brief review - hypertensionhyper.ahajournals.org/content/hypertensionaha/66/4/731.full.pdf · brief...

731

• Online Data Supplement

Hyperkalemia is a clinical problem with potential mecha-nisms ranging from increased cellular potassium release

(eg, pseudohyperkalemia, metabolic acidosis) to reduced potassium excretion (eg, reduced responsiveness to aldoste-rone, reduced aldosterone secretion, reduced distal sodium, and water delivery).1,2 Patients with chronic kidney disease (CKD), defined as an estimated glomerular filtration rate (eGFR) <45 mL/min per 1.73 m2, are at increased risk of hyperkalemia, resulting from ≥1 of these mechanisms.3 Renin–angiotensin–aldosterone system inhibitors (RAASis) are recommended by guidelines for lowering blood pressure, slowing CKD progres-sion in patients with CKD,4,5 and reducing cardiovascular mor-tality and heart failure hospitalizations in patients with heart failure and a reduced ejection fraction,6,7 but these drugs com-pound the hyperkalemia risk.1,8–10 The risk is magnified when the drugs are used in combination (eg, aliskiren in combina-tion with ACE inhibitors or angiotensin receptor blockers;8,11 mineralocorticoid receptor antagonists in combination with ACE inhibitors or angiotensin receptor blockers). Moreover, the risk for hyperkalemia is magnified in diseases, such as dia-betes mellitus and heart failure.4,5,12,13 The occurrence or fear of inducing hyperkalemia has led to premature discontinuation, suboptimal dosing, and often failure to use an RAASi, thereby exposing patients to increased cardiovascular risk.

Current treatment approaches for chronic hyperkalemia are limited. Options for the management of hyperkalemia include discontinuation or reduced doses of RAASi, admin-istration of loop diuretics, dietary potassium restriction, or sodium polystyrene sulfonate.14 None of these approaches are optimal because they require withholding life-saving or kid-ney preserving therapy (ie, RAASi), have a low rate of patient adherence (eg, dietary restriction), or have an unfavorable adverse effect profile and low tolerability (ie, sodium polysty-rene sulfonate).15

New agents to treat hyperkalemia are in the late stages of development. Clinical trial data suggest that these new agents effectively lower serum potassium and are well toler-ated.16–20 Therefore, these agents offer promising advantages

over existing management options. It is possible that these agents might also facilitate maintenance of RAASi across the broad spectrum of patients with RAASi intolerance because of hyperkalemia (eg, CKD and heart failure),18 and testing this hypothesis in larger clinical trials is warranted. This article reviews the clinical problem of hyperkalemia and identifies predictors of hyperkalemia in patients with hypertension, CKD, diabetes mellitus, and heart failure. It also presents recent clinical trial evidence of the efficacy and safety of new treatments for hyperkalemia, and it discusses how these agents may be used clinically, if approved.

Overview of HyperkalemiaThe rate of hyperkalemia is low in uncomplicated hyperten-sion patients treated with RAASi,21 but it rises in the setting of other comorbidities (eg, eGFR <60 and especially <45 mL/min per 1.73 m2, and heart failure) or dual RAAS inhi-bition.22 Hyperkalemia rates reported in observational studies vary by patient population (Table S1 in the online-only Data Supplement). Estimates of hyperkalemia rates are likely to be biased by underreporting, and actual rates may be higher, especially for patients with multiple risk factors (eg, CKD, diabetes mellitus, heart failure, and dual RAASi) or who are managed in routine clinical practice without the stringent monitoring protocols of clinical trials.23 Predictors of hyper-kalemia are shown in Table 1.22 These predictors reflect worse kidney function, advanced diabetes mellitus, or more severe heart failure.

Hyperkalemia is associated with an increased risk of death in patients with and without CKD.3 In an analysis of 15 803 patients with heart failure or hypertension treated with RAASi, twice as many deaths occurred in patients catego-rized as hyperkalemic (serum potassium >5 mEq/L, n=3868), although the absolute number of deaths was not reported.24 In a multiple logistic regression model, hyperkalemia was associated with an odds ratio for death of 1.56 (95% confi-dence interval, 1.30–1.88) in the total population and 1.63 (95% confidence interval, 1.04–2.55) among those with

Received June 3, 2015; first decision June 15, 2015; revision accepted July 23, 2015.From the Department of Medicine, University of Michigan School of Medicine, Ann Arbor (B.P.); and ASH Comprehensive Hypertension Center,

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Chicago Medicine, IL (G.L.B.)The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.

115.04889/-/DC1.Correspondence to Bertram Pitt, University of Michigan Medical School, Department of Medicine, 1500 E. Medical Center Dr, 3910 Tauman Center,

Ann Arbor, MI 48109, E-mail [email protected]

New Potassium Binders for the Treatment of HyperkalemiaCurrent Data and Opportunities for the Future

Bertram Pitt, George L. Bakris

(Hypertension. 2015;66:731-738. DOI: 10.1161/HYPERTENSIONAHA.115.04889.)© 2015 American Heart Association, Inc.

Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.115.04889

Brief Review

by guest on May 18, 2018

http://hyper.ahajournals.org/D

ownloaded from

by guest on M

ay 18, 2018http://hyper.ahajournals.org/

Dow

nloaded from



ownloaded from

by guest on M


Dow

nloaded from



ownloaded from

by guest on M


Dow

nloaded from



ownloaded from

by guest on M


Dow

nloaded from



ownloaded from

by guest on M


Dow

nloaded from



ownloaded from

by guest on M


Dow

nloaded from



ownloaded from

by guest on M


Dow

nloaded from



ownloaded from

http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.115.04889/-/DC1



mailto:[email protected]

http://hyper.ahajournals.org/















732 Hypertension October 2015

stages 3 to 5 CKD.24 The association between mortality risk and serum potassium among patients with stage 3 to 5 CKD is U-shaped, with an increased mortality risk at serum potas-sium >5.0 mEq/L and <4.1 mEq/L, even after adjustment for demographic characteristics and comorbidities.25 Patients ≥65 years of age and those with comorbidities (eg, heart failure, CKD, cardiovascular disease, or hypertension) have a greater mortality risk than younger patients or those without comor-bid conditions.26

In addition to the direct association between hyperka-lemia and all-cause mortality, hyperkalemia may theoreti-cally have an indirect impact on clinical outcomes because of the lost opportunity to treat patients with RAASi, either because of actual hyperkalemia or concerns about the risk of hyperkalemia.27 However, this theoretical effect has not been quantified.

Dietary Management of HyperkalemiaRestriction of dietary potassium to <2.4 g/d is recommended in patients with stage 3 (eGFR <60 mL/min per 1.73 m2) or higher CKD.14 However, specific guideline-directed advice is lacking on dietary potassium intake for other patient groups at risk of hyperkalemia. In patients with heart failure in whom sodium restriction is frequently advised, the use of salt substi-tutes including potassium chloride may expose these patients to the risk of hyperkalemia, especially if they have concomi-tant CKD or diabetes mellitus. Although patients are often educated to avoid commonly recognized high-potassium foods, many high-potassium foods may remain unrecognized by patients and healthcare providers (Table S2). Patients at risk for hyperkalemia should receive comprehensive dietary potassium education. This recommendation may be espe-cially important in patients who attempt the DASH (Dietary Approaches to Stop Hypertension) diet. Although the overall effects of the DASH diet seem beneficial, patients with CKD or diabetes mellitus may be placed at increased risk for hyper-kalemia and its consequences.

Novel Therapies in Development for Hyperkalemia

OverviewThe majority of potassium is renally excreted, but ≈5% to 10% is secreted in the colon (Figure 1). Two new agents, patiromer and sodium zirconium cyclosilicate (ZS-9), are in the late stages of clinical development for the treatment of hyperkalemia. These agents may offer advantages over exist-ing approaches to hyperkalemia treatment (Table 2). Both

patiromer and ZS-9 act to remove potassium by exchanging cations (calcium and sodium for patiromer and ZS-9, respec-tively) for potassium in the distal colon, binding potassium, and increasing its fecal excretion.28

Patiromer is an organic, nonabsorbed polymer (Figure 2) that increases fecal potassium excretion by exchanging potas-sium for calcium in the distal colon.17,18,29,30 It is a free-flowing, insoluble powder of small (≈100 µm) spherical beads with low viscosity.17,18,29,30 Sodium zirconium cyclosilicate (ZS-9) is an inorganic polymer, which selectively attracts potassium ions to its negatively charged crystalline lattice structure and exchanges them for sodium and hydrogen (Figure 3).16,28,29,31 It is formulated as a free-flowing, insoluble powder that is not absorbed systemically.31

Patiromer Clinical TrialsThe PEARL-HF study (Evaluation of RLY5016 in Heart Failure Patients) was a multicenter, randomized, double-blind, placebo-controlled parallel-group multiple-dose study to evaluate the effects of patiromer in patients with heart fail-ure.18 A total of 120 patients with chronic heart failure who were treated with standard background therapy and had an indication for spironolactone were enrolled. Patients were required to have serum potassium between 4.3 and 5.1 mEq/L at screening. All patients had either an eGFR of <60 mL/min or a documented history of RAASi discontinuation because of hyperkalemia within 6 months. 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 all patients 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.

Table 1. Key Predictors of Hyperkalemia* in People With Chronic Kidney Disease With or Without Diabetes Mellitus or Heart Failure

eGFR ≤45 mL/min per 1.73 m2 (regardless of pathogenesis)

Initial serum potassium >4.5 mEq/L9

BMI <25 g/m2

*Hyperkalemia is defined as a [K+] >5.5 mEq/L where renin–angiotensin–aldosterone system inhibitors alone or in combination were given. eGFR indicates estimated glomerular filtration rate.

Colon enterocyteApical

CFRT

ENaC

cAMPc

KCNMA1

HKα2ATPase

NKCC1

Cl– Cl– Cl–

2Cl–

ClC-2

Na+Na+

3Na+

KCNN4, KCNK5KCNQ1/KCNE3

K+

2K+K+

K+ K+

K+ K+

K+

H+

(–) (+)

(+)

(+)

Vm

Basolateral

ATPase

Figure 1. Mechanisms involved in potassium secretion in colonic epithelial cells in response to an increase in serum potassium levels. In the colonic enterocytes potassium enters the cell via the Na+, K+-ATPase, and Na+-2Cl−-K+ cotransporter (NKCC1) of the basolateral membrane and leaves the cell into the colon lumen via apical large conductance Ca2+-dependent potassium (KCNMA or BK) channels. In the basolateral membrane, several potassium channels (KCNQ1/KCNE3, KCNN4, and probably KCNK5) facilitate the electrogenic transport by hyperpolarizing the membrane voltage. CFRT indicates epithelial (cystic fibrosis transmembrane regulator) chloride channels; and ENaC, apical epithelial sodium channels. Reprinted from Tamargo et al28 with permission of the publisher. Copyright © 2014, Discovery Medicine.



ownloaded from


Pitt and Bakris New Agents for Hyperkalemia 733

The mean change in serum potassium from baseline to day 28 was the primary efficacy end point.18

Mean serum potassium was 4.7 mEq/L at baseline in both the groups. At 28 days, serum potassium was significantly lower in the patiromer group compared with placebo.18 This reduction was evident regardless of eGFR. Fewer patients randomized to patiromer experienced serum potassium of >5.5 mEq/L (7% versus 25%; P=0.015), and more patiromer-treated patients had serum potassium of <3.5 mEq/L, but the difference was not significant (6% versus 0%; P=0.094). Hypomagnesemia (<1.8 mg/dL) was reported in 13 (24%) of the patiromer patients and 1 (2%) of the placebo patients (P=0.001). The mean serum magnesium value remained within normal limits, although the patiromer group had a statistically significant reduction in serum magnesium from baseline compared with the placebo group. These electrolyte changes were not associated with an increased risk of ven-tricular arrhythmias. No significant changes in serum phos-phorous were noted. The spironolactone dose was increased in more patients randomized to patiromer than placebo (91% versus 74%; P=0.019). Gastrointestinal side effects were reported in 21% of patiromer-treated patients and 6% of pla-cebo patients, but there was no difference in adverse events leading to study drug discontinuation (7% versus 6%).18 The PEARL-HF data suggested that patiromer was well tolerated and may be an effective therapy to prevent hyperkalemia in patients with heart failure who are at risk for hyperkalemia, and it may enable initiation, maintenance, or higher doses of mineralocorticoid receptor antagonists in addition to back-ground RAASi therapy.18 Larger studies of this concept are warranted.

Patiromer was studied in 304 patients with type 2 dia-betes mellitus and CKD (eGFR, 15 to <60 mL/min per 1.73 m2) in the AMETHYST-DN (RLY5016 in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy) trial.19 In this multicenter, randomized, open-label, dose-ranging study, patients were enrolled who

developed hyperkalemia in the setting of RAASi dose optimi-zation for blood pressure control, or who were on an RAASi and hyperkalemic at the time of screening. Patients were stratified by baseline serum potassium, and those with serum potassium of >5 to 5.5 mEq/L (mild stratum) were equally ran-domized to patiromer 4.2, 8.4, or 12.6 g twice daily. Patients with serum potassium >5.5 to <6 mEq/L (moderate stratum) were randomized 1:1:1 to patiromer 8.4, 12.6, or 16.8 g twice daily. The study consisted of an 8-week treatment phase and a 44-week maintenance phase. The primary efficacy end point was the mean change in serum potassium from baseline to week 4. The mean baseline serum potassium was 5.3 mEq/L; 65% of patients had stage 3 CKD. Statistically significant reductions in mean serum potassium were observed within 48 hours, across the spectrum of baseline serum potassium levels. By week 4, the reduction from baseline in serum potas-sium was significant in both strata (mild, −0.47±0.04 mEq/L; moderate, −0.92±0.08 mEq/L) and for all dosing groups (all P<0.001). The reduction in serum potassium was maintained

Table 2. Comparison of Existing and New Potential Therapies for Chronic Hyperkalemia

Characteristic Kayexylate Patiromer ZS-9

Clinical pharmacology Cation-exchange resin, exchanges sodium for H+ in stomach, then exchange for H+ for other cations in large intestine

Nonabsorbed organic polymer28,29; preferentially binds K+ in the colon

Inorganic polymer; negative charge to framework enables cation exchange28,29

Clinical trials No Yes Yes

Efficacy Observed decreases in serum potassium between 0.82 and 1.14 mEq/L depending on dose29

Mean reduction in serum potassium at week 4 −1.01 mmol/L; 76% with normokalemia after 4 wk;17 60% placebo vs 15% patiromer had recurrent serum K+ ≥5.5 mmol/L during 8-week withdrawal phase17

Mean initial reduction in serum potassium (48 h) −0.46 to −1.1 mEq/L depending on dose16,20; 98% achieved normokalemia within 48 h; 71%–85% depending on ZS-9 dose maintained normokalemia during 28 day follow-up vs 48% with placebo20

Safety Risk of acute bowel necrosis, hypernatremia, diarrhea, and gastrointestinal intolerance15

Mild-to-moderate constipation most commonly reported (11% during initial treatment phase and 4% patiromer vs 0% placebo during 8-wk randomized withdrawal phase), hypokalemia (5%–6%), hypomagnesemia (3% in OPAL-HK, 7.2% in AMETHYST-DN, and 24% in PEARL-HF)

Gastrointestinal disorder reported in 2.1%–8.7% of ZS-9 patients (depending on dose and period of study) vs 2.4%–7.4% of placebo patients, hypokalemia (≈10% depending on dose), edema (2.4%)

Patiromer Calcium• Organic polymer• 2-Propenoic acid, 2-fluoro-, calcium salt (2:1), polymer with diethenylbenzene• and 1,7-octadiene• Cross-linked polymer of calcium 2-fluoroprop- 2-enoate with diethenylbenzene• and octa-1,7-diene

91 Ca2+ CO2–

F 182

10

n

H2C CH2

CH2

H2C

H2C

8

Figure 2. Properties of patiromer calcium. Reprinted from McCullough PA et al29 with permission of the publisher. Copyright © 2014, MedReviews ®, LLC.



ownloaded from



throughout the follow-up period. After patiromer discontinu-ation, serum potassium rose by 0.43±0.46 mEq/L in the mild stratum and 0.49±0.69 mEq/L in the moderate stratum during 28 days of follow-up.19 Serum potassium <3.5 mEq/L occurred in 17 patients (5.6%). Hypomagnesemia (7.2%), constipa-tion (4.6%), and diarrhea (2.7%) were the most commonly reported treatment-related adverse events.19 Mean serum mag-nesium was in the normal range (1.5–2.4 mg/dL) during the treatment period. The mean change in serum magnesium from baseline to week 52 was −0.1 to −0.2 across all doses within all strata. Mean phosphate decreased slightly from baseline to 52 weeks, with a mean reduction of −0.1 to −0.2 mg/dL in all dosing groups, except for a decrease of −0.8±0.9 mg/dL at the 8.4 g twice daily starting dose in the moderate hyperkalemia stratum.

The OPAL-HK (A Two-Part, Single-Blind, Phase 3 Study Evaluating the Efficacy and Safety of Patiromer for the Treatment of Hyperkalemia) trial was a 2-part, single-blind, phase 3 study, which evaluated the efficacy and safety of pati-romer for the treatment of hyperkalemia in patients with stage 3 or 4 CKD (eGFR, 15 to <60 mL/min per 1.73 m2), on ≥1 RAASi, and serum potassium of 5.1 to <6.5 mmol/L.17 The first study phase consisted of a 4-week, single-group, single-blind treatment phase (patiromer 4.2 g twice daily for base-line potassium 5.1 to <5.5 mmol/L or 8.4 g twice daily for baseline potassium 5.5 to <6.5 mmol/L with subsequent dose adjustments made according to a prespecified algorithm), followed by an 8-week placebo-controlled, single-blind, ran-domized withdrawal phase in the patients whose serum potas-sium was ≥5.5 mmol/L at the first-phase baseline and 3.8 to <5.1 mmol/L at the end of the initial treatment period. Patients were randomized to continue patiromer at the same dose as their week 4 dose during the initial treatment phase, or pla-cebo. The primary end points for the respective study phases were the mean change in serum potassium from baseline to week 4, and the between-group difference in the median serum potassium change from the beginning of the random-ized withdrawal phase to week 4 of the withdrawal phase.

In the initial treatment phase, 243 patients were enrolled. Of these, 107 continued into the randomized withdrawal phase. Comorbidities associated with hyperkalemia were com-mon: 57% had type 2 diabetes mellitus, 42% had heart failure, 97% had hypertension, all were on an RAASi, 17% were on dual RAASi, and 44% were receiving maximal RAASi doses. The mean eGFR was 35 mL/min per 1.73 m2. Patiromer sig-nificantly reduced serum potassium from baseline during the initial treatment phase (−1.01±0.03 mmol/L; 95% con-fidence interval, −1.07 to −0.95). The majority of patients (76%) had serum potassium levels within the target range (3.8 to <5.1 mmol/L) at the end of the initial treatment phase, and this finding was consistent among patients with mild or moderate-to-severe hyperkalemia at baseline. Serum potas-sium increased in the placebo group but not in the patiromer group during the first 4 weeks of the randomized withdrawal phase, resulting in a between-group difference in serum potas-sium of 0.72 mmol/L (P<0.001). Potassium >5.5 mmol/L occurred in 15% of patients randomized to patiromer con-tinuation compared with 60% of patients in the placebo group (P<0.001). Patiromer, although well tolerated, was associated

with constipation in 11% of patients during the initial treat-ment phase, whereas there was no constipation in the placebo group. Study drug was discontinued because of adverse events in 1 (2%) patient each in the patiromer and placebo groups.17 Serum potassium of <3.5 mmol/L occurred in 3% of patients during the initial treatment phase. Hypokalemia was defined as serum potassium of <3.8 mmol/L during the randomized withdrawal phase, and it was observed in 5% and 2% of the patiromer and placebo groups, respectively.17 Changes in magnesium were similar to those observed in other patiromer studies. Patients maintained overall normal serum magnesium levels with small decreases from baseline in the range of −0.1 to −0.2 mg/dL. Hypomagnesemia occurred in 8 (3%) patients during the initial treatment phase. No clinically relevant changes in calcium were observed.

Sodium Zirconium Cyclosilicate Clinical TrialsPackham et al16 conducted a 2-phase study of ZS-9 in patients with serum potassium of 5.0 to 6.5 mmol/L. Patients on dialy-sis were excluded, but no specific requirements for eGFR or RAASi use were specified. Patients were randomized to dou-ble-blind ZS-9 (1.25 g, 2.5 g, 5 g, or 10 g 3× daily) or placebo for 48 hours. Patients in the ZS-9 group whose serum potas-sium was 3.5 to 4.9 mmol/L at 48 hours were randomized to either continue their current ZS-9 dose once daily or placebo for 12 days. The primary end point of the initial phase was the between-group difference in the exponential rate of change in mean serum potassium during 48 hours. The maintenance phase primary end point was the between-group difference in mean serum potassium level during the 12-day treatment interval. A total of 754 patients entered the initial phase, and 543 patients continued to the 12-day maintenance phase. The

K+ Na+Ca2+

o

o

Si

Zr

A B C

Zr

Zr

Zr

Zr

Zr

Si

Si

Si

Si

Sio

o

o

o

o

Si

Si

Si

Si

Si

SiZr

Zr

Zr

o

o

o

o

o

o

o

o

o

o

o

o

o

o

Figure 3. Structure of ZS-9. Pore detail with potassium ion (A), sodium ion (B), and calcium ion (C). Blue spheres indicates oxygen atoms; green spheres, silicon atoms; and red spheres, zirconium atoms. Reprinted from Stavros et al31 with permission of the publisher. Copyright © 2014, the Authors.



ownloaded from



population reflected patients with risk factors for hyperkale-mia, including CKD (61%), heart failure (42%), diabetes mel-litus (61%), and RAASi use (64%). The mean rate of change (decrease) in serum potassium from baseline was greater for the ZS-9 2.5, 5, and 10 g groups compared with placebo (P<0.001), and normokalemia was reached within 48 hours for all these dosing groups compared with placebo (P<0.001). During the maintenance phase, normokalemia was maintained in the ZS-9 5 g and 10 g dosing groups compared with patients who were subsequently randomized to placebo. Recurrent hyperkalemia was observed within 1 week among patients treated with ZS-9 10 g who discontinued study drug at the end of the study.16 Gastrointestinal side effects were the most com-monly reported adverse events in both the initial treatment and maintenance phases. Hypokalemia <3.5 mmol/L was reported in 2 ZS-9 patients, 1 at the 2.5-g dose (maintenance) and 1 at the 10-g dose (initial treatment).16 A dose-dependent increase in serum bicarbonate was observed. There were no reports of hypomagnesemia.

The Hyperkalemia Randomized Intervention Multidose ZS-9 Maintenance (HARMONIZE) study was a randomized, double-blind, placebo-controlled trial in patients with serum potassium of ≥5.1 mEq/L.20 Patients were treated with ZS-9 10 g 3× daily for 48 hours during an open-label initial phase, and patients who achieved serum potassium 3.5 to 5.0 mEq/L were randomized to double-blind ZS-9 (5, 10, or 15 g) or pla-cebo for 28 days. The primary end point was the comparison of mean serum potassium levels between placebo and ZS-9 from days 8 through 29. A total of 258 patients entered the open-label phase, and 237 were randomized into the mainte-nance phase.20 The mean baseline serum potassium was 5.6 mEq/L, mean eGFR was 46 mL/min per 1.73 m2, and 69% had eGFR <60 mL/min per 1.73 m2. CKD was present in 66%, 36% had heart failure, 66% had diabetes mellitus, and 70% were treated with ≥1 RAASi. ZS-9 reduced serum potassium from baseline at 48 hours (−1.1 mEq/L, 95% confidence inter-val, −1.1 to −1.0; P<0.001), and normokalemia (serum potas-sium 3.5–5.0 mEq/L) was achieved in 84% and 98% within 24 and 48 hours, respectively. The median time to normokalemia was 2.2 hours. During the maintenance phase, mean serum potassium was lower in all the ZS-9 groups compared with placebo (P<0.001). ZS-9 was well tolerated. Gastrointestinal side effects were reported, but they did not differ between the placebo and ZS-9 groups (14% placebo, 7% 5 g, 2% 10 g, and 9% 15 g). During the maintenance phase, edema was reported in 2.4% of the placebo group and 2.2%, 5.9%, and 14.3% of the 5 g, 10 g, and 15 g dosing groups, respectively. Serum potassium of <3.5 mEq/L was observed in 10% of patients in the ZS-9 10 g group and 11% of patients in the ZS-9 15 g group versus no cases in the 5 g or placebo groups.20 No clini-cally significant changes in serum magnesium, phosphate, or bicarbonate were observed.

Practical Clinical Management of Hyperkalemia

Acute HyperkalemiaIn acute hyperkalemia, intravenous insulin or a β

2-agonist can

be used to shift potassium into cells. Sodium bicarbonate is

indicated in the setting of metabolic acidosis. However, in patients with hypertension and in those with heart failure, the use of sodium bicarbonate may be contraindicated because of the risk of increasing sodium retention and volume overload. Hyperkalemic patients presenting with evidence of cardiac instability should receive rapid therapy to stabilize the myo-cardium according to the standard of care (eg, intravenous calcium chloride or gluconate).32 Dialysis may also be consid-ered for the treatment of acute hyperkalemia.32

Acute therapy is recommended when serum potassium is >6.5 mmol/L or when cardiac manifestations of hyperkalemia are present regardless of the serum potassium concentration.33 However, it is important to recognize that the ECG can be normal, even with severe hyperkalemia. In addition, ventricu-lar fibrillation may develop without preceding cardiac rhythm abnormalities, and it is difficult to predict which patients are at risk for cardiac manifestations of hyperkalemia.33–35 The abso-lute level of serum potassium associated with an increased risk of ventricular arrhythmias and sudden cardiac death will, in part, depend on the rate of rise of serum potassium, the level of tissue potassium (as reflected by red blood cell potassium con-centration), calcium concentration, pH, and other factors. These considerations support instituting acute therapy for patients with moderate-to-severe hyperkalemia according to the criteria specified above,33 although minimal evidence from clinical tri-als is available on the acute treatment of hyperkalemia.36

Some data suggest that ZS-937 and patiromer38 may have an onset of action sufficient to allow the use of these agents in the acute setting. More data are needed to fully understand these findings and determine whether the observation of an early effect (1–4 hours with ZS-9) was because of shift-ing potassium (ie, because of postprandial insulin release in patients who were fasting before ZS-9 was administered or alkalization from the conversion of the sodium component of ZS-9 to bicarbonate), or to true potassium removal.

Chronic Hyperkalemia

TreatmentThe only available current treatment for chronic hyperkalemia is sodium or calcium polystyrene. Sodium or calcium poly-styrene are cation-exchange resins, which exchange sodium (or calcium) for secreted potassium in the lumen of the colon. Although these agents are effective in reducing serum potas-sium, their effects are not predictable.15 The onset of action is delayed until the resin reaches the colon. In addition, sodium polystyrene has been associated with gastrointestinal toxicity limiting its chronic use.15 Sodium polystyrene when admin-istered alone can cause severe constipation and impaction, which led to its administration with sorbitol. However, sor-bitol is a suspected contributor to the colonic necrosis that has been observed in patients treated with sodium polysty-rene.19 Because of these limitations, sodium polystyrene is not a viable option for routine chronic use, and discontinuation of RAASi is often the most clinically appropriate option for managing hyperkalemia.

However, if approved, patiromer and ZS-9 could play an important role in the current management of hyperkalemia. Patiromer and ZS-9 have demonstrated both early reductions



ownloaded from



in potassium and an ability to maintain normokalemia over weeks of therapy with acceptable side effect profiles.16–20 Although head-to-head trials of patiromer or ZS-9 versus sodium polystyrene sulfonate have not been conducted, the theoretical advantages of the new agents over existing therapy are apparent (Table 2).

Patient Selection and DosingAlthough the exact indication and labeling parameters will not be known until these drugs are approved, the patient selection criteria will probably mimic the eligibility criteria of the pati-romer and ZS-9 clinical trials. Thus, patients presenting with ele-vated serum potassium of >5 mmol/L will likely be candidates for therapy. It is not expected that specific thresholds for eGFR would be required for treatment if hyperkalemia is present. However, patients with end-stage renal disease on dialysis were not included in clinical trials. The clinical trial data suggest that potassium-lowering effects are observed within several hours and normokalemia within 24 hours.20 However, these agents are not intended for acute lowering of serum potassium, and their onset of action should be considered when determining the need for acute treatment. Until more data become available, clinical trial protocols should be used to help guide initial and mainte-nance dosing strategies if these agents are approved for use.

Treatment DurationPatiromer and ZS-9 are likely to be initially approved for relatively short treatment durations (30–60 days). However, the results of PEARL-HF and 1-year follow-up data with patiromer from AMETHYST-DN show effectiveness with no concerning safety signals when patiromer was administered daily for ≤1 year.18,19 A study with ZS-9 is also ongoing to gather 1-year data.

MonitoringIn the patiromer and ZS-9 clinical trials, potassium was monitored at weekly intervals. Serum potassium values were relatively stable during maintenance therapy. Firm monitor-ing recommendations cannot be made at the present time in the absence of approved labeling and lack of clinical experi-ence with the drug outside of a clinical trial setting. Serum magnesium, phosphorous, and bicarbonate levels should be routinely monitored along with serum potassium. Although of note, these patients with an advanced stage of nephropa-thy generally have higher magnesium and phosphate levels and lower bicarbonate values than the general population. Hence, given the magnitude of change observed with these agents, the impact on magnesium, phosphorous, and bicar-bonate may actually be beneficial. Drug interactions (eg, interference with drug absorption) are an important consid-eration. Data from drug interaction studies have not yet been published, but if these new potassium binders receive Food and Drug Administration approval, physicians should review the product labeling and published literature to understand potential interactions that might be relevant for individual patients.

AdherencePatient adherence will be of paramount importance in the con-text of using patiromer or ZS-9 after the initial achievement of

normokalemia. Patients who achieve normokalemia relatively quickly are likely to be maintained on existing RAASi therapy as was done safely in clinical trials. Patients who are nonadher-ent to patiromer or ZS-9 after achieving normokalemia have a substantial risk of recurrent hyperkalemia as demonstrated by the proportion of patients in clinical trials who developed recurrent hyperkalemia after randomized withdrawal to pla-cebo.16,17,19,20 Thus, once available for use, patients receiving patiromer or ZS-9 should receive specific patient education about the importance of adherence and the risks associated with nonadherence. This education should be reinforced at each visit or follow-up contact. Patients who demonstrate nonadherence are not optimal candidates for these therapies. In clinical trials, patients were educated to limit consump-tion of dietary potassium to ≤3 g/d. Patients in real-world settings outside of a clinical trial may or may not adhere to these dietary restrictions. The extent to which dietary nonad-herence might influence the response to patiromer or ZS-9 is not known.

Future Perspectives: Potential Clinical Applications

The new potassium binders present several potential oppor-tunities for clinical application and research. RAASi at tar-get doses are recommended by international guidelines for patients with hypertension, heart failure and a reduced ejec-tion fraction, CKD, and diabetes mellitus to improve cardio-vascular and renal outcomes.4,5,13 Target doses of RAASi are more effective than submaximal doses in patients with heart failure and a reduced ejection fraction, but they are often not attempted because of the fear of inducing hyperkalemia in patients with concomitant CKD or diabetes mellitus. There are suggestions that even higher doses of RAASi than cur-rently approved might be even more effective. However, these doses have not been systematically evaluated in large-scale randomized trials because of the fear of inducing hyperka-lemia. Dual RAAS inhibition, specifically an mineralocorti-coid receptor antagonist added to either an ACE inhibitor or angiotensin receptor blocker, is recommended for patients with heart failure and a reduced ejection fraction to improve survival and reduce morbidity,6,7 but similar tolerability con-cerns persist. Whether patiromer or ZS-9 can facilitate better RAASi tolerability and fill this treatment gap or enable higher doses to be studied are areas of active investigation.

ConclusionsHyperkalemia is a challenging clinical problem for clinicians caring for patients with CKD, diabetes mellitus, or heart fail-ure. The new agents on the horizon seem to offer better predict-ability, tolerability, and safety for patients with hyperkalemia. Beyond the treatment of hyperkalemia, patiromer and ZS-9 might also enable more patients to be started or maintained on guideline-recommended RAASi. This concept is actively being investigated, as is the expansion of RAASi in popula-tions excluded from previous studies because of hyperkalemia concerns. The clinical community eagerly awaits the regula-tory decisions about approval and the completion of ongoing trials with these agents.



ownloaded from



AcknowledgmentsWe acknowledge Wendy Gattis Stough, PharmD (Campbell University College of Pharmacy and Health Sciences and Expert Medical Communications and Consulting, LLC) for contributing to the development of this article. Wendy Gattis Stough is a consultant to Relypsa, CHU Nancy, European Drug Development Hub, European Society of Cardiology, Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America, Overcome, Stealth BioTherapeutics, Covis Pharmaceuticals, University of Gottingen, and University of North Carolina.

DisclosuresB. Pitt is a consultant for Relypsa, Pfizer, Bayer, Astra Zeneca, scPharmaceuticals, Stealth Peptides, Tricida, DaVinci Therapeutics, Forrest Laboratories, Aurasense; Stock options in Relypsa, scPhar-maceuticals, Tricida, DaVinci therapeutics, Aurasense; Patent pend-ing for site-specific delivery of eplerenone to the myocardium; Clinical events committee for Juventas; Data monitoring committee for Novartis, J&J, Oxygen Biotherpeutics. G.L. Bakris is a consultant for Relypsa, Medtronic, Novartis, Takeda, AbbVie, Stealth, Vascular Dynamics, Janssen, Boeringher-Ingelheim, Merck, GSK; Editor-in-Chief of American Journal of Nephrology, Hypertension-UpToDate; Associate Editor of Diabetes Care and Hypertension Research.

References 1. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-

angiotensin-aldosterone system. N Engl J Med. 2004;351:585–592. doi: 10.1056/NEJMra035279.

2. Palmer BF. A physiologic-based approach to the evaluation of a patient with hyperkalemia. Am J Kidney Dis. 2010;56:387–393. doi: 10.1053/j.ajkd.2010.01.020.

3. Einhorn LM, Zhan M, Hsu VD, Walker LD, Moen MF, Seliger SL, Weir MR, Fink JC. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med. 2009;169:1156–1162. doi: 10.1001/archinternmed.2009.132.

4. Kidney Disease Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and manage-ment of chronic kidney disease. Kidney inter, Suppl. 2013;3:1–150.

5. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507–520. doi: 10.1001/jama.2013.284427.

6. McMurray JJ, Adamopoulos S, Anker SD, et al; ESC Committee for Practice Guidelines. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33:1787–1847. doi: 10.1093/eurheartj/ehs104.

7. Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart fail-ure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147–e239. doi: 10.1016/j.jacc.2013.05.019.

8. Harel Z, Gilbert C, Wald R, Bell C, Perl J, Juurlink D, Beyene J, Shah PS. The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis. BMJ. 2012;344:e42.

9. Khosla N, Kalaitzidis R, Bakris GL. Predictors of hyperkalemia risk fol-lowing hypertension control with aldosterone blockade. Am J Nephrol. 2009;30:418–424. doi: 10.1159/000237742.

10. Weinberg JM, Appel LJ, Bakris G, Gassman JJ, Greene T, Kendrick CA, Wang X, Lash J, Lewis JA, Pogue V, Thornley-Brown D, Phillips RA; African American Study of Hypertension and Kidney Disease Collaborative Research Group. Risk of hyperkalemia in nondia-betic patients with chronic kidney disease receiving antihyperten-sive therapy. Arch Intern Med. 2009;169:1587–1594. doi: 10.1001/archinternmed.2009.284.

11. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Persson F, Desai AS, Nicolaides M, Richard A, Xiang Z, Brunel P, Pfeffer MA; ALTITUDE Investigators. Cardiorenal

end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367:2204–2213. doi: 10.1056/NEJMoa1208799.

12. Mancia G, Fagard R, Narkiewicz K, et al; Task Force Members. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31:1281–1357. doi: 10.1097/01.hjh.0000431740.32696.cc.

13. American Diabetes Association. Cardiovascular disease and risk manage-ment. Diabetes Care. 2015;38:S49–S57.

14. National Kidney Foundation. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;43:S1–S290.

15. 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;21:733–735. doi: 10.1681/ASN.2010010079.

16. Packham DK, Rasmussen HS, Lavin PT, El-Shahawy MA, Roger SD, Block G, Qunibi W, Pergola P, Singh B. Sodium zirconium cyclosili-cate in hyperkalemia. N Engl J Med. 2015;372:222–231. doi: 10.1056/NEJMoa1411487.

17. Weir MR, Bakris GL, Bushinsky DA, Mayo MR, Garza D, Stasiv Y, Wittes J, Christ-Schmidt H, Berman L, Pitt B; OPAL-HK Investigators. Patiromer in patients with kidney disease and hyperkalemia receiv-ing RAAS inhibitors. N Engl J Med. 2015;372:211–221. doi: 10.1056/NEJMoa1410853.

18. Pitt B, Anker SD, Bushinsky DA, Kitzman DW, Zannad F, Huang IZ; PEARL-HF Investigators. Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-con-trolled study in patients with chronic heart failure (the PEARL-HF) trial. Eur Heart J. 2011;32:820–828. doi: 10.1093/eurheartj/ehq502.

19. Bakris GL, Pitt B, Weir MR, Freeman MW, Mayo MR, Garza D, Stasiv Y, Zawadzki R, Berman L, Bushinsky DA; AMETHYST-DN Investigators. Effect of Patiromer on Serum Potassium Level in Patients With Hyperkalemia and Diabetic Kidney Disease: The AMETHYST-DN Randomized Clinical Trial. JAMA. 2015;314:151–161. doi: 10.1001/jama.2015.7446.

20. Kosiborod M, Rasmussen HS, Lavin P, Qunibi WY, Spinowitz B, Packham D, Roger SD, Yang A, Lerma E, Singh B. Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among out-patients with hyperkalemia: the HARMONIZE randomized clinical trial. JAMA. 2014;312:2223–2233. doi: 10.1001/jama.2014.15688.

21. Weir MR, Rolfe M. Potassium homeostasis and renin-angiotensin-aldo-sterone system inhibitors. Clin J Am Soc Nephrol. 2010;5:531–548. doi: 10.2215/CJN.07821109.

22. Lazich I, Bakris GL. Prediction and management of hyperkalemia across the spectrum of chronic kidney disease. Semin Nephrol. 2014;34:333–339. doi: 10.1016/j.semnephrol.2014.04.008.

23. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004;351:543–551. doi: 10.1056/NEJMoa040135.

24. Jain N, Kotla S, Little BB, Weideman RA, Brilakis ES, Reilly RF, Banerjee S. Predictors of hyperkalemia and death in patients with cardiac and renal disease. Am J Cardiol. 2012;109:1510–1513. doi: 10.1016/j.amjcard.2012.01.367.

25. Collins A, Reaven N, Funk S, McGaughey K, Bakris G, Pitt B, Bushinsky D. Potassium levels and mortality in patients with CKD [abstract]. J Am Soc Neprhol. 2014; Abstract No. TH-P0705.

26. Pitt B, Collins A, Reaven N, Funk S, Bakris G, Bushinsky D. Effect of cardiovascular comorbidities on the mortality risk associated with serum potassium [abstract]. Circulation. 2014;130:A13320.

27. Houghton AR, Cowley AJ. Why are angiotensin converting enzyme inhib-itors underutilised in the treatment of heart failure by general practitio-ners? Int J Cardiol. 1997;59:7–10.

28. Tamargo J, Caballero R, Delpón E. New drugs for the treatment of hyper-kalemia in patients treated with renin-angiotensin-aldosterone system inhibitors – hype or hope? Discov Med. 2014;18:249–254.

29. McCullough PA, Beaver TM, Bennett-Guerrero E, Emmett M, Fonarow GC, Goyal A, Herzog CA, Kosiborod M, Palmer BF. Acute and chronic cardiovascular effects of hyperkalemia: new insights into prevention and clinical management. Rev Cardiovasc Med. 2014;15:11–23.

30. Buysse JM, Huang IZ, Pitt B. PEARL-HF: prevention of hyperkalemia in patients with heart failure using a novel polymeric potassium binder, RLY5016. Future Cardiol. 2012;8:17–28. doi: 10.2217/fca.11.71.

31. Stavros F, Yang A, Leon A, Nuttall M, Rasmussen HS. Characterization of structure and function of ZS-9, a K+ selective ion trap. PLoS One. 2014;9:e114686. doi: 10.1371/journal.pone.0114686.



ownloaded from



32. Elliott MJ, Ronksley PE, Clase CM, Ahmed SB, Hemmelgarn BR. Management of patients with acute hyperkalemia. CMAJ. 2010;182:1631–1635. doi: 10.1503/cmaj.100461.

33. Weisberg LS. Management of severe hyperkalemia. Crit Care Med. 2008;36:3246–3251. doi: 10.1097/CCM.0b013e31818f222b.

34. Montague BT, Ouellette JR, Buller GK. Retrospective review of the frequency of ECG changes in hyperkalemia. Clin J Am Soc Nephrol. 2008;3:324–330. doi: 10.2215/CJN.04611007.

35. Szerlip HM, Weiss J, Singer I. Profound hyperkalemia without electrocar-diographic manifestations. Am J Kidney Dis. 1986;7:461–465.

36. Mahoney BA, Smith WA, Lo DS, Tsoi K, Tonelli M, Clase CM. Emergency interventions for hyperkalaemia. Cochrane Database Syst Rev. 2005;CD003235.

37. Kosiborod M, Peacock WF, Packham DK. Sodium zirconium cyclosilicate for urgent therapy of severe hyperkalemia. N Engl J Med. 2015;372:1577–1578. doi: 10.1056/NEJMc1500353.

38. Bushinsky DA, Bakris GL, Williams G, Pitt B, Mayo M, Garza D, Stasiv Y, Li E, Berman L. Patiromer induced a rapid onset of action and sus-tained K+ lowering throughout the dosing period in CKD patients with hyperkalemia [abstract SA-PO153]. J Am Soc Nephrol. 2014;25:669A.



ownloaded from


Bertram Pitt and George L. BakrisOpportunities for the Future

New Potassium Binders for the Treatment of Hyperkalemia: Current Data and

Print ISSN: 0194-911X. Online ISSN: 1524-4563 Copyright © 2015 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Hypertension doi: 10.1161/HYPERTENSIONAHA.115.048892015;66:731-738; originally published online August 24, 2015;Hypertension.

http://hyper.ahajournals.org/content/66/4/731World Wide Web at:

The online version of this article, along with updated information and services, is located on the

http://hyper.ahajournals.org/content/suppl/2015/08/24/HYPERTENSIONAHA.115.04889.DC1Data Supplement (unedited) at:

http://hyper.ahajournals.org//subscriptions/

is online at: Hypertension Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document. Permissions and Rights Question and Answer this process is available in the

click Request Permissions in the middle column of the Web page under Services. Further information aboutOffice. Once the online version of the published article for which permission is being requested is located,

can be obtained via RightsLink, a service of the Copyright Clearance Center, not the EditorialHypertensionin Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions:



ownloaded from

http://hyper.ahajournals.org/content/66/4/731

http://hyper.ahajournals.org/content/suppl/2015/08/24/HYPERTENSIONAHA.115.04889.DC1

http://www.ahajournals.org/site/rights/

http://www.lww.com/reprints

http://hyper.ahajournals.org//subscriptions/


NEW POTASSIUM BINDERS FOR THE TREATMENT OF HYPERKALEMIA:

CURRENT DATA AND OPPORTUNITIES FOR THE FUTURE

Online Supplement

Bertram Pitt, MD and George L. Bakris, MD

University of Michigan School of Medicine, Ann Arbor, Michigan, USA (BP); Director, ASH

Comprehensive Hypertension Center, The University of Chicago Medicine, Chicago, Illinois,

USA (G.L.B.)

2

Online Supplement References

1. Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor

blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme

inhibition in diabetic nephropathy. J Am Soc Nephrol. 2009;20:2641-2650.

2. Uijtendaal EV, Zwart-van Rijkom JE, van Solinge WW, Egberts TC. Frequency of

laboratory measurement and hyperkalaemia in hospitalised patients using serum potassium

concentration increasing drugs. Eur J Clin Pharmacol. 2011;67:933-940.

3. Reardon LC, Macpherson DS. Hyperkalemia in outpatients using angiotensin-converting

enzyme inhibitors. How much should we worry? Arch Intern Med. 1998;158:26-32.

4. Stevens MS, Dunlay RW. Hyperkalemia in hospitalized patients. Int Urol Nephrol.

2000;32:177-180.

5. Jarman PR, Kehely AM, Mather HM. Hyperkalaemia in diabetes: prevalence and

associations. Postgrad Med J. 1995;71:551-552.

6. Sarafidis PA, Blacklock R, Wood E, Rumjon A, Simmonds S, Fletcher-Rogers J,

Ariyanayagam R, Al-Yassin A, Sharpe C, Vinen K. Prevalence and factors associated with

hyperkalemia in predialysis patients followed in a low-clearance clinic. Clin J Am Soc

Nephrol. 2012;7:1234-1241.

7. Einhorn LM, Zhan M, Hsu VD, Walker LD, Moen MF, Seliger SL, Weir MR, Fink JC.

The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern

Med. 2009;169:1156-1162.

3

8. Harel Z, Gilbert C, Wald R, Bell C, Perl J, Juurlink D, Beyene J, Shah PS. The effect of

combination treatment with aliskiren and blockers of the renin-angiotensin system on

hyperkalaemia and acute kidney injury: systematic review and meta-analysis. BMJ.

2012;344:e42.

9. Van Buren PN, Adams-Huet B, Nguyen M, Molina C, Toto RD. Potassium handling with

dual renin-angiotensin system inhibition in diabetic nephropathy. Clin J Am Soc Nephrol.

2014;9:295-301.

10. Khosla N, Kalaitzidis R, Bakris GL. Predictors of hyperkalemia risk following

hypertension control with aldosterone blockade. Am J Nephrol. 2009;30:418-424.

11. Miao Y, Dobre D, Heerspink HJ, Brenner BM, Cooper ME, Parving HH, Shahinfar S,

Grobbee D, de ZD. Increased serum potassium affects renal outcomes: a post hoc analysis

of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan

(RENAAL) trial. Diabetologia. 2011;54:44-50.

12. Weinberg JM, Appel LJ, Bakris G, Gassman JJ, Greene T, Kendrick CA, Wang X, Lash J,

Lewis JA, Pogue V, Thornley-Brown D, Phillips RA. Risk of hyperkalemia in nondiabetic

patients with chronic kidney disease receiving antihypertensive therapy. Arch Intern Med.

2009;169:1587-1594.

Table S1. Literature-Reported Rates of Hyperkalemia

Study and Setting Design Patient Population Number of

Patients

Hyperkalemia

Definition

Rate

Mehdi et al.1

University medical

center in U.S.

Prospective,

randomized,

double-blind,

placebo

controlled trial of

placebo, losartan

100 mg/day, or

spironolactone 25

mg/day added to

lisinopril 20-80

mg/day

Type 1 or 2 diabetes

mellitus with SBP

>130 mmHg and

UACR ≥300 mg/g

despite ACEI or ARB

for 3 months.

80 ≥6 mEq/L 2/27 placebo

10/26 losartan

14/27

spironolactone

Uijtendaal et al.2

University hospital

Cross-sectional Hospitalized and

receiving ≥1 PID;

9,441 ≥5.5 mEq/L 5.9% (1 PID)

9.9% (≥2 PID)

Table S1. Literature-Reported Rates of Hyperkalemia (continued)

5


Patients

Hyperkalemia

Definition

Rate

in the Netherlands dialysis excluded

eGFR ≥80 ml/min

18%

eGFR 50-80 ml/min

23%

eGFR ≤50 ml/min

14%

Diabetes 20%

RAASi 60%

In subset with

eGFR ≤50 ml/min:

15.8% (1 PID)

16.9% (≥2 PID)

In subset with

diabetes:

10.1% (1 PID)

12.8% (≥2 PID)

Reardon et al.3

VA Medical Center

Case-control Patients with

hyperkalemia on

Mean SCr 1.3 mg/dL

Hypertension 88%

Diabetes 45%

1,818 ≥5.1 mmol/L 194 (11%)


6


Patients

Hyperkalemia

Definition

Rate

Heart failure 30%

ACE-inhibitor 100%

Stevens et al.4

Tertiary teaching

hospital in US

Case-control Dialysis excluded

CrCl 37 ml/min

Diabetes 54%

ACEI 46%

1,060 >5.5 mmol/L 35 (3.3%)

Jarman et al.5

Hospital diabetes

clinic

Observational Diabetes 100%

1,764 >5 mmol/L 270 (15%) >5

mmol/L

Sarafidis et al.6

CKD clinic in

tertiary university

hospital, US

Cross-sectional Pre-dialysis CKD

Mean age 66 years

Hypertension 95%

Diabetes 45%

eGFR 14.4

238 >5.0 mEq/L 54.2%


7


Patients

Hyperkalemia

Definition

Rate

mL/min/1.73 m2

ACE-inhibitor or

ARB 49.7%

ACEI/ARB 10%

MRA 1%

Einhorn et al7

Veterans Health

Administration

Retrospective,

observational

Veterans with 1

hospitalization,

outpatient

measurement of SCr

and ≥1potassium

value

245,808

174,935 no CKD

70,873 CKD (Stage

3, 81.6%; Stage 4,

11.8%; Stage 5

6.7%)

≥5.5 mEq/L 33,637/245,808

(13.7%)

CKD and RAASi:

7.67a

No CKD and

RAASi: 2.30 a

CKD and no

RAASi: 8.22a

No CKD and no


8


Patients

Hyperkalemia

Definition

Rate

RAASi: 1.77a

Harel et al8 Systematic

review

Varied by study;

hypertension, post-

MI, ACS, heart

failure, diabetes,

proteinuria

Aliskiren + ACEI or

ARB vs. ACEI or

ARB monotherapy

>5.5 mEq/L RR for

hyperkalemia:

aliskiren + ACEI

or ARB vs.

monotherapy 1.58

(95% CI 1.24-2.02)

Van Buren et al9

University Medical

Center

Prospective,

randomized,

double-blind

placebo

controlled trial of

Diabetes,

hypertension, UACR

>300 mg/g on

Lisinopril

Mean SCr 1.4 mg/dL

80 ≥6 mEq/L 7.4% placebo

38.5% losartan

51.9%

spironolactone


9


Patients

Hyperkalemia

Definition

Rate

losartan,

spironolactone, or

placebo on top of

lisinopril

(placebo), 1.7 mg/dL

(losartan), 1.8 mg/dL

(spironolactone)

Khosla et al10

Tertiary care,

university based

hypertension

clinics

Retrospective

cohort study

Hypertensive patients

in whom

spironolactone was

added to achieve goal

blood pressure

Diabetes: 87%

ACEI or ARB: 100%

eGFR 57

mL/min/1.73 m2

46 >5.5 mEq/L 8 (17.3%)

Miao et al11

Post-hoc analysis Type 2 diabetes and 1,513 ≥5 mmol/L 410 (30.6%)


10


Patients

Hyperkalemia

Definition

Rate

of RENAAL nephropathy enrolled

in the RENAAL trial

Weinberg et al.12

Retrospective

analysis of AASK

Non diabetic African

Americans with

hypertensive CKD

eGFR: 47

mL/min/1.73 m2

ACEI: 39%

1,053 >5.5 mEq/L 51 patients with

hyperkalemic

events

Event rates for

hyperkalemia:

eGFR ≤30

mL/min/m2: 6.87

b

eGFR >30 to ≤40:

2.75b

On RAASi: 2.45 b

aPer 100 patient-months;

bPer 100 patient-years

AASK = African American Study of Kidney Disease and Hypertension; ACEI = angiotensin converting enzyme inhibitor; ACS =

acute coronary syndrome; ARB = angiotensin receptor blocker; CKD = chronic kidney disease; eGFR = estimated glomerular


11

filtration rate; MI = myocardial infarction; PID = potassium increasing drug; RAASi = renin angiotensin aldosterone system inhibitor;

RENAAL = Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan trial; SBP = systolic blood pressure; SCr

= serum creatinine; UACR = urine albumin-to-creatinine ratio; VA = Veterans Affairs

Table S2. Common Sources of Dietary Potassium

Source Unit Measure Potassium (mg) per Unit

Measure

Molasses 1 cup (337 g) 4934

Pork loin backribs 1071 g 2870

Turkey breast (cooked) 863 g 2563

Cocoa powder (unsweetened) 86 g 2158

Canned soup, New England

Clam Chowder

1 can (519 g) 1749

Baked russet potatoes 299 g 1644

Rotisserie cooked chicken 483 g 1463

Raisins 1 cup (165 g) 1361

Dry roasted pistachio nuts 1 cup (123 g) 1239

Avocado, raw 1 cup (pureed) (230 g) 1166

Canned pureed tomatoes 1 cup (250 g) 1098

Roasted almonds 1 cup (157 g) 1097

Roasted peanuts 1 cup (144 g) 1045

Salmon 108 g 1037

Lima beans, boiled 1 cup (170 g) 969

Sweet potato, baked 1 cup (200 g) 950

Great northern beans, canned 1 cup (262 g) 920

Tomato soup, canned 1 cup (148 g) 832

Vegetable juice, V8, canned 8 oz (243 g) 819

Table S2. Common Sources of Dietary Potassium (continued)

13

Source Unit Measure Potassium (mg) per Unit

Measure

Bananas, raw 1 cup, mashed (225 g) 806

Black beans, cooked (boiled) 1 cup (185 g) 801

Refried beans, canned 1 cup (231 g) 795

Baked beans, canned 1 cup (253 g) 782

Pork chops, cooked 150 g 776

Cashews, dry roasted 1 cup (137 g) 774

Pinto beans, cooked (boiled) 1 cup (171 g) 746

Tomato sauce, canned 1 cup (245 g) 728

Beef ribeye, grilled 138 g 564

Kiwifruit 1 cup (180 g) 562

Fish, haddock, cooked 150 g 526

Orange juice 1 cup (248 g) 496

Milk (reduced fat 2%) 1 cup (246 g) 448

Yogurt, plain, low-fat 6 oz (170 g) 398

Chicken breast, grilled 3 oz (85 g) 357

Egg, whole, hard-boiled 1 cup (136 g) 171

Source: http://ndb.nal.usda.gov/ndb/nutrients/index

http://ndb.nal.usda.gov/ndb/nutrients/index

brief review - hypertensionhyper.ahajournals.org/content/hypertensionaha/66/4/731.full.pdf · brief...

Documents