Emerging Therapies For The Management of Chronic

CLINICAL REVIEW
MANAGEMENT OF CHRONIC HYPERKALEMIA
Emerging therapies for the management of chronic

hyperkalemia in the ambulatory care setting
Amy Henneman, Pharm.D., BCPS,
(amy_henneman@pba.edu)
Erenie Guirguis, Pharm.D., BCPS
Yasmin Grace, Pharm.D.
Dimple Patel
Bhoomi Shah
Lloyd L. Gregory School of Pharmacy,
Palm Beach Atlantic University, West Palm
Beach, FL.
Purpose. Emerging treatment options for the management of chronic hyperkalemia 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 administered orally and act by enhancing potassiums removal, predominantly through
the gastrointestinal tract. The safety and efficacy of sodium zirconium cyclosilicate 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 reninangiotensin system (RAS) inhibitor, an aldosterone antagonist, or both therapies. These clinical 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 longer. 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 cyclosilicate 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 antagonist, or both.
Am J Health-Syst Pharm. 2016; 73:33-44
Copyright 2016, American Society of

Health-System Pharmacists, Inc. All rights
reserved. 1079-2082/16/0102-0033.
DOI 10.2146/ajhp150457

pproximately 3% of the general 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 disease (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 intracellular 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 membrane potential of cells. It is essential
for proper neuromuscular functioning, exerting its effects on muscles,
nerves, and the heart.6 Potassium is
primarily absorbed from the gastrointestinal tract via the small intestine,
and the kidneys regulate potassium
excretion and reabsorption. Hyperkalemia 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 electrocardiographic changes resulting
from an abnormal serum potassium
concentration.1,8 Although hyperkalemia is most commonly associated
with potentially life-threatening cardiac 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,
AM J HEALTH-SYST PHARM|VOLUME 73|NUMBER 2|JANUARY 15, 201633
CLINICAL REVIEW
such as CKD, or are receiving medications that predispose them to the
development of acute or chronic hyperkalemia. Patients with the highest
risk of developing hyperkalemia are
those with heart failure, diabetes,
underlying or overt renal disease, or a
combination of the three, plus a prescription for a reninangiotensin system (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 have
renal insufficiency, and diabetes is a
leading cause of CKD.13,14 Results of
clinical studies have revealed benefits, including a mortality benefit,
with the use of RAS inhibitors and
aldosterone antagonists, particularly in patients with heart failure,
diabetes, or CKD or a combination
of these.15-26 The patients with the
highest risk for developing hyperkalemia are often the ones who will
derive the most benefit from the
administration of an RAS inhibitor or
an aldosterone antagonist. Followup studies have found that the widespread 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 meeting criteria for hospital admission
based on International Classification
of Diseases, Ninth Edition, requirements.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 angiotensin II-receptor blocker (ARB).9
The management of chronic hyperkalemia can be difficult. Management with medication is typically for
short-term, acute situations, with
longer-term solutions relying almost
solely on dietary restriction, chronic
diuretic administration (particularly
34
KEY POINTS
Currently available treatment
options for the management
of chronic hyperkalemia are
limited.
Two new medications, sodium
zirconium cyclosilicate and
patiromer, appear to normalize serum potassium quickly
and maintain them for several
weeks.
The frequency of adverse effects with both medications
was low, with adverse gastrointestinal effects being the
most common.
Patiromer was approved by
FDA 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 dosage of long-term medications (e.g.,
RAS inhibitors). For many patients
who would benefit from use of an
RAS inhibitor or aldosterone antagonist, particularly patients with renal
insufficiency and heart failure who
may have an indication for both an
RAS inhibitor and an aldosterone antagonist, 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 potassium concentrations above 5.5
meq/L. Routine predialysis screenings 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 creatinine concentration, 1.52.0 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 compared with heart failure patients with
normal renal function.
Currently available therapies

Current treatment options for
the management of chronic hyperkalemia are limited. The primary
treatment options include limiting
dietary potassium intake, discontinuation 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 outpatient basis to patients with chronic
acidosis.10
Many cases of hyperkalemia are
managed in an acute care setting.
Depending on the severity of the
hyperkalemia and the patients status, potassium abnormalities are
treated by antagonizing the cardiac
effects of potassium, redistributing
intracellular potassium, and removing excess potassium from the body.9
Some of the most common methods
for accomplishing this include the
use of i.v. insulin with dextrose, sodium bicarbonate, diuretics, inhaled
b-adrenergic agonists, sodium polystyrene sulfonate, and, in refractory
cases, dialysis. With the exception of
diuretics, sodium polystyrene sulfonate, and dialysis, the abovementioned 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 Administration (FDA) in 1958, remains
a cornerstone of treatment despite
controversy regarding its efficacy and
adverse-effect profile.32-36 A cationexchange resin, sodium polystyrene sulfonate binds potassium by
exchanging it with sodium in the
colon.33 Approximately 1 g of resin
will exchange 1 meq sodium for potassium.37 Sodium polystyrene sulfonate is typically administered orally
but may also be administered via a
retention enema.9 Long-term use of

sodium polystyrene sulfonate is often impractical due to its potential to
cause diarrhea in a large proportion
of patients as well as other safety issues accompanying long-term use.10
In 2005, FDA issued a black-box
warning for sodium polystyrene sulfonate regarding the potential development of colonic necrosis. This rare
but serious adverse effect has been
attributed to the sorbitol component present in many prepackaged
sodium polystyrene sulfonate solutions.33,34,36 In 2007, FDA limited the
use of sorbitol in sodium polystyrene
sulfonate solutions to a concentration of 33%; formulations with more
than 33% sorbitol had to be reformulated.33 However, cases of colonic necrosis with sodium polystyrene sulfonate in sorbitol solutions continue
to be reported.33,35 Additional adverse
effects associated with sodium polystyrene sulfonate include constipation, nausea, hypernatremia, and,
rarely, gastrointestinal ulceration.34,38
Sodium polystyrene sulfonate should
not be used in patients with obstructive bowel disease.34,35,39
Loop diuretics, most commonly
furosemide, can also be used to
treat hyperkalemia. Loop diuretics
increase the renal excretion of potassium, though patients with worsening 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 requirements 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
potassiums 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 treatment of chronic hyperkalemia with


5.16.5 meq/L without electrocardiographic changes requiring emergent
therapy.42-46
The safety and efficacy of sodium
zirconium cyclosilicate have been
evaluated in one Phase II trial41 and
two Phase III trials.43,44 Zirconium
is a biologically inert trace element
widely found in nature and has been
used extensively in biomedical applications.47-50 Sodium zirconium cyclosilicate was specifically engineered
to be highly selective and works by
trapping monovalent cations, potassium, and ammonium in the gastrointestinal tract.41,51 It is insoluble
and remains in the intestine during
transit. One study noted that sodium
zirconium 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 active 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 Patiromers 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 inhibitor or an aldosterone antagonist or
both therapies. Patients with severe
hyperkalemia who had electrocardiographic 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 electrocardiographic changes in an inpatient
setting in the one available Phase II
study.41
Sodium zirconium cyclosilicate.
Phase II trial. Sodium zirconium cyclosilicates safety and efficacy were
evaluated in a Phase II, prospective,
randomized, double-blind, placebocontrolled, dose-escalation, perprotocol study conducted at nine
CLINICAL REVIEW
U.S. sites.41 Patients age 18 years or
older with stable CKD, a glomerular
filtration rate (GFR) of 3060 mL/
min/1.73 m 2, and mildmoderate
hyperkalemia (serum potassium
concentration of 5.06.0 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 hyperkalemiarelated electrocardiographic changes.
Ninety patients met all eligibility
criteria and were randomized in a
2:1 ratio to receive sodium zirconium 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 treatment 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 concentrations (3.54.9 meq/L) were discharged. Patients whose serum potassium concentrations continued to
be elevated (5 meq/L) were allowed
to receive an additional two days of
inpatient treatment with sodium zirconium cyclosilicate. Patients did not
take sodium zirconium cyclosilicate
after discharge but returned to the
clinic on days 57 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 administration. Blood samples were
collected daily before the first dose of
sodium zirconium cyclosilicate. Serum potassium concentrations were
measured at 0.5, 1, 2, and 4 hours
CLINICAL REVIEW
after the initial dose on day 1 and
every 4 hours after dose administration thereafter. Safety was assessed
by evaluating vital signs, electrocardiographic findings, concomitant
medications, pertinent laboratory
findings (e.g., chemistry, hematology, urinalysis), and the frequency of
adverse events.
The rate of serum potassium
concentration decline was significant 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 potassium concentration decreased from
baseline by 0.11 0.46 meq/L 1 hour
after the first dose (p = 0.04 versus
placebo). 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 cyclosilicate was well tolerated with just three
adverse events, which were gastrointestinal 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 extrapolation of the results to a large population. The majority of patients included were male (58%), and 98% of
all patients were Caucasian. Fifty-six
percent of patients had a history of
36

diabetes, and 62% were receiving a
RAS inhibitor. Additionally, sodium
zirconium cyclosilicate was administered three times daily, which may
be associated with poor adherence
when extrapolated to a larger population. Guidelines recommend that
patients with CKD and hyperkalemia
limit their potassium intake to no
more than 3 g/day54; however, diet
does not appear to have been addressed or restricted in this study.
More than half the patients were
taking an RAS inhibitor, spironolactone, or combination therapy (62%);
though it was not part of the inclusion criteria, compliance with these
medications was monitored.41
Phase III trials. Sodium zirconium cyclosilicate has been evaluated in two Phase III studies. The
HARMONIZE trial evaluated the
efficacy and safety of sodium zirconium cyclosilicate over 28 days in
patients with hyperkalemia.43 This
randomized, double-blind, placebocontrolled trial enrolled outpatients
with a serum potassium concentration 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 openlabel phase of the study. Patients
reaching serum potassium concentrations of 3.55.0 meq/L were randomized to the double-blind phase
of the study. These patients received
sodium zirconium cyclosilicate dosages of 5, 10, or 15 mg once daily or
placebo for 28 days (n = 237). Patients
were excluded if they had pseudohyperkalemia; 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 sodium polystyrene sulfonate, lactulose,
xifaxan, or any nonabsorbed antibiotics for the treatment of high levels
of ammonia within 7 days of sodium
zirconium cyclosilicate administration; had prior participation in a trial
of sodium zirconium cyclosilicate;

or had prior use of any unapproved
study drug or device within the previous 30 days.
The mean age of patients included in the study was 64 years,
with a majority being male (58%) and
Caucasian (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 patients treated with sodium zirconium
cyclosilicate versus placebo. Safety
and tolerability were assessed via
documentation of adverse events,
electrocardiographic findings, vital
signs, body weight, physical examination results, hematology and
serum chemistry values, and urinalysis 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 cyclosilicate versus placebo.
For the primary endpoint, mean
serum potassium levels were significantly reduced during the 28-day
randomization phase in all sodium
zirconium cyclosilicate groups versus placebo (p < 0.001); however,
standard deviation was not noted.
Between-group differences in mean
serum potassium concentration
versus placebo for days 829 of the
randomized treatment phase were
0.3 meq/L (95% confidence interval [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 48hour open-label phase of the study,
sodium zirconium cyclosilicate was
found to significantly reduce serum
potassium concentrations. The absolute 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;

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, 7988%). At 48 hours, 98%
of patients (95% CI, 9699%) had
achieved serum potassium levels
within the normal range. Treatmentrelated adverse events occurred in
8% of treatment and placebo groups.
The most common adverse events
noted were edema, constipation,
and hypokalemia. Hypokalemia occurred 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 sodium
zirconium cyclosilicate was effective
in rapidly lowering serum potassium
to the normal range as well as maintaining normal serum potassium
levels for up to four weeks in patients
with various degrees of hyperkalemia. 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 contributed 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 inappropriate and increased the likelihood of an a 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
a two-stage, double-blind, randomized, placebo-controlled, doseranging study conducted over 15

days.44 The study enrolled 754 patients who were age 18 years or
older with a serum potassium concentration of 5.06.5 meq/L. Patients were excluded if they were
receiving dialysis or had any of the
following: diabetic ketoacidosis or
insulin-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. Patients continued to receive their
home medications throughout the
study period, and no dosage adjustments 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 <60 mL/min/1.73 m2
(n = 561); 296 of these patients had
an eGFR of 3059 mL/min/1.73 m2.
The majority of patients were receiving treatment with an RAS inhibitor
(70%) and had diabetes (66%), a
history of heart failure (36%), CKD
(66%), or a combination of these
three conditions; however, these
conditions were not requirements for
study inclusion.
The initial phase of the study lasted 48 hours. Patients received 1.25,
2.5, 5, or 10 g of sodium zirconium
cyclosilicate or placebo three times
daily with meals. The primary endpoint for the initial phase of the study
was the between-group difference in
the exponential rate of change in the
mean serum potassium level during the first 48 hours of treatment. A
significant decrease was found in the
serum potassium level from baseline
to 48 hours among all doses of sodium zirconium cyclosilicate except
the 1.25-g dose. The absolute mean
reductions in serum potassium concentration were 0.46 meq/L (95%
CI, 0.53 to 0.39 meq/L) in the 2.5-g
group, 0.54 meq/L (95% CI, 0.62
to 0.47 meq/L) in the 5-g group,
and0.73 meq/L (95% CI, 0.82 to
0.65 meq/L) in the 10-g group ver-
CLINICAL REVIEW
sus 0.25 meq/L (95% CI, 0.32 to
0.19 meq/L) in the placebo group
(p < 0.001 for all comparisons). Potassium levels normalized for all
patients in the 5- and 10-g groups
(n = 300), regardless of baseline potassium levels, concomitant medications, or concomitant diseases.
At the end of 48 hours, the maintenance phase began. Patients whose
serum potassium concentration had
fallen to 3.54.9 meq/L (n = 543) were
randomly assigned to receive either
their original sodium zirconium
cyclosilicate dose or placebo once
daily before breakfast until day 15.
Of those patients who did not meet
the criteria to enter into the maintenance phase, 129 were excluded due
to hyperkalemia, 61 of whom were
in the placebo group. Patients who
had been assigned to placebo during
the initial phase of the study and met
entry criteria for the maintenance
phase were randomized to either
sodium zirconium cyclosilicate 1.25
or 2.5 g during the maintenance
phase. The primary endpoint for the
maintenance phase of the study was
the between-group difference in the
mean serum potassium level during the 12-day maintenance phase
treatment interval. Both the 5- and
10-g doses of sodium zirconium cyclosilicate were significantly better
than placebo in maintaining normokalemia in patients (p = 0.008 and p <
0.001, respectively).
For tests of the primary efficacy
endpoint, both the initial and the
maintenance phases of the study had
a power of 90% with a two-tailed type
I error rate of 0.05. Additional safety
endpoints included adverse events,
vital signs, changes in electrocardiographic findings, and hematologic
and other laboratory analyses, including hypokalemia and hypomagnesemia. Adverse events were noted
in 12.9% of patients in the sodium
zirconium cyclosilicate group and
10.8% of patients in the placebo
group during the initial phase. During the maintenance phase of the
study, adverse events occurred in
CLINICAL REVIEW
25.1% of patients receiving any dose
of sodium zirconium cyclosilicate
and 24.5% of patients receiving placebo. Overall, adverse events were
considered mild, with diarrhea being the most common in both study
phases and at all doses. Hypokalemia
occurred in two patients, both of
whom received sodium zirconium
cyclosilicate (one during the initial
phase and one during the maintenance phase). Both cases resolved
without potassium repletion. 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 zirconium 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 hyperkalemia 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 often 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
38

conditions would be of benefit in this
population.
In the three studies examined,
sodium zirconium cyclosilicate appeared effective in lowering serum
potassium levels and maintaining
normalized potassium levels for several weeks when maintenance doses
were used. A third Phase III study is
currently examining the effectiveness of sodium zirconium cyclosilicate 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 determine whether the effects of sodium
zirconium cyclosilicate continue
with long-term use.
Patiromer. Phase II trials. In
PEARL-HF, a Phase IIb, randomized, multicenter, parallel-group,
placebo-controlled, double-blind
study, patiromer was evaluated in patients age 18 years or older with a history of chronic heart failure that had
an indication to initiate spironolactone 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 aldosterone antagonist, an ACE inhibitor,
an ARB, or a b-blocker six months
before the baseline visit. Patients taking b-blockers were excluded due to
their potential to interfere with the
movement of potassium into cells
via the sodiumpotassiumATPase
pump.57-61 The majority of patients
included had New York Heart Association (NYHA) classes II and III heart
failure (29% and 24%, respectively)
and had a left ventricular ejection
fraction of approximately 40%. Patients were ineligible for the study if
they had any of the following: severe
gastrointestinal disorders, major gastrointestinal surgery, bowel obstruction, swallowing disorders, significant
primary valvular disease, obstructive 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 scheduled cardiac surgery or intervention,
kidney transplant or need for transplantation, current or scheduled dialysis, systolic blood pressure of >170
mm Hg or diastolic blood pressure of
<90 mm Hg, elevated liver enzymes,
and any condition that could interfere
with compliance or patient safety.
Patients were randomized to receive patiromer 15 g or placebo in a
1:1 ratio. Spironolactone 25 mg was
initiated in both groups, with dosages increased to 50 mg after two
weeks if the patients serum potassium concentrations were within the
normal range (3.65.1 meq/L). The
primary efficacy endpoint was the
mean change in serum potassium
from baseline to day 28. The study
was powered at 90% to detect a difference of 0.7 meq/L in the mean
change of the serum potassium level
from baseline. Adverse events and
any clinically significant changes
from baseline in laboratory test
values, electrocardiographic findings, and vital signs were monitored
throughout the study.
Of the 120 patients who were
randomized, 105 were evaluated for
the primary efficacy endpoint. At
day 28, patients taking patiromer
had a mean change in serum potassium from baseline of approximately
0.22 meq/L, whereas patients in the
placebo group had a mean increase
of 0.23 meq/L, for a between-group
difference of 0.45 meq/L (p < 0.001).
The standard deviation was not
noted. Patients with a baseline eGFR
of <60 mL/min (15 in the treatment
group and 13 in the placebo group)
had a mean S.E. between-group
difference of 0.52 0.23 meq/L (p =
0.031). Patients with a baseline eGFR
of 60 mL/min (40 in the treatment
group and 36 in the placebo group)
had a mean S.E. between-group
difference of 0.35 0.10 meq/L
(p = 0.001). Fewer patients in the

patiromer group developed hyperkalemia 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 serum
potassium 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 patiromer initiation.42
The sample size of this study was
fairly small, and the study was of
short duration. Patients with gastrointestinal disorders, receiving dialysis, or with a kidney transplant were
excluded from this study, limiting its
extrapolation to this patient population. 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 patiromer in adults (mean baseline age,
66.3 years) with type 2 diabetes and
CKD who were taking an ACE inhibitor or ARB for at least 28 days before
study screening.45 Patients were excluded 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 A1c value exceeding
12%, a baseline systolic blood pressure of >180 mm Hg or a diastolic
blood pressure of >110 mm Hg, a
serum magnesium concentration
of <1.4 mg/dL, renal artery stenosis,
diabetic gastroparesis, nondiabetic
kidney disease, a severe gastrointestinal disorder, NYHA class III or IV
heart failure, a body mass index of
>40 kg/m2, a recent cardiovascular
event, a renal transplant, active cancer, or liver enzyme levels three times
the upper limit of normal. Patients
who were currently using polymerbased drugs of any kind or used a
potassium-sparing medication within the previous 7 days also were excluded. The study included a 4-week
run-in period, an 8-week initial
treatment phase followed by a maintenance 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
4.35.0 meq/L and a blood pressure
of 130180 mm Hg/80110 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 patients blood pressure
was above 130/80 mm Hg. In group 2,
patients were continued on their current RAS therapy and spironolactone
25 mg daily was added. The dose of
spironolactone could be adjusted in
either group if blood pressure control was not achieved with the 25-mg
daily dose. Patients whose serum
potassium concentration was 5.06.0
meq/L at the end of 4 weeks were
eligible for the treatment phase of the
study. Few patients met the screening 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
CLINICAL REVIEW
group 2 was discontinued. Patients
with serum potassium concentrations of 5.06.0 meq/L who met the
other run-in criteria were randomized directly into the treatment phase
of the study.
A total of 306 patients were randomized after the run-in period
and stratified by serum potassium
level into the treatment phase of the
study. Patients with a serum potassium concentration of 5.05.5 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 stratum 2 (n = 84). Within each stratum,
patients were randomized to receive
one of three patiromer dosages. Patients in stratum 1 were given patiromer 4.2, 8.4, or 12.6 g twice daily.
Patients in stratum 2 received patiromer 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 thereafter. During the 44-week maintenance phase, patients were assessed
monthly. Patiromer dosages could
be adjusted to maintain a serum
potassium concentration of 4.05.0
meq/L.
The primary efficacy endpoint
was the mean change in serum potassium 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 potassium 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, 0.220.48
meq/L), 0.51 meq/L (95% CI, 0.38
0.64 meq/L), and 0.55 meq/L (95%
CI, 0.420.68 meq/L) for the 8.4-,
16.8-, and 25.2-g groups, respectively.
In stratum 2, the least-squares mean
CLINICAL REVIEW
reductions in potassium concentration in patients with moderate
hyperkalemia were 0.87 meq/L (95%
CI, 0.601.14 meq/L), 0.97 meq/L
(95% CI, 0.701.23 meq/L), and 0.92
meq/L (95% CI, 0.671.17 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 serum potassium levels were seen at
the first postbaseline assessment
48 hours after initiation of the study
medicationin 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 stratum 2. The majority of patients had
either no dosage adjustment or one
dose adjustment during the treatment phase. The mean S.D. daily
doses at the end of the 8-week treatment phase were 19.6 9.3 g for stratum 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, significant 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 potassium concentrations within the
target range (3.85.0 meq/L) at each
monthly visit of the maintenance
phase were 83.192.7% in stratum 1
and 77.495.1% in stratum 2. A total
of 238 patients entered the posttreatment follow-up phase of the study.
By day 3, significant increases in
least-squares mean serum potassium 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 patiromer. The most frequently reported
patiromer-related adverse events
were hypomagnesemia (7.2%), constipation (4.6%), and diarrhea (2.7%).
Twenty-eight patients experienced
worsening CKD throughout the
40

study, which investigators deemed
unrelated to patiromer. A total of
24 patients were noted to have
increased blood pressure, though
investigators deemed this potentially related to patiromer for only
1 patient. Mean changes in serum
magnesium 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. According to study investigators, mean
serum magnesium levels remained
in the normal range throughout the
52-week study, with no patients developing severe hypomagnesemia
or associated cardiac arrhythmias
or neuromuscular abnormalities.
Just 17 patients (5.6%) developed
hypokalemia throughout the 52week study. A serum potassium
concentration of <3.0 meq/L was not
observed in any patient experiencing
hypokalemia. Of note, reductions
in both systolic and diastolic blood
pressures were noted at all dosages
of patiromer in both strata. The decrease was evident as early as day 3 of
the study and persisted throughout
the study, with mean decreases of
15.7 mm Hg (systolic) and 8.0 mm
Hg (diastolic) in stratum 1 and 17.1
mm Hg (systolic) and 9.2 mm Hg
(diastolic) in stratum 2 seen at week
52. Per the investigators, this effect
was noted to persist throughout the
posttreatment follow-up phase after
patiromer discontinuation.
The authors concluded that patiromer significantly reduced serum
potassium levels across all dosage
groups in patients with mild-tomoderate hyperkalemia.45 This was
the first long-term study of patiromer. The majority of patients in this
study had either stage 3 or 4 CKD
(87%); however, 100% of the patients
were Caucasian, limiting extrapolation of the findings to patients of
other races or ethnicities. The study
included a small number of patients
who also had heart failure (35%), but
those with NYHA class III or IV were

excluded. Investigators counseled
patients at each visit to restrict their
dietary intake of foods with high
levels of potassium, limiting their
intake of potassium to no more than
3 g daily. This restriction was unique
in that dietary intake of potassium
was not addressed in other studies of
patiromer. Investigators did not note
how compliance with the study drug,
RAS, aldosterone inhibitors, or diet
was monitored throughout the study.
This study did not exclude dialysis
patients; however, patients with a
prior kidney transplant or in need of
a kidney transplant were excluded,
limiting extrapolation of findings.
In addition, this was an open-label
study and therefore had the potential
to introduce observer bias.
Phase III trial. Weir et al.46 evaluated the safety and efficacy of
patiromer in a randomized, run-in,
single-blind, multicenter, placebocontrolled, parallel-group, prospective, intention-to-treat, superiority,
Phase III study. The primary objective was to assess the safety and efficacy of patiromer in patients with
CKD who were receiving at least one
RAS inhibitor and who had chronic
hyperkalemia. A total of 243 patients
age 1880 years were included in the
study. Patients had to have stage 3 or
4 CKD (eGFR, 1560 mL/min/1.73
m2), as well as hyperkalemia, defined
as a serum potassium concentration
of 5.1 to less than 6.5 meq/L, while
on stable doses of an ACE inhibitor,
ARB, or aldosterone antagonist for at
least 28 days before study initiation.
Patients were excluded if they had
CKD that was a result of type 1 diabetes or an autoimmune-related disease (e.g., lupus, renal scleroderma),
potassium-related electrocardiographic changes, a severe gastrointestinal disorder, uncontrolled
arrhythmia, a recent cardiac surgery
or acute coronary syndrome, a kidney or heart transplant, a transient
ischemic attack within the previous
two months, a systolic blood pressure greater than 180 mm Hg or less

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 fourweek single-group, single-blind,
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 starting dosages according to the severity
of their hyperkalemia. Patients with
mild hyperkalemia (serum potassium
concentration of 5.1 to <5.5 meq/L)
received patiromer 4.2 g twice daily,
and patients with moderatesevere
hyperkalemia (serum potassium
concentration of 5.5 to <6.5 meq/L)
received patiromer 8.4 g twice daily.
After completing the initial treatment phase, patients were eligible for
the randomized withdrawal phase
if they had a serum potassium concentration of 5.5 meq/L at baseline
of the initial treatment phase and if
their serum potassium concentration at the end of the initial treatment
phase was within the target range
(3.85.1 meq/L) while receiving patiromer and an RAS inhibitor. Qualifying patients were randomly assigned
in a 1:1 ratio to continue patiromer at
the same dosage received during the
initial treatment phase or to receive
placebo.
The primary outcome for the initial phase was the mean change in
serum potassium level from baseline
to week 4. The primary outcome for
the second phase was the change
from baseline serum potassium
between patiromer and placebo at
either week 4 (for patients whose
serum potassium concentration remained 3.85.5 meq/L) or when the
patient first had a serum potassium
concentration of <3.8 or 5.5 meq/L.
A total of 219 patients completed
the initial treatment phase. During
this phase, the investigators found

a mean S.E. change in serum concentration from baseline to week 4

of 1.01 0.03 meq/L (95% CI, 1.07
to 0.95 meq/L; p = 0.0001). Of the
patients who completed the initial
treatment phase, 109 were not eligible to enter the randomized withdrawal phase. The most common
reason for ineligibility was a baseline
serum potassium concentration
of <5.5 meq/L. An additional 3 patients declined further participation
in the study. A total of 107 patients
were included in the randomized
withdrawal phase. At the start of the
randomized withdrawal phase, the
mean potassium concentration was
4.45 meq/L in the placebo group
(n = 52) and 4.49 meq/L in the group
assigned to continue patiromer (n =
55). The estimated median change
in potassium concentration from the
start of the randomized withdrawal
phase to week 4 was 0.72 meq/L in
the placebo group and 0 meq/L in
the patiromer group for a betweengroup difference of 0.72 meq/L (95%
CI, 0.460.99 meq/L; p < 0.001).
Forty-seven percent of patients
experienced at least one adverse
event. The most common adverse
events in the patiromer group were
gastrointestinal in nature, including
mild-to-moderate constipation, diarrhea, and nausea. The rate of hypokalemia was 3% throughout both the
initial and randomization phases of
the study. The authors noted that hypomagnesemia occurred in approximately 8 patients (3%) throughout
the initial and randomized phases
of the study. The mean daily doses
of patiromer in the initial treatment
phase were 12.8 g in patients with
mild hyperkalemia and 21.4 g in
patients with moderate-to-severe
hyperkalemia. A similar number of
dosage adjustments occurred in both
groups, with a majority of patients
requiring only one dosage adjustment. The study authors concluded
that patiromer was more effective at
lowering potassium levels compared
with placebo in both the initial and
maintenance phases of the study.
CLINICAL REVIEW
Patients with severe gastrointestinal disorders were excluded from
this study, limiting its extrapolation
to this population. In addition, since
patiromer is being studied for chronic treatment of hyperkalemia, the
study duration of only 12 weeks does
not establish the safety and efficacy
of long-term administration.
Discussion
Clinical trials have found that
sodium zirconium cyclosilicate and
patiromer normalize serum potassium levels quickly and maintain
normalized serum potassium levels
over several weeks. Based on available studies, both medications cause
a rapid decrease in serum potassium,
with two studies examining efficacy
endpoints for 12 weeks or longer.
All studies of the effects of sodium
zirconium cyclosilicate on serum
potassium levels found decreases in
potassium levels one hour after administration of one dose of sodium
zirconium cyclosilicate. 41,43,44 For
patiromer, the earliest that serum
potassium levels were measured after initiation of the study medication
was one day, and investigators did
note decreases in serum potassium
levels at the one-day measurement.42
One open-label study investigated
the effects of patiromer administration for up to 52 weeks and noted
few adverse effects; however, caution should be used if administering
either of these medications longer
than 12 weeks until further longterm studies are completed.45
Both medications appear to lower
serum potassium levels with few
adverse effects. The most common
adverse events were gastrointestinal
in nature, though their overall frequency was low. The frequency of adverse gastrointestinal effects in Phase
III studies with sodium zirconium
cyclosilicate was approximately
24%, with constipation being most
common.43,44 The rate of adverse gastrointestinal effects in the one Phase
III study of patiromer was approximately 4%, with the frequencies of
CLINICAL REVIEW
constipation, nausea, and diarrhea
being approximately equal.46 These
medications may prove advantageous over sodium polystyrene sulfonate in that they offer a lower, less
severe adverse-effect profile overall.
Of note, patients with gastrointestinal 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 polystyrene 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 hypomagnesemia.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 observed effect of these medications.
Only one study observed an increase
in serum bicarbonate: the Phase III
study of sodium zirconium cyclosilicate 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 cyclosilicate, it could prove useful in CKD
patients who frequently experience
metabolic acidosis in addition to hyperkalemia. 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 <30 mL/min), limiting
its use in this patient population.
All studies involved ambulatory
care patients except the study by Ash
et al.41 None of the studies involved
patients who were exhibiting any
signs or symptoms of hyperkalemia,
42

such as cardiac arrhythmias. Based on
the available trial data thus far, these
medications appear to be best used in
an outpatient setting in patients with
asymptomatic hyperkalemia. There
was little reference made to diet, vitamins, minerals, and nonprescription
medications taken during several of
the clinical trials; this area would be
worthy of further exploration in order
to accurately assess the full impact
of the study medications. Long-term
studies are needed to fully ascertain
the effects of these medications,
particularly in patients with chronic
hyperkalemia due to CKD, heart failure, or the use of RAS inhibitors or an
aldosterone antagonist.
Patiromer was approved by FDA
on October 21, 2015, for the treatment
of hypokalemia and is expected to be
available in early 2016.62 The NDA for
accepted by FDA in July 2015 with an
action goal date of May 2016.63
Conclusion
Options for the management of
hyperkalemia, particularly chronic
hyperkalemia in the outpatient setting, are limited. Both sodium zirconium cyclosilicate 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 antagonist, or both.
Disclosures
The authors have declared no potential
conflicts of interest.
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