emerging therapies for the management of chronic
TRANSCRIPT
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MANAGEMENT OF CHRONIC HYPERKALEMIA CLINICAL REVIEW
Emerging therapies for the management of chronichyperkalemia in the ambulatory care setting
Amy Henneman, Pharm.D., BCPS,
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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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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MANAGEMENT OF CHRONIC HYPERKALEMIA CLINICAL REVIEW
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
a serum potassium concentration of
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
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MANAGEMENT OF CHRONIC HYPERKALEMIA CLINICAL REVIEW
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
a serum potassium concentration of
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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CLINICAL REVIEW MANAGEMENT OF CHRONIC HYPERKALEMIA
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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MANAGEMENT OF CHRONIC HYPERKALEMIA CLINICAL REVIEW
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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CLINICAL REVIEW MANAGEMENT OF CHRONIC HYPERKALEMIA
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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MANAGEMENT OF CHRONIC HYPERKALEMIA CLINICAL REVIEW
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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 .