Emerging Therapies for the Management of Chronic

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AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 2 | JANUARY 15, 2016 33

MANAGEMENT OF CHRONIC HYPERKALEMIA CLINICAL REVIEW

Emerging therapies for the management of chronichyperkalemia in the ambulatory care setting

Amy Henneman, Pharm.D., BCPS,

( [email protected] )

Erenie Guirguis, Pharm.D., BCPS

Yasmin Grace, Pharm.D.

Dimple Patel

Bhoomi Shah

Lloyd L. Gregory School of Pharmacy,Palm Beach Atlantic University, West PalmBeach, FL.

Copyright © 2016, American Society ofHealth-System Pharmacists, Inc. All rightsreserved. 1079-2082/16/0102-0033.

DOI 10.2146/ajhp150457

CLINICAL REVIEW

Purpose. Emerging treatment options for the management of chronic hyperka-

lemia in the outpatient setting are reviewed.

Summary. Current treatment options for the management of hyperkalemia are

limited and often accompanied by serious adverse effects. Two investigational

drugs for the treatment of hyperkalemia are being evaluated in Phase III trials:

sodium zirconium cyclosilicate and patiromer. Both of these drugs are adminis-

tered orally and act by enhancing potassium’s removal, predominantly through

the gastrointestinal tract. The safety and efficacy of sodium zirconium cyclosili-

cate and patiromer were evaluated in Phase II and III trials. Both agents were

studied in patients with chronic mild-to-severe hyperkalemia, chronic kidney

disease (CKD), or heart failure as well as those taking a renin–angiotensin sys-

tem (RAS) inhibitor, an aldosterone antagonist, or both therapies. These clini-

cal trials found that sodium zirconium cyclosilicate and patiromer normalized

serum potassium levels quickly and maintained normalized serum potassium

levels over several weeks. Both medications caused a rapid decrease in serum

potassium, with two studies examining efficacy endpoints for 12 weeks or lon-

ger. The overall frequency of adverse effects in these clinical trials was low, with

gastrointestinal adverse events being the most commonly observed.

Conclusion. Options for the management of hyperkalemia, particularly chronic

hyperkalemia in the outpatient setting, are limited. Both sodium zirconium cy-

closilicate and patiromer are emerging therapies that may provide long-term

management of hyperkalemia, particularly in patients with underlying heart

failure or CKD as well as those taking an RAS inhibitor, an aldosterone antago-

nist, or both.

Am J Health-Syst Pharm. 2016; 73:33-44

A pproximately 3% of the gen-

eral population suffers from

hyperkalemia.1 Certain diseases and

medication classes increase the risk of

developing hyperkalemia. Kovesdy.1

found the risk to be upward of 50%

in patients with chronic kidney dis-

ease (CKD). Hyperkalemia has been

associated with increased all-cause

and inhospital mortality rates as well

as poor outcomes in various patient

populations.2-4

Potassium is the main intracellu-

lar cation in the body; as such, small

changes in potassium homeostasis

can have major effects on cellular

functioning.5 Potassium plays a major

role in maintaining the resting mem-

brane potential of cells. It is essential

for proper neuromuscular function-

ing, exerting its effects on muscles,

nerves, and the heart.6 Potassium is

primarily absorbed from the gastro-

intestinal tract via the small intestine,

and the kidneys regulate potassium

excretion and reabsorption. Hyperka-

lemia is defined as a serum potassium

concentration of >5.0 meq/L.7 While

the definitions of mild, moderate,

and severe hyperkalemia vary, severe

hyperkalemia is most often defined

as a serum potassium concentration

of >6.5 meq/L or the presence of elec-

trocardiographic changes resulting

from an abnormal serum potassium

concentration.1,8 Although hyperka-

lemia is most commonly associated

with potentially life-threatening car-

diac arrhythmias, other symptoms of

hyperkalemia include altered mental

status, confusion, muscle cramps and

weakness, and paresthesia.2,4,9

A large portion of ambulatory care

patients have medical conditions,

mailto:amy_henneman%40pba.edu?subject=mailto:amy_henneman%40pba.edu?subject=


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34 AM J HEALTH-SYST PHARM | VOLUME 73 | NUMBER 2 | JANUARY 15, 2016

CLINICAL REVIEW MANAGEMENT OF CHRONIC HYPERKALEMIA

such as CKD, or are receiving medi-

cations that predispose them to the

development of acute or chronic hy-

perkalemia. Patients with the highest

risk of developing hyperkalemia are

those with heart failure, diabetes,

underlying or overt renal disease, or acombination of the three, plus a pre-

scription for a renin–angiotensin sys-

tem (RAS) inhibitor or aldosterone

antagonist.10 In 2012, approximately

29.1 million Americans had diabetes,

and 5.1 million had heart failure.11,12

In 2014, the Centers for Disease

Control and Prevention estimated

that approximately 20 million people

in the United States had CKD.13 An

estimated one third to one half of

patients with heart failure also haverenal insufficiency, and diabetes is a

leading cause of CKD.13,14 Results of

clinical studies have revealed ben-

efits, including a mortality benefit,

with the use of RAS inhibitors and

aldosterone antagonists, particu-

larly in patients with heart failure,

diabetes, or CKD or a combination

of these.15-26 The patients with the

highest risk for developing hyper-

kalemia are often the ones who will

derive the most benefit from the

administration of an RAS inhibitor or

an aldosterone antagonist. Follow-

up studies have found that the wide-

spread use of these medications

increased the frequency of clinically

significant hyperkalemia, defined as

a serum potassium concentration of

at least 6 meq/L or a patient meet-

ing criteria for hospital admission

based on International Classification

of Diseases, Ninth Edition, require-

ments.27,28 Hyperkalemia has been

reported to occur in approximately

10% of outpatients within a year of

initiating an angiotensin-converting

enzyme (ACE) inhibitor or angioten-

sin II-receptor blocker (ARB).9

The management of chronic hy-

perkalemia can be difficult. Manage-

ment with medication is typically for

short-term, acute situations, with

longer-term solutions relying almost

solely on dietary restriction, chronic

diuretic administration (particularly

KEY POINTS

• Currently available treatment

options for the management

of chronic hyperkalemia are

limited.

• Two new medications, sodium

zirconium cyclosilicate and

patiromer, appear to normal-

ize serum potassium quickly

and maintain them for several

weeks.

• The frequency of adverse ef-

fects with both medications

was low, with adverse gas-

trointestinal effects being the

most common.

• Patiromer was approved byFDA on October 21, 2015, for

the treatment of hyperkalemia

and will be available in 2016.

in patients with both heart failure

and CKD), and reduction in the dos-

age of long-term medications (e.g.,

RAS inhibitors). For many patients

who would benefit from use of an

RAS inhibitor or aldosterone antago-

nist, particularly patients with renal

insufficiency and heart failure who

may have an indication for both an

RAS inhibitor and an aldosterone an-

tagonist, providers avoid or prescribe

very low doses of these medications

in an effort to avoid or decrease the

likelihood of the patient developing

hyperkalemia.14 A study by Einhorn

et al.29 noted that of U.S. veterans

diagnosed with CKD, 3.2% had po-

tassium concentrations above 5.5

meq/L. Routine predialysis screen-

ings have found that approximately

45% of patients undergoing chronic

hemodialysis have hyperkalemia.30

Furthermore, Shah et al.31 noted

that heart failure patients who had

impaired renal function (serum cre-

atinine concentration, 1.5–2.0 mg/

dL) and who were taking both an RAS

inhibitor and aldosterone antagonist

had a 35% risk of developing hyper-

kalemia over a three-month period

after initiating RAS blockade com-

pared with heart failure patients with

normal renal function.

Currently available therapies

Current treatment options forthe management of chronic hyper-

kalemia are limited. The primary

treatment options include limiting

dietary potassium intake, discontin-

uation or a reduction in the dosage

of medications that may impair renal

potassium excretion, and the use of

diuretics. Oral sodium bicarbonate

may be administered on an outpa-

tient basis to patients with chronic

acidosis.10

Many cases of hyperkalemia aremanaged in an acute care setting.

Depending on the severity of the

hyperkalemia and the patient’s sta-

tus, potassium abnormalities are

treated by antagonizing the cardiac

effects of potassium, redistributing

intracellular potassium, and remov-

ing excess potassium from the body.9

Some of the most common methods

for accomplishing this include the

use of i.v. insulin with dextrose, so-

dium bicarbonate, diuretics, inhaled

β-adrenergic agonists, sodium poly-

styrene sulfonate, and, in refractory

cases, dialysis. With the exception of

diuretics, sodium polystyrene sul-

fonate, and dialysis, the abovemen-

tioned mechanisms for managing

hyperkalemia do not remove excess

potassium from the body and have

only short-term effects.1

Sodium polystyrene sulfonate,

approved by the Food and Drug Ad-

ministration (FDA) in 1958, remains

a cornerstone of treatment despitecontroversy regarding its efficacy and

adverse-effect profile.32-36 A cation-

exchange resin, sodium polysty-

rene sulfonate binds potassium by

exchanging it with sodium in the

colon.33 Approximately 1 g of resin

will exchange 1 meq sodium for po-

tassium.37 Sodium polystyrene sulfo-

nate is typically administered orally

but may also be administered via a

retention enema.9 Long-term use of


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sodium polystyrene sulfonate is of-

ten impractical due to its potential to

cause diarrhea in a large proportion

of patients as well as other safety is-

sues accompanying long-term use.10

In 2005, FDA issued a black-box

warning for sodium polystyrene sul-fonate regarding the potential devel-

opment of colonic necrosis. This rare

but serious adverse effect has been

attributed to the sorbitol compo-

nent present in many prepackaged

sodium polystyrene sulfonate solu-

tions.33,34,36 In 2007, FDA limited the

use of sorbitol in sodium polystyrene

sulfonate solutions to a concentra-

tion of 33%; formulations with more

than 33% sorbitol had to be reformu-

lated.

33

However, cases of colonic ne-crosis with sodium polystyrene sul-

fonate in sorbitol solutions continue

to be reported.33,35 Additional adverse

effects associated with sodium poly-

styrene sulfonate include constipa-

tion, nausea, hypernatremia, and,

rarely, gastrointestinal ulceration.34,38

Sodium polystyrene sulfonate should

not be used in patients with obstruc-

tive bowel disease.34,35,39

Loop diuretics, most commonly

furosemide, can also be used to

treat hyperkalemia. Loop diuretics

increase the renal excretion of potas-

sium, though patients with worsen-

ing renal function become resistant

to the effects of diuretics as renal

function declines. Loop diuretics for

the treatment of hyperkalemia are

recommended to be administered

intravenously, limiting their use to

the inpatient setting so that fluid re-

quirements and renal function may

be monitored.40

Emerging therapies

Two investigational drugs for

the treatment of hyperkalemia are

being evaluated in Phase III trials.

Both medications act by enhancing

potassium’s removal, predominantly

through the gastrointestinal tract.41,42

In addition, both are oral agents

that will likely soon be available in

the outpatient setting for the treat-

ment of chronic hyperkalemia with


5.1–6.5 meq/L without electrocardio-

graphic changes requiring emergent

therapy.42-46

The safety and efficacy of sodium

zirconium cyclosilicate have been

evaluated in one Phase II trial41

andtwo Phase III trials.43,44 Zirconium

is a biologically inert trace element

widely found in nature and has been

used extensively in biomedical appli-

cations.47-50 Sodium zirconium cyclo-

silicate was specifically engineered

to be highly selective and works by

trapping monovalent cations, potas-

sium, and ammonium in the gas-

trointestinal tract.41,51 It is insoluble

and remains in the intestine during

transit. One study noted that sodiumzirconium cyclosilicate appeared to

trap 10 times as much potassium as

sodium polystyrene sulfonate.52

Patiromer will be available as an

oral suspension that contains an ac-

tive moiety that is a nonabsorbed

polymer that binds potassium in

exchange for calcium primarily in

the distal colon, thus increasing fecal

excretion of potassium.42,45,46,53 Pa-

tiromer’s safety and efficacy were

evaluated and published in two Phase

II trials42,45 and one Phase III trial.46

Both agents have been studied in

patients with chronic mild-to-severe

hyperkalemia, CKD, or heart failure

as well as those taking an RAS inhibi-

tor or an aldosterone antagonist or

both therapies. Patients with severe

hyperkalemia who had electrocar-

diographic changes were excluded

from these studies, as these patients

require emergent inpatient therapy.

Sodium zirconium cyclosilicate was

studied for the treatment of acute

hyperkalemia without electrocar-

diographic changes in an inpatient

setting in the one available Phase II

study.41

Sodium zirconium cyclosilicate.

Phase II trial. Sodium zirconium cy-

closilicate’s safety and efficacy were

evaluated in a Phase II, prospective,

randomized, double-blind, placebo-

controlled, dose-escalation, per-

protocol study conducted at nine

U.S. sites.41 Patients age 18 years or

older with stable CKD, a glomerular

filtration rate (GFR) of 30–60 mL/

min/1.73 m2, and mild–moderate

hyperkalemia (serum potassium

concentration of 5.0–6.0 meq/L)

were considered for study inclusion.Patients with diabetes, heart failure,

and hypertension were included.

Patients were instructed to maintain

treatment with RAS inhibitors and

other prescribed medications during

the study. Exclusion criteria included

pseudohyperkalemia, treatment with

oral sodium polystyrene sulfonate or

phosphate binders within seven days

of enrollment, severe acidosis, acute

kidney injury, and hyperkalemia-

related electrocardiographic changes.Ninety patients met all eligibility

criteria and were randomized in a

2:1 ratio to receive sodium zirco-

nium cyclosilicate 0.3 g (n = 12), 3 g

(n = 24), and 10 g (n = 24) or placebo

(n = 30). The study included both

inpatient and outpatient treatment

phases. During the inpatient treat-

ment phase, patients were treated

with sodium zirconium cyclosilicate

or matching placebo three times

daily with meals, administered as a

suspension in water for the first 48

hours to normalize serum potassium

levels. After 48 hours, patients with

normalized serum potassium con-

centrations (3.5–4.9 meq/L) were dis-

charged. Patients whose serum po-

tassium concentrations continued to

be elevated (≥5 meq/L) were allowed

to receive an additional two days of

inpatient treatment with sodium zir-

conium cyclosilicate. Patients did not

take sodium zirconium cyclosilicate

after discharge but returned to the

clinic on days 5–7 to have their serum

potassium levels assessed.

The primary efficacy endpoint

was the rate of serum potassium

decline within the first 48 hours of

sodium zirconium cyclosilicate ad-

ministration. Blood samples were

collected daily before the first dose of

sodium zirconium cyclosilicate. Se-

rum potassium concentrations were

measured at 0.5, 1, 2, and 4 hours


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after the initial dose on day 1 and

every 4 hours after dose administra-

tion thereafter. Safety was assessed

by evaluating vital signs, electrocar-

diographic findings, concomitant

medications, pertinent laboratory

findings (e.g., chemistry, hematol-ogy, urinalysis), and the frequency of

adverse events.

The rate of serum potassium

concentration decline was signifi-

cant for both the 3- and 10-g sodium

zirconium cyclosilicate groups when

compared with placebo (p = 0.048

and p < 0.0001, respectively). In the

10-g group, the mean serum potas-

sium concentration decreased from

baseline by 0.11 ± 0.46 meq/L 1 hour

after the first dose (p = 0.04 versusplacebo). The rate of decline in the

3-g group occurred at a slower rate,

reaching significance after 8 hours

versus 1 hour in the 10-g group

(p < 0.05). Serum potassium levels

remained significantly lower in the

10-g group when compared with

placebo for the duration of the study.

A mean ± S.D. maximum reduction

in serum potassium of 0.92 ± 0.52

meq/L was noted with the 10-g group

38 hours into the study (p < 0.001).

Overall, sodium zirconium cyclosili-

cate was well tolerated with just three

adverse events, which were gastro-

intestinal in nature, reported during

the study. No adverse event required

discontinuation of the study drug.

Administration of sodium zirconium

cyclosilicate did not appear to affect

serum chemistry values, outside of

serum potassium concentration, or

vital signs throughout the duration

of the study. The authors concluded

that sodium zirconium cyclosilicate

was well tolerated and effective at

acutely reducing serum potassium

levels in hyperkalemic patients with

stable stage 3 CKD.41

The short study duration and

small sample size limit the extrapola-

tion of the results to a large popula-

tion. The majority of patients in-

cluded were male (58%), and 98% of

all patients were Caucasian. Fifty-six

percent of patients had a history of

diabetes, and 62% were receiving a

RAS inhibitor. Additionally, sodium

zirconium cyclosilicate was admin-

istered three times daily, which may

be associated with poor adherence

when extrapolated to a larger popu-

lation. Guidelines recommend thatpatients with CKD and hyperkalemia

limit their potassium intake to no

more than 3 g/day 54; however, diet

does not appear to have been ad-

dressed or restricted in this study.

More than half the patients were

taking an RAS inhibitor, spironolac-

tone, or combination therapy (62%);

though it was not part of the inclu-

sion criteria, compliance with these

medications was monitored.41

Phase III trials . Sodium zirco-nium cyclosilicate has been evalu-

ated in two Phase III studies. The

HARMONIZE trial evaluated the

efficacy and safety of sodium zirco-

nium cyclosilicate over 28 days in

patients with hyperkalemia.43 This

randomized, double-blind, placebo-

controlled trial enrolled outpatients

with a serum potassium concentra-

tion of ≥5.1 meq/L. A total of 258

patients with at least two consecutive

serum potassium concentrations of

≥5.1 meq/L were treated with sodium

zirconium cyclosilicate 10 g three

times daily during a 48-hour open-

label phase of the study. Patients

reaching serum potassium concen-

trations of 3.5–5.0 meq/L were ran-

domized to the double-blind phase

of the study. These patients received

sodium zirconium cyclosilicate dos-

ages of 5, 10, or 15 mg once daily or

placebo for 28 days (n = 237). Patients

were excluded if they had pseudo-

hyperkalemia; required dialysis; had

a life expectancy of less than three

months; were pregnant; had cardiac

arrhythmias requiring immediate

treatment; had diabetic ketoacidosis;

were actively being treated with sodi-

um polystyrene sulfonate, lactulose,

xifaxan, or any nonabsorbed antibi-

otics for the treatment of high levels

of ammonia within 7 days of sodium

zirconium cyclosilicate administra-

tion; had prior participation in a trial

of sodium zirconium cyclosilicate;

or had prior use of any unapproved

study drug or device within the previ-

ous 30 days.

The mean age of patients in-

cluded in the study was 64 years,

with a majority being male (58%) andCaucasian (83%). Eighty percent of

patients were enrolled at U.S. study

sites. In addition, 66% of patients had

CKD or diabetes (66%), and only 36%

had heart failure. Approximately 70%

were receiving treatment with an RAS

inhibitor.

The primary endpoint was the

mean serum potassium levels of pa-

tients treated with sodium zirconium

cyclosilicate versus placebo. Safety

and tolerability were assessed viadocumentation of adverse events,

electrocardiographic findings, vital

signs, body weight, physical ex-

amination results, hematology and

serum chemistry values, and urinaly-

sis results. Power was set at 90% to

detect a 0.3-meq/L mean difference

in serum potassium concentrations

during the randomization phase for

each dose of sodium zirconium cy-

closilicate versus placebo.

For the primary endpoint, mean

serum potassium levels were sig-

nificantly reduced during the 28-day

randomization phase in all sodium

zirconium cyclosilicate groups ver-

sus placebo (p < 0.001); however,

standard deviation was not noted.

Between-group differences in mean

serum potassium concentration

versus placebo for days 8–29 of the

randomized treatment phase were

–0.3 meq/L (95% confidence inter-

val [CI], –0.3 to –0.3 meq/L), –0.6

meq/L (95% CI, –0.6 to –0.5 meq/L),

and –0.7 meq/L (95% CI, –0.7 to

–0.7 meq/L) for the 5-, 10-, and 15-g

groups, respectively. During the 48-

hour open-label phase of the study,

sodium zirconium cyclosilicate was

found to significantly reduce serum

potassium concentrations. The ab-

solute changes in serum potassium

were –0.7 meq/L (95% CI, –0.7 to –0.6

meq/L; –12%) at 24 hours and –1.1

meq/L (95% CI, –1.1 to –1.0 meq/L;


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–19%) at the end of the 48-hour

open-label phase (p < 0.001 for all).

At 24 hours after administration, the

serum potassium level was in the

normal range for 84% of patients

(95% CI, 79–88%). At 48 hours, 98%

of patients (95% CI, 96–99%) hadachieved serum potassium levels

within the normal range. Treatment-

related adverse events occurred in

8% of treatment and placebo groups.

The most common adverse events

noted were edema, constipation,

and hypokalemia. Hypokalemia oc-

curred in a total of 11 patients in the

10- and 15-g groups combined and

in no patients in the 5-g and placebo

groups.43

The authors noted that sodiumzirconium cyclosilicate was effective

in rapidly lowering serum potassium

to the normal range as well as main-

taining normal serum potassium

levels for up to four weeks in patients

with various degrees of hyperkale-

mia. The potassium-lowering effect

of sodium zirconium cyclosilicate

appeared to be consistent across all

patient subgroups.

The first phase of the study was

open label, which may have contrib-

uted to potential bias. Per the study

protocol, a two-sided t test was used

to analyze the primary endpoint.

However, with four groups being

analyzed, the use of this test was in-

appropriate and increased the likeli-

hood of an α error. Further, diet was

not evaluated for potassium content,

and the use of medications outside

of RAS inhibitors was not assessed.

The short duration of this study

limits its extrapolation to patients

with chronic hyperkalemia who may

benefit from treatment for more than

1 month. An extension of this study is

ongoing and is examining the safety

and efficacy of sodium zirconium

cyclosilicate when administered for

up to 12 months.55

The other Phase III study with

sodium zirconium cyclosilicate was

a two-stage, double-blind, ran-

domized, placebo-controlled, dose-

ranging study conducted over 15

days.44 The study enrolled 754 pa-

tients who were age 18 years or

older with a serum potassium con-

centration of 5.0–6.5 meq/L. Pa-

tients were excluded if they were

receiving dialysis or had any of the

following: diabetic ketoacidosis orinsulin-dependent diabetes mellitus,

a serum potassium concentration

of >6.5 meq/L, cardiac arrhythmia

requiring immediate treatment, or

treatment with an organic polymer

resin or phosphate binder within

one week before enrollment. Pa-

tients continued to receive their

home medications throughout the

study period, and no dosage adjust-

ments were made to the study drug

throughout the duration of the study.The mean age of the patients in the

study was 65 years. The majority of

patients (74.5%) had an estimated

GFR (eGFR) of


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25.1% of patients receiving any dose

of sodium zirconium cyclosilicate

and 24.5% of patients receiving pla-

cebo. Overall, adverse events were

considered mild, with diarrhea be-

ing the most common in both study

phases and at all doses. Hypokalemiaoccurred in two patients, both of

whom received sodium zirconium

cyclosilicate (one during the initial

phase and one during the mainte-

nance phase). Both cases resolved

with ou t pota ss iu m repl et io n. A

dose-dependent increase in serum

bicarbonate levels was noted in these

patients; no other abnormalities in

laboratory test values were reported.

An increase in the corrected Q-T

interval was noted in the sodium zir-conium cyclosilicate groups during

the initial phase. This increase was

consistent with a decrease in serum

potassium levels and was considered

dose related. The authors concluded

that the administration of sodium

zirconium cyclosilicate doses of 2.5 g

or greater three times daily induced a

rapid decline in patients’ potassium

levels and that these decreases were

maintained for up to 15 days.44

This study had several limitations.

The dosage of the RAS inhibitor and

duration of time patients had been

receiving the drug before study entry

were not noted. Other medications

that may have an effect on serum

potassium, such as diuretics and

aldosterone antagonists, were not

assessed. It is difficult to know if the

study drug would be as effective in

patients treated with high-dose RAS

inhibitors. Further, although the the

numbers of patients with conditions

commonly associated with hyper-

kalemia were noted, the authors did

not state how many patients had

more than one of the associated

concomitant conditions. In practice,

it is common for patients to have a

combination of CKD, heart failure,

and diabetes. These patients are of-

ten difficult to treat and often have

hyperkalemia that is refractory to

treatment. A drug that is effective in

patients with more than one of these

conditions would be of benefit in this

population.

In the three studies examined,

sodium zirconium cyclosilicate ap-

peared effective in lowering serum

potassium levels and maintaining

normalized potassium levels for sev-eral weeks when maintenance doses

were used. A third Phase III study is

currently examining the effective-

ness of sodium zirconium cyclosili-

cate in maintaining normokalemia

when used for at least 12 months

in patients with hyperkalemia and

diabetes at baseline.56 Results of this

study and the extension phase of the

HARMONIZE study will help deter-

mine whether the effects of sodium

zirconium cyclosilicate continue with long-term use.

Patiromer. Phase II trials. In

PEARL-HF, a Phase IIb, random-

ized, multicenter, parallel-group,

placebo-controlled, double-blind

study, patiromer was evaluated in pa-

tients age 18 years or older with a his-

tory of chronic heart failure that had

an indication to initiate spironolac-

tone therapy.42 Patients were included

in the study if they (1) had CKD and

were taking at least one medication

with an indication for heart failure or

(2) had a history of hyperkalemia that

led to the discontinuation of an aldo-

sterone antagonist, an ACE inhibitor,

an ARB, or a β-blocker six months

before the baseline visit. Patients tak-

ing β-blockers were excluded due to

their potential to interfere with the

movement of potassium into cells

via the sodium–potassium–ATPase

pump.57-61 The majority of patients

included had New York Heart Asso-

ciation (NYHA) classes II and III heart

failure (29% and 24%, respectively)

and had a left ventricular ejection

fraction of approximately 40%. Pa-

tients were ineligible for the study if

they had any of the following: severe

gastrointestinal disorders, major gas-

trointestinal surgery, bowel obstruc-

tion, swallowing disorders, significant

primary valvular disease, obstruc-

tive or restrictive cardiomyopathy,

uncontrolled arrhythmia, episodes

of unstable angina within the three

months before baseline assessment,

acute coronary syndrome, transient

ischemic attack, Q-Tc interval of

>500 milliseconds, recent or sched-

uled cardiac surgery or intervention,

kidney transplant or need for trans-plantation, current or scheduled di-

alysis, systolic blood pressure of >170

mm Hg or diastolic blood pressure of


7/13



patiromer group developed hyper-

kalemia compared with the placebo

group (7% versus 25%, p = 0.015).

More patients in the patiromer

group were able to increase their

spironolactone dose compared with

the placebo group based on serumpotassium levels (91% versus 74%,

p = 0.019). Approximately 54% of

patients in the patiromer group and

31% of patients in the placebo group

experienced at least one adverse

event. The most commonly reported

adverse events were gastrointestinal

in nature (flatulence, constipation,

diarrhea, vomiting). These adverse

gastrointestinal events were reported

more frequently in the patiromer

group than in the placebo group. While no patients in the placebo

group developed hypokalemia, 6%

of patients in the treatment group

became hypokalemic. The authors

concluded that patiromer decreased

serum potassium levels, reduced

the frequency of hyperkalemia, and

increased the number of patients

who could tolerate higher doses of

spironolactone. The reduction in

serum potassium concentration was

observed about two days after patir-

omer initiation.42

The sample size of this study was

fairly small, and the study was of

short duration. Patients with gastro-

intestinal disorders, receiving dialy-

sis, or with a kidney transplant were

excluded from this study, limiting its

extrapolation to this patient popula-

tion. Lastly, researchers found that a

patiromer dosage of 15 g twice daily

lowered potassium levels, though no

other dosage ranges were evaluated,

making it difficult to infer the effects

of other doses on potassium levels in

this patient population.

The AMETHYST-DN study was a

Phase II, open-label, dose-ranging

study that evaluated the use of pa-

tiromer in adults (mean baseline age,

66.3 years) with type 2 diabetes and

CKD who were taking an ACE inhibi-

tor or ARB for at least 28 days before

study screening.45 Patients were ex-

cluded from the study if they needed

emergency treatment for their type

2 diabetes within the previous three

months or had any of the following:

a hemoglobin A 1c

value exceeding

12%, a baseline systolic blood pres-

sure of >180 mm Hg or a diastolic

blood pressure of >110 mm Hg, aserum magnesium concentration

of 40 kg/m2, a recent cardiovascular

event, a renal transplant, active can-

cer, or liver enzyme levels three times

the upper limit of normal. Patients

who were currently using polymer-

based drugs of any kind or used apotassium-sparing medication with-

in the previous 7 days also were ex-

cluded. The study included a 4-week

run-in period, an 8-week initial

treatment phase followed by a main-

tenance phase of up to 44 weeks, and

a follow-up period of up to 4 weeks

after stopping the study medication.

At study screening, patients who had


4.3–5.0 meq/L and a blood pressure

of 130–180 mm Hg/80–110 mm Hg

were randomly assigned to one of

two groups in a 3:1 ratio. In group

1, patients’ current RAS medication

was discontinued, and losartan 100

mg daily was initiated. After 2 weeks,

spironolactone 25 mg daily was

added if the patient’s blood pressure

was above 130/80 mm Hg. In group 2,

patients were continued on their cur-

rent RAS therapy and spironolactone

25 mg daily was added. The dose of

spironolactone could be adjusted in

either group if blood pressure con-

trol was not achieved with the 25-mg

daily dose. Patients whose serum

potassium concentration was 5.0–6.0

meq/L at the end of 4 weeks were

eligible for the treatment phase of the

study. Few patients met the screen-

ing criteria, so the study protocol was

amended after approximately four

months to include a third group of

patients who were hyperkalemic at

the initial screening. Enrollment into

group 2 was discontinued. Patients

with serum potassium concentra-

tions of 5.0–6.0 meq/L who met the

other run-in criteria were random-

ized directly into the treatment phase

of the study.

A total of 306 patients were ran-domized after the run-in period

and stratified by serum potassium

level into the treatment phase of the

study. Patients with a serum potas-

sium concentration of 5.0–5.5 meq/L

composed stratum 1 (n = 222), and

patients with a serum potassium

concentration greater than 5.5 but

less than 6.0 meq/L composed stra-

tum 2 (n = 84). Within each stratum,

patients were randomized to receive

one of three patiromer dosages. Pa-tients in stratum 1 were given patir-

omer 4.2, 8.4, or 12.6 g twice daily.

Patients in stratum 2 received patir-

omer 8.4, 12.6, or 16.8 g twice daily.

During the initial 8-week treatment

phase, patients were assessed on

day 3, at week 1, and weekly there-

after. During the 44-week mainte-

nance phase, patients were assessed

monthly. Patiromer dosages could

be adjusted to maintain a serum

potassium concentration of 4.0–5.0

meq/L.

The primary efficacy endpoint

was the mean change in serum po-

tassium level from baseline to week

4 or before dosage adjustment. The

primary safety endpoints were the

frequency and severity of adverse

events through week 52. A total of

42 patients in each patiromer group

were needed to provide 90% power

to detect an effect size of 0.5 meq/L

for the mean change in serum po-

tassium from baseline to week 4 or

before dosage adjustment.

For the primary outcome, the

least-squares mean reductions in

serum potassium concentration in

patients with mild hyperkalemia

were 0.35 meq/L (95% CI, 0.22–0.48

meq/L), 0.51 meq/L (95% CI, 0.38–

0.64 meq/L), and 0.55 meq/L (95%

CI, 0.42–0.68 meq/L) for the 8.4-,

16.8-, and 25.2-g groups, respectively.

In stratum 2, the least-squares mean


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reductions in potassium concen-

tration in patients with moderate

hyperkalemia were 0.87 meq/L (95%

CI, 0.60–1.14 meq/L), 0.97 meq/L

(95% CI, 0.70–1.23 meq/L), and 0.92

meq/L (95% CI, 0.67–1.17 meq/L) for

the 16.8-, 25.2-, and 33.6-g groups,respectively. The change in serum

postassium level from baseline was

significant for all groups (p < 0.001).

Significant reductions in mean se-

rum potassium levels were seen at

the first postbaseline assessment—

48 hours after initiation of the study

medication—in both strata (p <

0.001). Mean ± S.D. daily doses for

the first four weeks were 18.5 ± 7.5 g

for stratum 1 and 26.9 ± 8.3 g for stra-

tum 2. The majority of patients hadeither no dosage adjustment or one

dose adjustment during the treat-

ment phase. The mean ± S.D. daily

doses at the end of the 8-week treat-

ment phase were 19.6 ± 9.3 g for stra-

tum 1 and 28.0 ± 12.4 g for stratum 2.

A total of 246 patients entered

the maintenance phase of the study.

From week 4 through week 52, sig-

nificant mean decreases in serum

potassium levels were noted at each

monthly visit in each stratum (p <

0.001). Researchers noted that the

proportions of patients with potas-

sium concentrations within the

target range (3.8–5.0 meq/L) at each

monthly visit of the maintenance

phase were 83.1–92.7% in stratum 1

and 77.4–95.1% in stratum 2. A total

of 238 patients entered the posttreat-

ment follow-up phase of the study.

By day 3, significant increases in

least-squares mean serum potassi-

um levels were noted in both groups

(p < 0.001).

Throughout the entire 52-week

study, approximately 69% of patients

reported at least one adverse event.

Of those, 20% were considered by

investigators to be related to patir-

omer. The most frequently reported

patiromer-related adverse events

were hypomagnesemia (7.2%), con-

stipation (4.6%), and diarrhea (2.7%).

Twenty-eight patients experienced

wors en in g CK D th ro ug hout the

study, which investigators deemed

unrelated to patiromer. A total of

24 patients were noted to have

increased blood pressure, though

investigators deemed this poten-

tially related to patiromer for only

1 patient. Mean changes in serummagnesium levels from baseline to

week 4 were –0.10 to –0.20 mg/dL

in stratum 1 and –0.10 to –0.30 mg/

dL in stratum 2. Mean changes from

baseline throughout the duration

of the study remained similar to the

decrease seen in the first 4 weeks. Ac-

cording to study investigators, mean

serum magnesium levels remained

in the normal range throughout the

52-week study, with no patients de-

veloping severe hypomagnesemiaor associated cardiac arrhythmias

or neuromuscular abnormalities.

Just 17 patients (5.6%) developed

hypokalemia throughout the 52-

week study. A seru m potassium

concentration of


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than 110 mm Hg, a diastolic blood

pressure greater than 110 mm Hg

or less than 60 mm Hg, diabetic

ketoacidosis, an acute heart failure

exacerbation within the previous

three months, or NYHA class IV heart

failure.This trial included an initial four-

week single-group, single-b lind,

initial treatment phase followed by

an eight-week, placebo-controlled,

single-blind, randomized withdrawal

phase. Patients who met inclusion

criteria were initially assigned to

receive one of two patiromer start-

ing dosages according to the severity

of their hyperkalemia. Patients with

mild hyperkalemia (serum potassium

concentration of 5.1 to


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constipation, nausea, and diarrhea

being approximately equal.46 These

medications may prove advanta-

geous over sodium polystyrene sul-

fonate in that they offer a lower, less

severe adverse-effect profile overall.

Of note, patients with gastrointes-tinal disorders were not excluded

from sodium zirconium cyclosilicate

studies, but they were excluded in all

studies with patiromer, which may

limit the use this agent in patients

already unable to use sodium poly-

styrene sulfonate. Further studies in

patients with severe gastrointestinal

disorders are needed.

Rates of hypokalemia were low

in all studies, ranging from 0% to

7%. Of note, the PEARL-HF and AMETHYST-DN studies (patiromer)

as well as the HARMONIZE study

(sodium zirconium cyclosilicate) did

detect several cases of mild hypo-

magnesemia.42,43,45 This adverse effect

was not observed in other studies

involving these medications. Further

studies are needed to determine if

hypomagnesemia is a regularly ob-

served effect of these medications.

Only one study observed an increase

in serum bicarbonate: the Phase III

study of sodium zirconium cyclo-

silicate by Packham et al.44 However,

the overall frequency of increases in

serum bicarbonate concentrations in

the study was not reported. If found

to be a frequently observed adverse

effect of sodium zirconium cyclo-

silicate, it could prove useful in CKD

patients who frequently experience

metabolic acidosis in addition to hy-

perkalemia. However, further study

is needed in this patient population.

With the exception of the studies

by Bakris et al.45 and Weir et al.46 of

patiromer, safety and efficacy have

not been evaluated in patients with

end-stage renal disease (creatinine

clearance of


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C o p y r i g h t o f A m e r i c a n J o u r n a l o f H e a l t h - S y s t e m P h a r m a c y i s t h e p r o p e r t y o f A m e r i c a n

S o c i e t y o f H e a l t h S y s t e m P h a r m a c i s t s a n d i t s c o n t e n t m a y n o t b e c o p i e d o r e m a i l e d t o

m u l t i p l e s i t e s o r p o s t e d t o a l i s t s e r v w i t h o u t t h e c o p y r i g h t h o l d e r ' s e x p r e s s w r i t t e n p e r m i s s i o n .

H o w e v e r , u s e r s m a y p r i n t , d o w n l o a d , o r e m a i l a r t i c l e s f o r i n d i v i d u a l u s e .

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