Getting Hyped Over a
Possible Hyperkalemia
Solution
T
he potassium from your daily banana may
be wonderful for the heart, but eat a bunch
or a boatload, and the excess of potassium
can be deadly. Hyperkalemia is generally defined as
occurring when the body’s potassium concentration
exceeds 5.0 mEq/l, and it is often considered a medical emergency. Clinically, hyperkalemia can manifest
as electrocardiographic changes ranging from peaked
T waves and progressive paralysis of the atria to
conduction abnormalities, bradycardias, and cardiac
arrest due to ventricular fibrillation, asystole, or
pulseless electrical activity.1 Not something to mess
around with.
While relatively rare in the general population,
hyperkalemia is more common in patients with
chronic kidney disease (CKD), and more common
yet in patients with CKD and comorbid diabetes, cardiovascular disease, or acute kidney injury. Several
medications have the potential to raise serum potassium levels, including beta-blockers and heparin, but
their effects are small.
“The most important medication class linked to
hyperkalemia are inhibitors of the renin-angiotensinaldosterone system (RAAS), such as angiotensinconverting enzyme inhibitors, angiotensin receptor
blockers, direct renin inhibitors, and mineralocorticoid receptor blockers,” according to Csaba
P. Kovesdy, MD, University of Tennessee Health
Science Center, Memphis, TN, in a review on the
management of hyperkalemia published in late June.2
RAAS dual therapy is associated with hyperkalemia incidence between 5% and 10% in
patients with CKD. Unfortunately, these agents
have proven survival benefits in heart failure and
are also renoprotective. Since one of the most effective treatments of drug-related hyperkalemia is
to stop the drug, potassium elevations often leave
the patients who most need RAAS inhibitors
without them.
Aldosterone inhibitors, such as spironolactone
and eplerenone (or the new-generation mineralocorticoid receptor antagonist [MRA] finerenone),
are also associated with increased potassium levels.
These agents help control hypertension, decrease left
ventricular mass and left atrial size, reduce hospitalizations, and may reduce cardiovascular mortality in
high risk patients.3
Their use, however, has been limited, in part,
because of hyperkalemia concerns. Some researchers have labeled this risk quite low, but Abbas et
al.4 recently published some worrisome data from a
massive German nested case-control study of heart
failure patients receiving spironolactone plus continuous ACE/ARB therapy (n = 1,491,894). In this
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CardioSource WorldNews
diverse real-world
population, the risk
of hyperkalemia
associated with
spironolactone use in those taking continuous ACE/
ARB therapy was much higher (with odds ratio,
13.59) than that observed in clinical trials.
Previously, treatment of hyperkalemia was
limited to drug cessation, cardiac monitoring, administration of potassium-lowering mediations,
or emergency dialysis. In patients with sufficient
renal function, forced diuresis with loop diuretics
might be employed to remove potassium that has
been redistributed into the extracellular space by
other therapies.
The only agent currently available in the U.S.
that actually lowers total body potassium levels is
sodium-polystyrene sulfonate, which was approved
based on a tr ial from the early 1960s conducted in
32 hyperkalemic patients with azotemia at a time
before dialysis was available, said Dr. Kovesdy. Its
effects on serum potassium are considered unpredictable.
“By today’s standard, sodium-polystyrene
sulfonate has never undergone rigorous enough
testing in clinical trials to prove its efficacy and
safety for treatment of acute or chronic hyperkalemia,” wrote Dr. Kovesdy. Indeed, recent reports of
colonic necrosis prompted a U.S. Food and Drug
Administration (FDA) black box warning in 2009
banning the combination use of sodium-polystyrene sulfonate with 70% sorbitol (often added to
alleviate its constipating effect).
Enter patiromer (Relypsa, Inc.) and sodium zirconium cyclosilicate (ZS Pharma), two drugs that bind
potassium and clear it from the body, albeit with
differing mechanisms of action. Patiromer is a potassium binder in oral suspension form. It has been
submitted to the FDA for approval with a decision
expected on October 21, 2015. ZS-9 is an insoluble
zirconium silicate with a three-dimensional crystalline lattice structure designed to preferentially trap
potassium ions. An NDA for ZS-9 was submitted to
the FDA on May 26, 2015.
In phase III clinical trials, both drugs normalize
plasma potassium levels in hyperkalemic patients
with CKD, diabetes, or heart failure receiving RAAS
inhibitors.5,6 In the recently published AMETHYSTDN trial,7 Bakris and colleagues conducted a phase
II dose-finding trial of patiromer in patients with
stage 3 and 4 CKD who received RAAS inhibitors
and had a baseline potassium level >5.0 mEq/l. Depending on their level of hyperkalemia, participants
were given one of three starting doses, with adjust-
ments made to achieve target potassium concentrations of 5 mEq/l or less.
Potassium concentrations were significantly
reduced in each baseline hyperkalemia stratum at 4
weeks, with results persisting to 8 weeks. Perhaps
more importantly, over an additional 44 weeks
of maintenance therapy, most patiromer-treated
patients remained normokalemic, with potassium
levels increasing quickly once the study drug was
stopped.
“These drugs are going to help markedly keep
patients on the drugs that are cardio- and reno-protective,” said Peter McCullough, MD. “For instance,
the MRA drugs—we only use them in about 40% of
the patients who need them because we’re limited by
hyperkalemia, so this should be a dramatic change
in our practice and I think we’re very hopeful that
we will see improved outcomes over time once these
new drugs get on the market and get in use.”
Once approved based on the surrogate of potassium concentration, the hyperkalemia drugs need
to be further tested to see if they will allow patients
who are about to or have failed RAAS inhibitor treatment to stay on their drugs, according to nephrologist Wolfgang C. Winkelmayer, MD, ScD, from
Baylor College of Medicine, Houston, TX, and an
associate editor at JAMA.8
Since motivation in industry to do these trials
may be lacking, “as part of the approval process, the
FDA and other agencies should consider mandating
a sizeable postmarketing trial and safety surveillance
program to clearly establish whether the assumptions underlying the value proposition of chronic
hyperkalemia treatments actually hold,” said Dr.
Winkelmayer. With this further study, he noted,
these agents have “the potential to fundamentally
change the current treatment approach for hyperkalemia.” ■
REFERENCES
1. “Hyperkalemia.” lifeinthefastlane.com/ecg-library/basics/
hyperkalaemia. Accessed on 2015 July 17.
2. Kovesdy CP. Am J Med. 2015 Jun 17. [Epub ahead of print]
3. Miller RJ, Howlett JG. Curr Opin Cardiol. 2015 Jan 8.
[Epub ahead of print]
4. Abbas S, Ihle P, Harder S, Schubert I. Parmacoepidemiol
Drug Saf. 2015;24:406-13.
5. Weir MR, Bakris GL, Bushinsky DA, et al. N Engl J Med.
2015;372:211-21.
6. Packham DK, Rasmussen HS, Lavin PT, et al. Engl J Med.
2015;372:222-31.
7. Bakris GL, Pitt B, Weir MR, et al. JAMA. 2015;314:151-61.
8. Winkelmayer WC. JAMA. 2015;314:129-30.
August 2015