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Original Investigation |

Effect of Sodium Zirconium Cyclosilicate on Potassium Lowering for 28 Days Among Outpatients With Hyperkalemia The HARMONIZE Randomized Clinical Trial FREE

Mikhail Kosiborod, MD1,2; Henrik S. Rasmussen, MD, PhD3; Philip Lavin, PhD4; Wajeh Y. Qunibi, MD5; Bruce Spinowitz, MD6; David Packham, MD7; Simon D. Roger, MD8; Alex Yang, MD9; Edgar Lerma, MD10,11; Bhupinder Singh, MD3
[+] Author Affiliations
1Saint Luke’s Mid America Heart Institute, Kansas City, Missouri
2University of Missouri–Kansas City
3ZS Pharma, Coppell, Texas
4Boston Biostatistics Research Foundation, Framingham, Massachusetts
5University of Texas Health Science Center at San Antonio
6Weill Medical College of Cornell University, New York, New York
7Melbourne Renal Research Group and Department of Medicine, University of Melbourne, Melbourne, Australia
8Renal Research, Gosford, Australia
9Xelay Acumen, Belmont, California
10University of Illinois at Chicago College of Medicine, Chicago
11Advocate Christ Medical Center, Oak Lawn, Illinois
JAMA. 2014;312(21):2223-2233. doi:10.1001/jama.2014.15688.
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Published online

Importance  Hyperkalemia is a common electrolyte abnormality that may be difficult to manage because of a lack of effective therapies. Sodium zirconium cyclosilicate is a nonabsorbed cation exchanger that selectively binds potassium in the intestine.

Objective  To evaluate the efficacy and safety of zirconium cyclosilicate for 28 days in patients with hyperkalemia.

Design, Setting, and Participants  HARMONIZE was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial evaluating zirconium cyclosilicate in outpatients with hyperkalemia (serum potassium ≥5.1 mEq/L) recruited from 44 sites in the United States, Australia, and South Africa (March-August 2014).

Interventions  Patients (n = 258) received 10 g of zirconium cyclosilicate 3 times daily in the initial 48-hour open-label phase. Patients (n = 237) achieving normokalemia (3.5-5.0 mEq/L) were then randomized to receive zirconium cyclosilicate, 5 g (n = 45 patients), 10 g (n = 51), or 15 g (n = 56), or placebo (n = 85) daily for 28 days.

Main Outcomes and Measures  The primary end point was mean serum potassium level in each zirconium cyclosilicate group vs placebo during days 8-29 of the randomized phase.

Results  In the open-label phase, serum potassium levels declined from 5.6 mEq/L at baseline to 4.5 mEq/L at 48 hours. Median time to normalization was 2.2 hours, with 84% of patients (95% CI, 79%-88%) achieving normokalemia by 24 hours and 98% (95% CI, 96%-99%) by 48 hours. In the randomized phase, serum potassium was significantly lower during days 8-29 with all 3 zirconium cyclosilicate doses vs placebo (4.8 mEq/L [95% CI, 4.6-4.9], 4.5 mEq/L [95% CI, 4.4-4.6], and 4.4 mEq/L [95% CI, 4.3-4.5] for 5 g, 10 g, and 15 g; 5.1 mEq/L [95% CI, 5.0-5.2] for placebo; P < .001 for all comparisons). The proportion of patients with mean potassium <5.1 mEq/L during days 8-29 was significantly higher in all zirconium cyclosilicate groups vs placebo (36/45 [80%], 45/50 [90%], and 51/54 [94%] for the 5-g, 10-g, and 15-g groups, vs 38/82 [46%] with placebo; P < .001 for each dose vs placebo). Adverse events were comparable between zirconium cyclosilicate and placebo, although edema was more common in the 15-g group (edema incidence: 2/85 [2%], 1/45 [2%], 3/51 [6%], and 8/56 [14%] patients in the placebo, 5-g, 10-g, and 15-g groups). Hypokalemia developed in 5/51 (10%) and 6/56 patients (11%) in the 10-g and 15-g zirconium cyclosilicate groups, vs none in the 5-g or placebo groups.

Conclusions and Relevance  Among outpatients with hyperkalemia, open-label sodium zirconium cyclosilicate reduced serum potassium to normal levels within 48 hours; compared with placebo, all 3 doses of zirconium cyclosilicate resulted in lower potassium levels and a higher proportion of patients with normal potassium levels for up to 28 days. Further studies are needed to evaluate the efficacy and safety of zirconium cyclosilicate beyond 4 weeks and to assess long-term clinical outcomes.

Trial Registration  clinicaltrials.gov Identifier: NCT02088073

Figures in this Article

Hyperkalemia is a common electrolyte disorder that can cause potentially life-threatening cardiac arrhythmias and is associated with poor prognosis in various patient populations.1,2 Common comorbidities associated with hyperkalemia, such as chronic kidney disease (CKD), heart failure, and diabetes mellitus, are the same conditions in which renin-angiotensin-aldosterone system (RAAS) inhibitors improve outcomes, leading to their strong endorsement in practice guidelines.3 However, broader use of RAAS inhibitors, which mechanistically increase potassium levels,4 accompanied by the parallel increase in the number of individuals with CKD,5,6 heart failure,7 and diabetes,8 have led to higher prevalence of hyperkalemia and an increase in hyperkalemia-related hospitalizations and deaths.9

Although effective and safe therapies for acute and chronic management of hyperkalemia are needed, such treatment options are currently lacking in the outpatient setting. Cation exchange resins such as sodium polystyrene sulfonate (SPS) are commonly used, but their effectiveness is uncertain10 and has not been demonstrated in randomized controlled trials; furthermore, they have been associated with reports of serious intestinal toxicity.11,12 Other strategies for acute management of hyperkalemia (eg, intravenous insulin and dextrose, intravenous sodium bicarbonate, diuretics, and inhaled β-adrenergic agonists) are impractical in the outpatient setting. Dietary restriction of potassium is associated with variable adherence and limits healthy food options for some patients.13

Sodium zirconium cyclosilicate (zirconium cyclosilicate; also known as ZS-9) is a highly selective inorganic cation exchanger designed to entrap potassium in the intestine. In previous studies, zirconium cyclosilicate was well tolerated and effective in lowering potassium within 48 hours of administration.14,15 This study evaluated the efficacy and safety of zirconium cyclosilicate for 28 days in patients with hyperkalemia.

The Hyperkalemia Randomized Intervention Multidose ZS-9 Maintenance (HARMONIZE) study was a phase 3, randomized, double-blind, placebo-controlled trial that enrolled ambulatory patients with a potassium level of 5.1 mEq/L or greater. Patients were treated with zirconium cyclosilicate (10 g 3 times daily) in the 48-hour open-label phase; those achieving normokalemia (potassium, 3.5-5.0 mEq/L) were randomized to receive 3 different zirconium cyclosilicate doses or matching placebo for 28 days. The study was conducted in 44 sites from the United States, Australia, and South Africa (March through August 2014). The full study protocol and list of participating sites and investigators can be found in the trial protocol in Supplement 1 and eTable 1 in Supplement 2. The primary aim of the trial was to evaluate the efficacy and safety of 3 zirconium cyclosilicate doses in patients with hyperkalemia for up to 28 days. The study was conducted in accordance with the ICH E6(R1) Guidelines of Good Clinical Practice and the Declaration of Helsinki.

Patient Selection

Full inclusion and exclusion criteria may be found in the trial protocol in Supplement 1. Adult ambulatory patients with a history or laboratory evidence of hyperkalemia were recruited from nephrology, cardiology, and general research sites and screened for participation. To be eligible for enrollment, patients had to have documented hyperkalemia (2 consecutive potassium values, measured 60 minutes apart, both ≥5.1 mEq/L), be able to have repeated blood draws, and provide written informed consent (collected by the principal investigator or designee).

Exclusion criteria were pseudohyperkalemia, dialysis requirement, life expectancy less than 3 months, pregnancy, cardiac arrhythmias requiring immediate treatment, diabetic ketoacidosis, active treatment with sodium polystyrene sulfonate or lactulose, prior participation in another zirconium cyclosilicate trial or treatment with an unapproved drug or device within 30 days of study entry, any severe condition that would affect adherence or place a patient at undue risk, and known hypersensitivity to zirconium cyclosilicate.

Data on race and ethnicity were collected (based on prior literature noting differences in hyperkalemia by race)1618 using a 2-question format in which study participants self-reported race/ethnicity information. No monetary compensation was provided for study participation (other than reimbursement of travel expenses for study visits). The study was approved by national regulatory authorities in each country and the institutional review board or local ethics committee for each site.

Study Design

Patients who were deemed eligible by meeting inclusion and exclusion criteria, agreed to participate, and signed informed consent were enrolled in the open-label phase, during which they received 10 g of zirconium cyclosilicate 3 times daily with meals for 48 hours (6 doses total). Zirconium cyclosilicate was administered as an odorless, tasteless white powder mixed with water (240 mL with each dose). No protocol-directed advice on dietary potassium was provided to participants.

Patients who achieved normokalemia at the end of the open-label phase entered the double-blind randomized phase (Figure 1). Patients were randomized (4:4:4:7) to once-daily zirconium cyclosilicate (5, 10, or 15 g) or placebo, respectively, for 28 days. If a patient’s potassium value was between 3.0 and 3.4 mEq/L at any time during the randomized phase, the dose was reduced from once daily to every other day for the remainder of the study. If a patient developed significant hypokalemia (potassium <3.0 mEq/L) at any time, or severe hyperkalemia (potassium >6.2 mEq/L) or significant arrhythmias (ventricular tachycardia/fibrillation, new atrial fibrillation/flutter, paroxysmal supraventricular tachycardia, second- or third-degree atrioventricular block or significant bradycardia [heart rate <40 beats/min]) during the randomized phase, study drug was discontinued, and the patient was withdrawn from the study and referred to his or her treating physician for the standard of care.

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Figure 1.
Patient Screening and Selection for Open-Label and Randomized Phases of the HARMONIZE Trial

Patients who discontinued study treatment but had at least 1 follow-up serum potassium measurement between days 8-29 were included in the randomized phase intent-to-treat population.aElectrocardiogram (ECG) withdrawal criteria included significant increase in PR interval (>250 milliseconds in the absence of preexisting atrioventricular block), or widening of the QRS complex (>140 milliseconds in the absence of preexisting bundle branch block) or peaked T-wave or an increase in QTc interval >25 milliseconds to more than 500 milliseconds or >25 milliseconds in somebody with a baseline QTc of >500 milliseconds.bAccording to the study protocol, all clinical decisions to withdraw patients because of a potassium level <3.0 mEq/L were based on i-STAT values; however, in all of these cases, subsequent central laboratory values for serum potassium were ≥3.0 mEq/L.

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Potassium Measurements

All potassium levels were measured (after an 8-hour fast) in whole blood with a point-of-care device (i-STAT; Abbott Laboratories). All samples were then centrifuged on site and serum sent to a central laboratory (Beckman-Coulter-AU680 chemistry analyzer). Patient eligibility for enrollment and randomization and treatment decisions were based on i-STAT values. Statistical analyses were based on central laboratory values; if these data were missing, i-STAT values were used (adjusted to reflect the mean difference between i-STAT and laboratory potassium from all available paired samples).

Potassium was measured at 1, 2, and 4 hours after first dose on day 1, as well as just prior to and 1 hour after first dose on day 2 of the open-label phase. Eligibility for randomization was based on i-STAT potassium level obtained on the morning of study day 3 (after 48 hours of open-label treatment). After randomization, potassium was measured before the dose on days 1, 2, 5, 8, 12, 15, 19, 22, 26, and 29.

Study End Points

The primary end point was the comparison of mean serum potassium levels between placebo and each treatment group (highest to lowest) during days 8 through 29 of the randomized phase. Prespecified secondary efficacy end points for the randomized phase included proportion of patients who were normokalemic at end of study (morning of day 29); absolute and percentage change in serum potassium levels from open-label and randomized phase baselines and proportion of normokalemic patients at measured time intervals; cumulative days patients remained normokalemic between days 8-29 of the randomized phase; time to first recurrence of hyperkalemia (potassium ≥5.1 mEq/L) and time to first return to open-label phase baseline potassium level; mean intrapatient standard deviation in potassium levels between days 8-29 of the randomized phase; and mean change in serum aldosterone and plasma renin between open-label phase baseline and day 29 (US sites only). An additional prespecified analysis compared the proportion of patients with mean potassium level less than 5.1 mEq/L during days 8-29 of the randomized phase between each treatment group and placebo.

Secondary end points for the open-label phase included absolute and percentage change from baseline in serum potassium levels at all measured time intervals after initiation of treatment, proportion of patients who achieved normokalemia by 24 and 48 hours, time to normalization, and exponential rate of change in serum potassium.

Safety and tolerability were assessed throughout the study via ascertainment of adverse events (AEs) and serious adverse events (SAEs), monitoring of serial electrocardiograms, vital signs, body weight, physical examinations, and laboratory assessments (standard hematology and serum chemistry, including serum calcium, magnesium, phosphate, creatinine, blood urea nitrogen, and bicarbonate; urine analysis [including urinary sodium excretion]; and urine culture).

Statistical Analysis

Full details of the statistical analysis may be found in the trial protocol in Supplement 1. A sample size of 232 patients in the randomized phase had 90% power to detect a 0.3-mEq/L mean difference in potassium levels during days 8-29 (assuming a 0.5 participant-level SD) for each dose of zirconium cyclosilicate vs placebo for a 2-sided t test with 5.0% type I error.

All patients who received study drug were included in the safety population. The open-label phase intent-to-treat population included all patients in the open-label phase who had at least 1 postbaseline potassium level. The randomized phase modified intent-to-treat population included all patients who had at least 1 postbaseline potassium value on or after day 8 of the randomized phase.

For the primary end point, a log transformation was applied to serum potassium levels to reduce the effect of outliers. A longitudinal generalized estimating equation (GEE) model was used to simultaneously compare each active dose (highest to lowest) vs placebo for the mean day 8-29 values; the model included all serum potassium levels collected at scheduled study visits, baseline covariates for estimated glomerular filtration rate (eGFR), baseline serum potassium, age, sex, and binary indicators for prespecified subgroups (RAAS inhibitors, CKD, heart failure, diabetes mellitus). The longitudinal GEE model uses all available observations in the sequence of data points and a variance-covariance matrix that deals with correlations between consecutive observations to produce population-based estimates of treatment effects without imputing individual patient-specific missing data points. This accounts for missing data.19

Additional efficacy end points were evaluated using a logistic regression model (proportion normokalemic at day 29); 2-sample t test (absolute and percentage change in potassium levels from open-label and randomized phase baselines at measured time intervals and for changes in aldosterone and renin at day 29); Fisher exact test (proportions of normokalemic patients at measured time intervals and patients with mean day 8-29 potassium <5.1 mEq/L); linear regression model (cumulative days with normokalemia); Kaplan-Meier life table and Wilcoxon-Gehan test (median time to hyperkalemia and return to open-label phase baseline potassium level); and analysis of covariance (mean intrapatient standard deviation).

For the open-label phase efficacy end points, the absolute and percentage change from baseline in potassium at all time points (including 24 and 48 hours) were assessed using 1-sample t test to test the null hypotheses that the mean changes from baseline were 0. Kaplan-Meier life table was used to estimate time to normokalemia. Exponential rate of change in serum potassium level was assessed by fitting a straight line through the log of all postbaseline potassium values through 48 hours controlling for age, sex, baseline potassium, baseline eGFR, CKD, diabetes, heart failure, and use of RAAS inhibitors.

Two-sided P ≤ .05 was considered statistically significant for all end points. All analyses were conducted using SAS version 9.1 (SAS Institute).

In total, 425 patients were assessed for eligibility (Figure 1), and 258 patients were enrolled into the open-label phase. After 48 hours of open-label therapy with zirconium cyclosilicate, 10 g, 3 times daily, 237 patients were randomized to receive either once-daily zirconium cyclosilicate (n = 45 to 5 g, n = 51 to 10 g, n = 56 to 15 g) or matching placebo (n = 85). Six patients (3 in placebo, 1 in 10-g dose, 2 in 15-g dose) did not have follow-up potassium measurements between days 8-29 and were not included in the randomized phase modified intent-to-treat analyses.

Baseline characteristics are listed in Table 1. Mean age was 64 years, 58% were men, and 83% were white. Eighty percent of patients were enrolled in the United States, 8% in Australia, and 12% in South Africa (eTable 1 in Supplement 2). Substantial proportions of patients had CKD (169/258 [66%]), heart failure (94 [36%]), and diabetes (170 [66%]) and were treated with RAAS inhibitors (180 [70%]). Mean baseline serum potassium was 5.6 mEq/L, 100 patients (39%) had moderate hyperkalemia (potassium 5.5 to <6.0 mEq/L), 39 patients (15%) had severe hyperkalemia (potassium ≥6.0 mEq/L), and mean eGFR was 46 mL/min/1.73 m2 (Table 1). Overall, 6.2% of potassium values were missing during randomized phase. Higher proportions of patients taking zirconium cyclosilicate had heart failure, CKD, eGFR less than 60 mL/min/1.73 m2, and diabetes, and brain natriuretic peptide levels were higher in the 5-g and 15-g dose groups, compared with placebo (Table 1).

Table Graphic Jump LocationTable 1.  Baseline Characteristics of Ambulatory Patients With Hyperkalemia Enrolled in HARMONIZE Trial According to the Study Group
Efficacy
Open-Label 48-Hour Phase

Zirconium cyclosilicate significantly reduced serum potassium during the initial 48 hours vs baseline (Figure 2A). A significant change in potassium (−0.2 mEq/L; 95% CI, −0.3 to −0.2) was noted 1 hour after the first 10-g dose compared with baseline (P < .001). At 2 and 4 hours after the first dose, mean change in potassium was −0.4 mEq/L (95% CI, −0.5 to −0.4) and −0.5 mEq/L (95% CI, −0.6 to −0.5), respectively (P < .001 for both time points). Absolute change in serum potassium was −0.7 mEq/L (95% CI, −0.7 to −0.6; −12%) at 24 hours and −1.1 mEq/L (95% CI, −1.1 to −1.0; −19%) at 48 hours (P < .001 for both time points). Patients with higher baseline potassium experienced greater magnitude of potassium reduction (Figure 2B). Serum potassium was within the normal range in 84% of patients (95% CI, 79% to 88%) by 24 hours and in 98% (95% CI, 96% to 99%) by 48 hours. Median time to potassium normalization was 2.2 hours (interquartile range, 1.0 to 22.3). The effect of zirconium cyclosilicate was consistent across all prespecified subgroups and all ranges of hyperkalemia at baseline (Figure 2B). Mean exponential rate of change in potassium at 48 hours was −0.3% per hour (95% CI, −0.4% to −0.3% per hour).

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Figure 2.
Serum Potassium Levels During the Open-Label Phase (48 Hours)

A, Mean serum potassium levels over time in patients treated during the open-label phase with zirconium cyclosilicate, 10 g, 3 times daily for 48 hours. B, Mean serum potassium levels at 0 and 48 hours across prespecified subgroups of chronic kidney disease (CKD) (by patient history and by estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), heart failure, diabetes mellitus, concomitant renin-angiotensin-aldosterone system inhibitor (RAASi) use, and baseline potassium levels. Error bars indicate 95% confidence intervals; shaded region, normal potassium range.

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Randomized 28-Day Phase

Mean serum potassium during days 8-29 was significantly reduced in all zirconium cyclosilicate groups vs placebo, with numerically lower potassium achieved with higher doses (4.8 mEq/L [95% CI, 4.6-4.9], 4.5 mEq/L [95% CI, 4.4-4.6], and 4.4 mEq/L [95% CI, 4.3-4.5] for 5-g, 10-g, and 15-g doses, respectively; 5.1 mEq/L [95% CI, 5.0-5.2] for placebo; P < .001 for each zirconium cyclosilicate dose vs placebo comparison (Figure 3A and Table 2). This effect was consistent throughout the randomized phase (Figure 3B). The greater degree of potassium lowering with zirconium cyclosilicate compared with placebo was consistent across all prespecified subgroups (eFigure in the Supplement).

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Figure 3.
Serum Potassium Levels During the Randomized Phase (Days 8-29) According to Study Group

A, Primary end point: mean serum potassium over days 8-29 of the randomized phase in the placebo and 5-g, 10-g, and 15-g doses of zirconium cyclosilicate. B, Serum potassium levels during the randomized phase: patients received placebo or zirconium cyclosilicate, 5 g, 10 g, or 15 g, once daily for 28 days. Error bars indicate 95% confidence interval; shaded region, normal potassium range.

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Table Graphic Jump LocationTable 2.  Randomized Phase End Points

Corresponding between-group differences for mean serum potassium level during days 8-29 of the randomized phase were −0.3 mEq/L (95% CI, −0.3 to −0.3), −0.6 mEq/L (95% CI, −0.5 to −0.6), and −0.7 mEq/L (95% CI, −0.7 to −0.7) for 5-g, 10-g, and 15-g doses, respectively, vs placebo. The proportion of patients who had normal potassium levels at the end of the randomized phase was significantly higher in each of the 3 zirconium cyclosilicate groups compared with placebo and was numerically greater with higher doses (71%, 76%, and 85% for 5-g, 10-g, and 15-g groups, respectively, vs 48% with placebo; P = .01 for 5-g, P = .002 for 10-g, P < .001 for 15-g dose of zirconium cyclosilicate vs placebo). Similarly, the proportion of patients with mean potassium less than 5.1 mEq/L during randomized phase days 8-29 was significantly higher in all zirconium cyclosilicate groups vs placebo and was numerically higher with higher doses (80%, 90%, and 94% for 5-g, 10-g, and 15-g groups, respectively, vs 46% with placebo; P < .001 for each dose vs placebo). Other secondary efficacy end points are presented in Table 2, and all demonstrated superiority for all 3 doses of zirconium cyclosilicate compared with placebo (with the exception of mean intrapatient standard deviation in serum potassium levels, which was higher in the 10-g group vs placebo, and plasma renin, which was lower in the 10-g group vs placebo).

Safety

The most common AEs are listed in Table 3. Edema occurred in 2 of 85 patients (2%), 1 of 45 patients (2%), 3 of 51 patients (6%), and 8 of 56 patients (14%) in the placebo, 5-g, 10-g, and 15-g groups, respectively. Seven of 14 patients who developed edema (1/1 in 5-g group, 3/3 in 10-g group, 3/8 in 15-g group) did not require any changes in therapy; 13 of 14 patients who developed edema completed the study. Gastrointestinal AEs were reported in 12 patients (14%) taking placebo vs 3 patients (7%), 1 patient (2%), and 5 patients (9%) in the 5-g, 10-g, and 15-g groups. No drug-related serious AEs were reported (Table 3). Treatment-related AEs were recorded in 8% of placebo patients vs 8% of zirconium cyclosilicate patients (eTable 2 in Supplement 2). One death (10-g zirconium cyclosilicate group), of a patient with stage 5 CKD, diabetes, hypertension, and known cardiovascular disease that was due to myocardial infarction, occurred on randomized phase day 18 and was deemed not related to study drug.

Table Graphic Jump LocationTable 3.  Adverse Events Occurring in 5% or More of Patients in Any Group and All Serious Adverse Events

Hypokalemia (defined as potassium level <3.5 mEq/L) developed in 5 of 51 patients (10%) and 6 of 56 patients (11%) receiving 10 g and 15 g of zirconium cyclosilicate vs no patients in the 5-g or placebo groups. All cases of hypokalemia were mild (3.0-3.4 mEq/L) and resolved after the dose of study drug was reduced. No clinically significant changes in vital signs or other electrolytes (including sodium, calcium, and magnesium) were observed. Specifically, there were no significant changes in blood pressure, heart rate, or body weight at any dose level. No dose-dependent increase in urinary sodium excretion was noted. No clinically significant arrhythmias occurred in any of the zirconium cyclosilicate groups or placebo.

The HARMONIZE randomized trial was designed to evaluate the efficacy and safety of zirconium cyclosilicate for up to 4 weeks in patients with hyperkalemia, a common and potentially serious electrolyte abnormality.2022 Our findings demonstrate that zirconium cyclosilicate was effective both in rapidly lowering potassium to normal range and maintaining normal potassium levels for up to 4 weeks in patients with various degrees of hyperkalemia. The potassium-lowering effect of zirconium cyclosilicate was consistent across all patient subgroups and observed immediately (after 1 hour of the first dose), and normokalemia was achieved in 84% of the patients within 24 hours and 98% within 48 hours of treatment initiation. Compared with placebo, all 3 doses of zirconium cyclosilicate resulted in significantly higher proportions of patients with normal potassium levels for up to 28 days. These outcomes occurred with a tolerability profile that was comparable with that of placebo.

Because of the increase in the common comorbid risk factors for developing hyperkalemia, such as CKD, heart failure, diabetes, aging population, and broader use of RAAS inhibitors, the prevalence of hyperkalemia and related hospitalizations has been increasing.3,4,23 Because hyperkalemia is associated with serious cardiac arrhythmias, conduction system abnormalities, and increased mortality, strategies for lowering potassium are often necessary to minimize potential harm to patients. Treatments commonly used for severe hyperkalemia in the hospital—such as intravenous calcium, insulin, sodium bicarbonate, and inhaled β-adrenergic agonists—do not eliminate excess potassium and are typically not feasible in the outpatient setting.2427 Dietary interventions that limit potassium intake13,28 are met with nonadherence and can limit healthier food options. Withdrawal of RAAS and mineralocorticoid receptor antagonists is also potentially problematic because these agents improve survival in several at-risk patient populations, such as those with heart failure and CKD (particularly when accompanied by proteinuria).29,30

Although polymeric exchange resins (SPS) are commonly used for treatment of hyperkalemia, their effectiveness is uncertain, as they have not been evaluated in randomized trials.3133 Furthermore, numerous reports of serious, even fatal gastrointestinal complications associated with SPS coadministration with 70% sorbitol (leading to the US Food and Drug Administration recommendations to avoid its use in 200934) and other SPS preparations have led to calls to significantly limit their clinical use.11,12,3537 Moreover, the poor gastrointestinal tolerability of polymer exchange resins makes these agents generally unsuitable for chronic use. Therefore, there is a substantial need for novel, effective, and safe treatment strategies in patients with hyperkalemia.

Zirconium cyclosilicate is unique in its potassium-lowering mechanism, which offers several potential benefits compared with currently available treatments. One advantage over polymer resins is that the crystal structure of zirconium cyclosilicate selectively entraps potassium in the intestinal tract, thereby limiting potassium’s enteric recirculation.38 In addition, zirconium cyclosilicate is substantially (ie, >125 times) more selective for potassium than organic polymer exchange resins that also bind calcium and magnesium and hence can cause hypocalcemia and hypomagnesemia.38 Zirconium cyclosilicate binds potassium throughout the gastrointestinal tract, including potassium in food, which may explain its rapid onset of action. Zirconium cyclosilicate is insoluble, does not expand on contact with water, and is not systemically absorbed, which may explain its tolerability.38

In this study, we observed a favorable safety and tolerability profile for zirconium cyclosilicate, with no major treatment-related SAEs. Treatment-related AEs, including gastrointestinal AEs, were comparable across the groups. Edema was observed more frequently with 15-g zirconium cyclosilicate dose than with the other doses or with placebo; however, this difference might be explained by significantly higher baseline rates of heart failure and eGFR less than 60 mL/min/1.73 m2 and higher baseline levels of brain natriuretic peptide among patients randomized to receive the 15-g dose compared with placebo. There was a numerically higher rate of hypokalemia with higher zirconium cyclosilicate doses, which is expected given its mechanism of action; all episodes of hypokalemia were mild and were corrected with protocol-directed dose adjustments. Nevertheless, monitoring for hypokalemia and appropriate dose optimization should be incorporated with higher doses of zirconium cyclosilicate.

This study should be interpreted in the context of several potential limitations. First, some patient groups that may benefit from potassium-lowering treatments, such as those receiving dialysis, were not included. However, a substantial proportion of patients in the study (36%) had severe CKD (stages 4 and 5). Second, because this study focused on the effects of zirconium cyclosilicate for up to 4 weeks in the outpatient setting, hospitalized patients and those with life-threatening arrhythmias were also excluded. The effectiveness and safety of zirconium cyclosilicate in these patient groups will need to be demonstrated in future studies. Third, the randomized study duration was 28 days, and clinical outcomes other than potassium levels were not assessed. Whether better control of chronic hyperkalemia will improve long-term patient outcomes, such as survival and quality of life, remains to be established.

Among ambulatory patients with hyperkalemia, open-label administration of sodium zirconium cyclosilicate reduced serum potassium levels to the normal range within 48 hours, and in the randomized phase, compared with placebo, administration of all 3 doses of zirconium cyclosilicate resulted in lower potassium levels and a higher proportion of patients with normal potassium levels for up to 28 days. Further studies are needed to evaluate the efficacy and safety of zirconium cyclosilicate beyond 4 weeks and to assess long-term clinical outcomes.

Corresponding Author: Mikhail Kosiborod, MD, Saint Luke’s Mid America Heart Institute, 4401 Wornall Rd, Kansas City, MO 64111 (mkosiborod@saint-lukes.org).

Published Online: November 17, 2014. doi:10.1001/jama.2014.15688.

Author Contributions: Drs Kosiborod and Lavin had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Kosiborod, Rasmussen, Lavin.

Acquisition, analysis, or interpretation of data: Kosiborod, Rasmussen, Lavin, Qunibi, Spinowitz, Packham, Roger, Yang, Lerma, Singh.

Drafting of the manuscript: Kosiborod, Rasmussen, Lavin, Roger, Yang.

Critical revision of the manuscript for important intellectual content: Kosiborod, Rasmussen, Lavin, Qunibi, Spinowitz, Packham, Yang, Lerma, Singh.

Statistical analysis: Rasmussen, Lavin.

Obtained funding: Rasmussen.

Administrative, technical, or material support: Rasmussen, Yang.

Study supervision: Kosiborod, Rasmussen, Singh.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kosiborod reported having served as a consultant for ZS Pharma and being an investigator for the HARMONIZE study. Dr Rasmussen reported being an employee of ZS Pharma and having ownership interest in ZS Pharma. Dr Lavin reported being an employee of Boston Biostatistics Research Foundation, which conducted the statistical analyses for the study, and having received grant support from ZS Pharma. Dr Qunibi reported having received grant support from ZS Pharma. Dr Spinowitz reported having received grant support from ZS Pharma and Relypsa and having served as a consultant for ZS Pharma. Dr Packham reported having received travel fees and honorarium for serving on advisory boards from ZS Pharma. Dr Roger reported having received travel fees for investigator meetings and honorarium for serving on advisory boards for ZS Pharma. Dr Yang reported being employed by Xelay Acumen, being a paid consultant to ZS Pharma, and holding stock options in ZS Pharma. Dr Lerma reported being a subinvestigator with Research by Design and having received grant support from ZS Pharma. Dr Singh reported having been an independent contractor with Apex Research of Riverside at the time of the study, joining ZS Pharma in August 2014, and having received consulting fees and grant support from ZS Pharma.

Funding/Support: The study was sponsored and funded by ZS Pharma.

Role of the Funder/Sponsor: ZS Pharma had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Jocelyn Hybiske, PhD, and Ingrid Koo, PhD, of Xelay Acumen provided editorial assistance (but did not draft the manuscript or edit the manuscript for important intellectual content), and Alan Chang, BS, of Xelay Acumen provided data analytical support. None of the individuals received compensation for their contributions besides salary.

Correction: This article was corrected online December 22, 2014, for a dosage error in Figure 2 and May 21, 2015, for a typo in a unit of measure for serum potassium in Table 1.

Khanagavi  J, Gupta  T, Aronow  WS,  et al.  Hyperkalemia among hospitalized patients and association between duration of hyperkalemia and outcomes. Arch Med Sci. 2014;10(2):251-257.
PubMed   |  Link to Article
An  JN, Lee  JP, Jeon  HJ,  et al.  Severe hyperkalemia requiring hospitalization: predictors of mortality. Crit Care. 2012;16(6):R225.
PubMed   |  Link to Article
Jain  N, Kotla  S, Little  BB,  et al.  Predictors of hyperkalemia and death in patients with cardiac and renal disease. Am J Cardiol. 2012;109(10):1510-1513.
PubMed   |  Link to Article
Navaneethan  SD, Nigwekar  SU, Sehgal  AR, Strippoli  GF.  Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2009;4(3):542-551.
PubMed   |  Link to Article
Ahn  SY, Ryu  J, Baek  SH,  et al.  Incident chronic kidney disease and newly developed complications related to renal dysfunction in an elderly population during 5 years: a community-based elderly population cohort study. PLoS One. 2013;8(12):e84467.
PubMed   |  Link to Article
Palmer  BF, Fenves  AZ.  Optimizing blood pressure control in patients with chronic kidney disease. Proc (Bayl Univ Med Cent). 2010;23(3):239-245.
PubMed
Vardeny  O, Claggett  B, Anand  I,  et al; Randomized Aldactone Evaluation Study (RALES) Investigators.  Incidence, predictors, and outcomes related to hypo- and hyperkalemia in patients with severe heart failure treated with a mineralocorticoid receptor antagonist. Circ Heart Fail. 2014;7(4):573-579.
PubMed   |  Link to Article
St Peter  WL, Odum  LE, Whaley-Connell  AT.  To RAS or not to RAS? the evidence for and cautions with renin-angiotensin system inhibition in patients with diabetic kidney disease. Pharmacotherapy. 2013;33(5):496-514.
PubMed   |  Link to Article
Juurlink  DN, Mamdani  MM, Lee  DS,  et al.  Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004;351(6):543-551.
PubMed   |  Link to Article
Sterns  RH, Rojas  M, Bernstein  P, Chennupati  S.  Ion-exchange resins for the treatment of hyperkalemia: are they safe and effective? J Am Soc Nephrol. 2010;21(5):733-735.
PubMed   |  Link to Article
Harel  Z, Harel  S, Shah  PS, Wald  R, Perl  J, Bell  CM.  Gastrointestinal adverse events with sodium polystyrene sulfonate (Kayexalate) use: a systematic review. Am J Med. 2013;126(3):264.e9-264.e24.
PubMed   |  Link to Article
Yuan  CM, Nee  R, Little  DJ, Abbott  KC.  Incidence of sodium polystyrene sulfonate-associated colonic necrosis. Am J Med. 2013;126(9):e13.
PubMed   |  Link to Article
Aaron  KJ, Sanders  PW.  Role of dietary salt and potassium intake in cardiovascular health and disease: a review of the evidence. Mayo Clin Proc. 2013;88(9):987-995.
PubMed   |  Link to Article
Ash  S, Singh  B, Lavin  P, Stavros  F, Rasmussen  H.  Safety and efficacy of ZS-9, a novel selective cation trap, for treatment of hyperkalemia in CKD patients [abstract]. J Am Soc Nephrol. 2013;24:2B.
El Shahawy  M, Rasmussen  H, Lavin  P, Yang  A, Packham  D. Acute-phase efficacy in a phase 3 multicenter, randomised, double-blind, placebo-controlled trial of ZS-9 for hyperkalaemia. Poster presented at 51st European Renal Association and European Dialysis and Transplant Association Congress 2014. http://www.postersessiononline.eu/pr/aula_poster.asp?congreso=796093165. Accessed October 24, 2014.
Weinberg  JM, Appel  LJ, Bakris  G,  et al; African American Study of Hypertension and Kidney Disease Collaborative Research Group.  Risk of hyperkalemia in nondiabetic patients with chronic kidney disease receiving antihypertensive therapy. Arch Intern Med. 2009;169(17):1587-1594.
PubMed   |  Link to Article
Rossignol  P, Dobre  D, McMurray  JJ,  et al.  Incidence, determinants, and prognostic significance of hyperkalemia and worsening renal function in patients with heart failure receiving the mineralocorticoid receptor antagonist eplerenone or placebo in addition to optimal medical therapy: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Circ Heart Fail. 2014;7(1):51-58.
PubMed   |  Link to Article
Vardeny  O, Cavallari  LH, Claggett  B,  et al; Randomized Aldactone Evaluation Study (RALES) Investigators.  Race influences the safety and efficacy of spironolactone in severe heart failure. Circ Heart Fail. 2013;6(5):970-976.
PubMed   |  Link to Article
Burton  P, Gurrin  L, Sly  P.  Extending the simple linear regression model to account for correlated responses: an introduction to generalized estimating equations and multi-level mixed modelling. Stat Med. 1998;17(11):1261-1291.
PubMed   |  Link to Article
Einhorn  LM, Zhan  M, Hsu  VD,  et al.  The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med. 2009;169(12):1156-1162.
PubMed   |  Link to Article
McMahon  GM, Mendu  ML, Gibbons  FK, Christopher  KB.  Association between hyperkalemia at critical care initiation and mortality. Intensive Care Med. 2012;38(11):1834-1842.
PubMed   |  Link to Article
Goyal  A, Spertus  JA, Gosch  K,  et al.  Serum potassium levels and mortality in acute myocardial infarction. JAMA. 2012;307(2):157-164.
PubMed   |  Link to Article
Svensson  M, Gustafsson  F, Galatius  S, Hildebrandt  PR, Atar  D.  How prevalent is hyperkalemia and renal dysfunction during treatment with spironolactone in patients with congestive heart failure? J Card Fail. 2004;10(4):297-303.
PubMed   |  Link to Article
Fordjour  KN, Walton  T, Doran  JJ.  Management of hyperkalemia in hospitalized patients. Am J Med Sci. 2014;347(2):93-100.
PubMed   |  Link to Article
Łoniewski  I, Wesson  DE.  Bicarbonate therapy for prevention of chronic kidney disease progression. Kidney Int. 2014;85(3):529-535.
PubMed   |  Link to Article
Blumberg  A, Weidmann  P, Ferrari  P.  Effect of prolonged bicarbonate administration on plasma potassium in terminal renal failure. Kidney Int. 1992;41(2):369-374.
PubMed   |  Link to Article
Abramowitz  MK, Melamed  ML, Bauer  C, Raff  AC, Hostetter  TH.  Effects of oral sodium bicarbonate in patients with CKD. Clin J Am Soc Nephrol. 2013;8(5):714-720.
PubMed   |  Link to Article
Goraya  N, Wesson  DE.  Dietary management of chronic kidney disease: protein restriction and beyond. Curr Opin Nephrol Hypertens. 2012;21(6):635-640.
PubMed   |  Link to Article
Kuijvenhoven  MA, Haak  EA, Gombert-Handoko  KB, Crul  M.  Evaluation of the concurrent use of potassium-influencing drugs as risk factors for the development of hyperkalemia. Int J Clin Pharm. 2013;35(6):1099-1104.
PubMed   |  Link to Article
Cohn  JN.  Reducing cardiovascular risk by blockade of the renin-angiotensin-aldosterone system. Adv Ther. 2007;24(6):1290-1304.
PubMed   |  Link to Article
Kessler  C, Ng  J, Valdez  K, Xie  H, Geiger  B.  The use of sodium polystyrene sulfonate in the inpatient management of hyperkalemia. J Hosp Med. 2011;6(3):136-140.
PubMed   |  Link to Article
Scherr  L, Ogden  DA, Mead  AW, Spritz  N, Rubin  AL.  Management of hyperkalemia with a cation-exchange resin. N Engl J Med. 1961;264:115-119.
PubMed   |  Link to Article
Flinn  RB, Merrill  JP, Welzant  WR.  Treatment of the oliguric patient with a new sodium-exchange resin and sorbitol; a preliminary report. N Engl J Med. 1961;264:111-115.
PubMed   |  Link to Article
Watson  M, Abbott  KC, Yuan  CM.  Damned if you do, damned if you don’t: potassium binding resins in hyperkalemia. Clin J Am Soc Nephrol. 2010;5(10):1723-1726.
PubMed   |  Link to Article
Watson  MA, Baker  TP, Nguyen  A,  et al.  Association of prescription of oral sodium polystyrene sulfonate with sorbitol in an inpatient setting with colonic necrosis: a retrospective cohort study. Am J Kidney Dis. 2012;60(3):409-416.
PubMed   |  Link to Article
Tongyoo  A, Sriussadaporn  E, Limpavitayaporn  P, Mingmalairak  C.  Acute intestinal obstruction due to Kalimate, a potassium-lowering agent: a case report and literature review. J Med Assoc Thai. 2013;96(12):1617-1620.
PubMed
Castillo-Cejas  MD, De-Torres-Ramírez  I, Alonso-Cotoner  C.  Colonic necrosis due to calcium polystyrene sulfonate (Kalimate) not suspended in sorbitol. Rev Esp Enferm Dig. 2013;105(4):232-234.
PubMed   |  Link to Article
Yang  A, Leon  A, Nuttall  M, Low  J, Rasmussen  H.  In vitro ion exchange capacity and selectivity of ZS-9, a novel, selective cation trap for the treatment of hyperkalemia. Am J Kidney Dis. 2014;63(5):B115.

Figures

Place holder to copy figure label and caption
Figure 1.
Patient Screening and Selection for Open-Label and Randomized Phases of the HARMONIZE Trial

Patients who discontinued study treatment but had at least 1 follow-up serum potassium measurement between days 8-29 were included in the randomized phase intent-to-treat population.aElectrocardiogram (ECG) withdrawal criteria included significant increase in PR interval (>250 milliseconds in the absence of preexisting atrioventricular block), or widening of the QRS complex (>140 milliseconds in the absence of preexisting bundle branch block) or peaked T-wave or an increase in QTc interval >25 milliseconds to more than 500 milliseconds or >25 milliseconds in somebody with a baseline QTc of >500 milliseconds.bAccording to the study protocol, all clinical decisions to withdraw patients because of a potassium level <3.0 mEq/L were based on i-STAT values; however, in all of these cases, subsequent central laboratory values for serum potassium were ≥3.0 mEq/L.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Serum Potassium Levels During the Open-Label Phase (48 Hours)

A, Mean serum potassium levels over time in patients treated during the open-label phase with zirconium cyclosilicate, 10 g, 3 times daily for 48 hours. B, Mean serum potassium levels at 0 and 48 hours across prespecified subgroups of chronic kidney disease (CKD) (by patient history and by estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), heart failure, diabetes mellitus, concomitant renin-angiotensin-aldosterone system inhibitor (RAASi) use, and baseline potassium levels. Error bars indicate 95% confidence intervals; shaded region, normal potassium range.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.
Serum Potassium Levels During the Randomized Phase (Days 8-29) According to Study Group

A, Primary end point: mean serum potassium over days 8-29 of the randomized phase in the placebo and 5-g, 10-g, and 15-g doses of zirconium cyclosilicate. B, Serum potassium levels during the randomized phase: patients received placebo or zirconium cyclosilicate, 5 g, 10 g, or 15 g, once daily for 28 days. Error bars indicate 95% confidence interval; shaded region, normal potassium range.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Baseline Characteristics of Ambulatory Patients With Hyperkalemia Enrolled in HARMONIZE Trial According to the Study Group
Table Graphic Jump LocationTable 2.  Randomized Phase End Points
Table Graphic Jump LocationTable 3.  Adverse Events Occurring in 5% or More of Patients in Any Group and All Serious Adverse Events

References

Khanagavi  J, Gupta  T, Aronow  WS,  et al.  Hyperkalemia among hospitalized patients and association between duration of hyperkalemia and outcomes. Arch Med Sci. 2014;10(2):251-257.
PubMed   |  Link to Article
An  JN, Lee  JP, Jeon  HJ,  et al.  Severe hyperkalemia requiring hospitalization: predictors of mortality. Crit Care. 2012;16(6):R225.
PubMed   |  Link to Article
Jain  N, Kotla  S, Little  BB,  et al.  Predictors of hyperkalemia and death in patients with cardiac and renal disease. Am J Cardiol. 2012;109(10):1510-1513.
PubMed   |  Link to Article
Navaneethan  SD, Nigwekar  SU, Sehgal  AR, Strippoli  GF.  Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2009;4(3):542-551.
PubMed   |  Link to Article
Ahn  SY, Ryu  J, Baek  SH,  et al.  Incident chronic kidney disease and newly developed complications related to renal dysfunction in an elderly population during 5 years: a community-based elderly population cohort study. PLoS One. 2013;8(12):e84467.
PubMed   |  Link to Article
Palmer  BF, Fenves  AZ.  Optimizing blood pressure control in patients with chronic kidney disease. Proc (Bayl Univ Med Cent). 2010;23(3):239-245.
PubMed
Vardeny  O, Claggett  B, Anand  I,  et al; Randomized Aldactone Evaluation Study (RALES) Investigators.  Incidence, predictors, and outcomes related to hypo- and hyperkalemia in patients with severe heart failure treated with a mineralocorticoid receptor antagonist. Circ Heart Fail. 2014;7(4):573-579.
PubMed   |  Link to Article
St Peter  WL, Odum  LE, Whaley-Connell  AT.  To RAS or not to RAS? the evidence for and cautions with renin-angiotensin system inhibition in patients with diabetic kidney disease. Pharmacotherapy. 2013;33(5):496-514.
PubMed   |  Link to Article
Juurlink  DN, Mamdani  MM, Lee  DS,  et al.  Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004;351(6):543-551.
PubMed   |  Link to Article
Sterns  RH, Rojas  M, Bernstein  P, Chennupati  S.  Ion-exchange resins for the treatment of hyperkalemia: are they safe and effective? J Am Soc Nephrol. 2010;21(5):733-735.
PubMed   |  Link to Article
Harel  Z, Harel  S, Shah  PS, Wald  R, Perl  J, Bell  CM.  Gastrointestinal adverse events with sodium polystyrene sulfonate (Kayexalate) use: a systematic review. Am J Med. 2013;126(3):264.e9-264.e24.
PubMed   |  Link to Article
Yuan  CM, Nee  R, Little  DJ, Abbott  KC.  Incidence of sodium polystyrene sulfonate-associated colonic necrosis. Am J Med. 2013;126(9):e13.
PubMed   |  Link to Article
Aaron  KJ, Sanders  PW.  Role of dietary salt and potassium intake in cardiovascular health and disease: a review of the evidence. Mayo Clin Proc. 2013;88(9):987-995.
PubMed   |  Link to Article
Ash  S, Singh  B, Lavin  P, Stavros  F, Rasmussen  H.  Safety and efficacy of ZS-9, a novel selective cation trap, for treatment of hyperkalemia in CKD patients [abstract]. J Am Soc Nephrol. 2013;24:2B.
El Shahawy  M, Rasmussen  H, Lavin  P, Yang  A, Packham  D. Acute-phase efficacy in a phase 3 multicenter, randomised, double-blind, placebo-controlled trial of ZS-9 for hyperkalaemia. Poster presented at 51st European Renal Association and European Dialysis and Transplant Association Congress 2014. http://www.postersessiononline.eu/pr/aula_poster.asp?congreso=796093165. Accessed October 24, 2014.
Weinberg  JM, Appel  LJ, Bakris  G,  et al; African American Study of Hypertension and Kidney Disease Collaborative Research Group.  Risk of hyperkalemia in nondiabetic patients with chronic kidney disease receiving antihypertensive therapy. Arch Intern Med. 2009;169(17):1587-1594.
PubMed   |  Link to Article
Rossignol  P, Dobre  D, McMurray  JJ,  et al.  Incidence, determinants, and prognostic significance of hyperkalemia and worsening renal function in patients with heart failure receiving the mineralocorticoid receptor antagonist eplerenone or placebo in addition to optimal medical therapy: results from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF). Circ Heart Fail. 2014;7(1):51-58.
PubMed   |  Link to Article
Vardeny  O, Cavallari  LH, Claggett  B,  et al; Randomized Aldactone Evaluation Study (RALES) Investigators.  Race influences the safety and efficacy of spironolactone in severe heart failure. Circ Heart Fail. 2013;6(5):970-976.
PubMed   |  Link to Article
Burton  P, Gurrin  L, Sly  P.  Extending the simple linear regression model to account for correlated responses: an introduction to generalized estimating equations and multi-level mixed modelling. Stat Med. 1998;17(11):1261-1291.
PubMed   |  Link to Article
Einhorn  LM, Zhan  M, Hsu  VD,  et al.  The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med. 2009;169(12):1156-1162.
PubMed   |  Link to Article
McMahon  GM, Mendu  ML, Gibbons  FK, Christopher  KB.  Association between hyperkalemia at critical care initiation and mortality. Intensive Care Med. 2012;38(11):1834-1842.
PubMed   |  Link to Article
Goyal  A, Spertus  JA, Gosch  K,  et al.  Serum potassium levels and mortality in acute myocardial infarction. JAMA. 2012;307(2):157-164.
PubMed   |  Link to Article
Svensson  M, Gustafsson  F, Galatius  S, Hildebrandt  PR, Atar  D.  How prevalent is hyperkalemia and renal dysfunction during treatment with spironolactone in patients with congestive heart failure? J Card Fail. 2004;10(4):297-303.
PubMed   |  Link to Article
Fordjour  KN, Walton  T, Doran  JJ.  Management of hyperkalemia in hospitalized patients. Am J Med Sci. 2014;347(2):93-100.
PubMed   |  Link to Article
Łoniewski  I, Wesson  DE.  Bicarbonate therapy for prevention of chronic kidney disease progression. Kidney Int. 2014;85(3):529-535.
PubMed   |  Link to Article
Blumberg  A, Weidmann  P, Ferrari  P.  Effect of prolonged bicarbonate administration on plasma potassium in terminal renal failure. Kidney Int. 1992;41(2):369-374.
PubMed   |  Link to Article
Abramowitz  MK, Melamed  ML, Bauer  C, Raff  AC, Hostetter  TH.  Effects of oral sodium bicarbonate in patients with CKD. Clin J Am Soc Nephrol. 2013;8(5):714-720.
PubMed   |  Link to Article
Goraya  N, Wesson  DE.  Dietary management of chronic kidney disease: protein restriction and beyond. Curr Opin Nephrol Hypertens. 2012;21(6):635-640.
PubMed   |  Link to Article
Kuijvenhoven  MA, Haak  EA, Gombert-Handoko  KB, Crul  M.  Evaluation of the concurrent use of potassium-influencing drugs as risk factors for the development of hyperkalemia. Int J Clin Pharm. 2013;35(6):1099-1104.
PubMed   |  Link to Article
Cohn  JN.  Reducing cardiovascular risk by blockade of the renin-angiotensin-aldosterone system. Adv Ther. 2007;24(6):1290-1304.
PubMed   |  Link to Article
Kessler  C, Ng  J, Valdez  K, Xie  H, Geiger  B.  The use of sodium polystyrene sulfonate in the inpatient management of hyperkalemia. J Hosp Med. 2011;6(3):136-140.
PubMed   |  Link to Article
Scherr  L, Ogden  DA, Mead  AW, Spritz  N, Rubin  AL.  Management of hyperkalemia with a cation-exchange resin. N Engl J Med. 1961;264:115-119.
PubMed   |  Link to Article
Flinn  RB, Merrill  JP, Welzant  WR.  Treatment of the oliguric patient with a new sodium-exchange resin and sorbitol; a preliminary report. N Engl J Med. 1961;264:111-115.
PubMed   |  Link to Article
Watson  M, Abbott  KC, Yuan  CM.  Damned if you do, damned if you don’t: potassium binding resins in hyperkalemia. Clin J Am Soc Nephrol. 2010;5(10):1723-1726.
PubMed   |  Link to Article
Watson  MA, Baker  TP, Nguyen  A,  et al.  Association of prescription of oral sodium polystyrene sulfonate with sorbitol in an inpatient setting with colonic necrosis: a retrospective cohort study. Am J Kidney Dis. 2012;60(3):409-416.
PubMed   |  Link to Article
Tongyoo  A, Sriussadaporn  E, Limpavitayaporn  P, Mingmalairak  C.  Acute intestinal obstruction due to Kalimate, a potassium-lowering agent: a case report and literature review. J Med Assoc Thai. 2013;96(12):1617-1620.
PubMed
Castillo-Cejas  MD, De-Torres-Ramírez  I, Alonso-Cotoner  C.  Colonic necrosis due to calcium polystyrene sulfonate (Kalimate) not suspended in sorbitol. Rev Esp Enferm Dig. 2013;105(4):232-234.
PubMed   |  Link to Article
Yang  A, Leon  A, Nuttall  M, Low  J, Rasmussen  H.  In vitro ion exchange capacity and selectivity of ZS-9, a novel, selective cation trap for the treatment of hyperkalemia. Am J Kidney Dis. 2014;63(5):B115.
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Multimedia

Supplement 1.

Trial protocol

Supplemental Content
Supplement 2.

eTable 1. List of HARMONIZE sites and Investigators (by country)

eTable 2. Summary of treatment-related adverse events

eFigure. Mean serum potassium across pre-specified subgroups of chronic kidney disease (CKD), heart failure (HF), diabetes mellitus (DM), and concomitant RAASi (renin angiotensin aldosterone system inhibitor) use. Mean serum potassium levels over Days 8-29 of the randomized phase are shown for patients receiving placebo versus once daily zirconium cyclosilicate (A) 5g, (B) 10g, and (C) 15g

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