B, Bakris GL. New potassium binders for the treatment of hyperkalemia: Current data and opportunities for the future. Hypertension. 2015;66(4):731-728.

4. Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Eng J Med. 2015;372(3):211-221.

5. Eschmann E, Beeler PE, Kaplan V, et al. Patient- and physician-related risk factors for hyperkalemia in potassium-increasing drug–drug interactions. Eur J Clin Pharmacol. 2014;70(2);215-223.

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