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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
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,
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.
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
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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
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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
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-
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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
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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
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
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
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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