Hyperkalemia in Heart Failure

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 68, NO. 14, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER

http://dx.doi.org/10.1016/j.jacc.2016.06.060

THE PRESENT AND FUTURE REVIEW TOPIC OF THE WEEK

Hyperkalemia in Heart Failure Chaudhry M.S. Sarwar, MD,a Lampros Papadimitriou, MD, PHD,a Bertram Pitt, MD,b Ileana Piña, MD, MPH,c Faiez Zannad, MD,d Stefan D. Anker, MD, PHD,e Mihai Gheorghiade, MD,f Javed Butler, MD, MPH, MBAa

ABSTRACT Disorders of potassium homeostasis can potentiate the already elevated risk of arrhythmia in heart failure. Heart failure patients have a high prevalence of chronic kidney disease, which further heightens the risk of hyperkalemia, especially when renin-angiotensin-aldosterone system inhibitors are used. Acute treatment for hyperkalemia may not be tolerated in the long term. Recent data for patiromer and sodium zirconium cyclosilicate, used to treat and prevent high serum potassium levels on a more chronic basis, have sparked interest in the treatment of hyperkalemia, as well as the potential use of renin-angiotensin-aldosterone system inhibitors in patients who were previously unable to take these drugs or tolerated only low doses. This review discusses the epidemiology, pathophysiology, and outcomes of hyperkalemia in heart failure; provides an overview of traditional and novel ways to approach management of hyperkalemia; and discusses the need for further research to optimally treat heart failure. (J Am Coll Cardiol 2016;68:1575–89) © 2016 by the American College of Cardiology Foundation.

H

yperkalemia

threatening

(RAASi) are at 2 to 3 times higher risk for hyperkale-

because of the associated risk for arrhyth-

can

be

life

mia (4–6). In hospitalized patients admitted with

mias and conduction system abnormalities

worsening HF, despite aggressive diuresis, increases

(1,2). Generally, a serum potassium level higher than

in serum potassium levels are observed (7). With

5.0 mmol/l is defined as hyperkalemia (1). Among pa-

growing numbers of CKD and HF patients taking

tients hospitalized for any cause, the prevalence of

RAASi and mineralocorticoid receptor antagonists

hyperkalemia has been estimated at 1% to 10% (3). Pa-

(MRAs), hyperkalemia has become a more common

tients with chronic kidney disease (CKD), heart fail-

concern. Angiotensin-converting enzyme inhibitors

ure (HF), and diabetes mellitus and those using

(ACEi), angiotensin-receptor blockers (ARBs), and

renin-angiotensin-aldosterone

MRAs have proven benefit in patients who are also

system

inhibitors

From the aCardiology Division, Stony Brook University, Stony Brook, New York; bCardiology Division, University of Michigan, Ann Arbor, Michigan; cCardiology Division, Albert Einstein College of Medicine; Bronx, New York; dINSERM, Centre d’Investigation Clinique 9501 and Unité 961, Centre Hospitalier Universitaire, and the Department of Cardiology, Nancy University, Université de Lorraine, Nancy, France; eInnovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center, Göttingen, Germany; and the fCenter for Cardiovascular Drug Development and Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Dr. Pitt is a compensated board member for Novartis; consultant for Takeda, AstraZeneca, Boehringer-Ingelheim, GE Healthcare, Relypsa, BG Medicine, Nile Therapeutics, Merck, Forest Laboratories, and Novartis; has received grant support from Forest Laboratories and Novartis; and holds stock in Relypsa, BG Medicine, Nile Therapeutics, and Aurasenc. Dr. Piña is a consultant for the U.S. Food and Drug Administration; and is on the advisory board of Novartis. Dr. Zannad is a compensated board member for Boston Scientific; consultant for Novartis, Takeda, AstraZeneca, Boehringer-Ingelheim, GE Healthcare, Relypsa, Servier, Boston Scientific, Bayer, Johnson & Johnson, and Resmed; and is a compensated speaker with Pfizer Listen to this manuscript’s

and AstraZeneca. Dr. Anker has received honoraria from and is a consultant for ThermoFisher Scientific, Cardiorentis, Bayer

audio summary by

HealthCare AG, ZS Pharma, Relypsa, Novartis Pharma AG, and Vifor Pharma. Dr. Gheorghiade has consulted for Abbott Labora-

JACC Editor-in-Chief

tories, Astellas, AstraZeneca, Bayer HealthCare AG, CorThera, Cytokinetics, DebioPharm SA, Errekappa Terapeutici, Glaxo-

Dr. Valentin Fuster.

SmithKline, Ikaria, Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, Sanofi, Sigma Tau, Solvay Pharmaceuticals, Takeda Pharmaceutical, and Trevena Therapeutics. Dr. Butler has received research support from the National Institutes of Health and the European Union; and is a consultant for Amgen, Bayer, Boehringer-Ingelheim, Cardiocell, Celladon, Novartis, Trevena, Relypsa, Z Pharma, and Zensun. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received June 20, 2016; accepted June 28, 2016.

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Hyperkalemia in HF

ABBREVIATIONS

at high risk for hyperkalemia (8). Even more

circulation, and liver (12). A role for the pituitary

AND ACRONYMS

challenging is the fact that many patients

gland in potassium homeostasis has been shown in

have several of these comorbidities simulta-

rats where renal potassium excretion was impaired

neously and are attempting to use 1 or more

post-hypophysectomy (16,17). In human subjects,

RAASi together. Thus, many patients in

hourly increased renal and gastrointestinal potassium

blocker

need for these therapies are unable to

excretion after 35 mmol of oral potassium persisted

CKD = chronic kidney disease

tolerate them, or if these medicines are pre-

following

scribed, they are prescribed at less than

gastrointestinal-renal kaliuretic signaling axis that is

ACEi = angiotensin-converting enzyme inhibitor

ARB = angiotensin receptor

eGFR = estimated glomerular

aldosterone

blockade,

suggesting

a

filtration rate

optimal dosages. RAASi discontinuation for

independent of the changes in serum potassium

HF = heart failure

hyperkalemia represents an undesirable clin-

concentration and aldosterone (18).

MRA = mineralocorticoid

ical compromise. Importantly, many clinical

receptor antagonist

trials have excluded patients with advanced

RAASi = renin-angiotensin-

CKD and those with or at risk for hyperkale-

aldosterone system inhibitor

mia, leaving a critical evidence gap in phar-

ZS-9 = sodium zirconium

macotherapy for these high-risk patients.

HYPERKALEMIA IN PATIENTS WITH HF: ROLE OF RENAL DISEASE AND THERAPY Approximately 26 million people globally have HF (19). These patients, by virtue of their disease, comorbid-

cyclosilicate

POTASSIUM HOMEOSTASIS

ities, and medical therapy, are at risk for hyperkalemia. Hyperkalemia can be classified into 2 types:

Under

normal

circumstances,

the

kidneys

are

responsible for excreting 90% of the potassium that is consumed daily (9). Most of the potassium is freely filtered by the glomerulus and is absorbed in the proximal tubule and loop of Henle, and only 10% reaches the distal tubule (10,11). Principal cells in the renal collecting duct are responsible for secreting excess potassium from the circulation into the tubular lumen and excreting it in the urine. Luminal membrane potassium channels that respond to the

1. Inherent hyperkalemia: includes hormonal disorders

(e.g.,

Addison’s

disease,

hyporeninemic

hypoaldosteronism), diabetes mellitus, CKD, and diseases with cell membrane instability that can cause intracellular and extracellular potassium shifts (20,21); and 2. Treatment-related

hyperkalemia:

medications

(e.g., RAASi, MRA, nonsteroidal anti-inflammatory drugs, diuretic agents, heparin).

electrochemical gradient for potassium generated by

In addition, excess dietary intake of foods high in

the basolateral membrane sodium-potassium adeno-

potassium or sodium supplements containing high

sine triphosphatase (Na þ/K þ-ATPase) and a luminal

potassium content can cause hyperkalemia (22–24)

membrane sodium channel accomplish this secretion.

(Figures 2 and 3). MRAs or RAASi increase the risk of

In states of potassium depletion, potassium secretion

hyperkalemia (25). As the use of RAASi has increased,

by the principal cells is inhibited, and the luminal

especially in higher doses and in combination (26–29),

membrane hydrogen-potassium adenosine triphos-

hyperkalemia has become more common. The use of

phatase (Hþ/Kþ-ATPase) is activated in the interca-

ACEi is attributed to the development of hyper-

lated cells to reabsorb the potassium (Figure 1) (12).

kalemia in 10% to 38% of hospitalized patients (3,30),

Secretion of potassium by the collecting duct is

whereas hyperkalemia develops in up to 10% of the

regulated by the serum aldosterone and sodium

outpatient population within 1 year of prescribing

concentration in the distal tubule (11). Aldosterone is

RAASi (31). Patients with impaired renal function and

regulated by the renin-angiotensin-aldosterone sys-

those with diabetes are at higher risk of hyperkalemia

tem (RAAS) and by serum potassium levels (13). In

(11). In the PARADIGM-HF (Prospective comparison of

HF, when the renal perfusion pressure falls, juxta-

ARNI with ACEI to Determine Impact on Global Mor-

glomerular

converts

tality and morbidity in Heart Failure) trial, despite

angiotensinogen to angiotensin II, in conjunction

renal function, potassium-based eligibility criteria,

with angiotensin-converting enzyme (ACE) (14).

and a run-in period, approximately 15% of patients in

Angiotensin II acts on zona glomerulosa of the adre-

both the LCZ696 and the enalapril arms developed

nal glands and stimulates aldosterone secretion. High

hyperkalemia (32). In a recent HF study (n ¼ 19,194),

serum potassium is also a stimulator of aldosterone,

11.3% of patients had hyperkalemia over a mean

which lowers serum potassium by stimulating potas-

follow-up of 3.9  3.2 years, yielding an incidence of

cells

secrete

renin,

which

2.90/100 person-years (95% confidence interval [CI]:

sium excretion from distal tubule (13,15). Increased potassium intake increases kaliuresis, and

it

is

postulated

that

potassium

receptors

also reside in gastrointestinal tract, enterohepatic

2.78 to 3.02) (33). Similarly,

in

RALES

(Randomized

Aldactone

Evaluation Study), although the beneficial effect of

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Hyperkalemia in HF

F I G U R E 1 Segmental Handling of Potassium Under Normal Conditions or With Potassium Excess or Deficiency

Normal or high K intake: Reabsorbs ∼67% of filtered K

Normal or high K intake: Secretes 10%-50% of filtered K Low K: Reabsorbs ∼3% of filtered K

Low K: Reabsorbs ∼67% of filtered K

Na+

DT

Lumen

Collecting Duct

Glom

Proximal Tubule

K+

Secretion

Principal cell K+

CCD

Normal or high K intake: Reabsorbs ∼25% of filtered K

Normal or high K intake: Secretes 5%-30% of filtered K

MTAL

Low K: Reabsorbs ∼25% of filtered K

2K+ ATP ADP+Pi Blood 3Na+

Low K: Reabsorbs ∼10% of filtered K

OMCD

K+ Lumen ATP Loop of Henle

ADP+Pi

IMCD

ATP ADP+Pi H+ H+ Intercalated cell 2K+

K+ ATP ADP+Pi

Reabsorption Blood

Normal or high K intake: Secretes 15%-80% of filtered K

Low K: Reabsorbs ∼1% of filtered K

3Na+

Excess potassium is secreted into the tubule lumen and urine by the principal cells in the collecting duct. The secretion is medicated by the potassium channels in the luminal membrane, which respond to the electrochemical gradient for potassium generated by the combined action of the basolateral membrane sodium-potassium adenosine triphosphatase (Naþ/Kþ-ATPase) and a luminal membrane sodium channel. With potassium depletion, potassium secretion by the principal cells is inhibited, and the luminal membrane hydrogen-potassium adenosine triphosphatase (Hþ/Kþ-ATPase) is activated in the intercalated cells to reclaim the potassium that remains in the tubular fluid, thereby limiting urinary potassium wasting. Reprinted with permission from Greenlee et al. (12). ADP ¼ adenosine diphosphate; ATP ¼ adenosine triphosphate; CCD ¼ cortical collecting duct; DT ¼ distal tubule; Glom ¼ glomerulus; H ¼ hydrogen; IMCD ¼ inner medullary collecting duct; K ¼ potassium; MTAL ¼ medullary thick ascending limb of Henle loop; Na ¼ sodium; OMCD ¼ outer medullary collecting duct; Pi ¼ inorganic phosphate.

spironolactone continued in the treatment group

increased to 11 of 1,000 patients in 2001 compared

versus placebo, despite higher potassium levels in the

with 2.4 of 1,000 patients in 1994 (p < 0.001) (8).

treatment group (4.54  0.49 mmol/l vs. 4.28  0.50

Additionally, the rate of in-hospital hyperkalemia-

mmol/l, respectively; p < 0.001), a higher mortality

associated death in HF patients increased from 0.10 of

risk was observed when potassium levels increased

1,000 patients in 1994 to 0.39 of 1,000 patients in 2001

to more than 5.5 mmol/l in the spironolactone group

(p < 0.001) (8). These data underscore both the

(34). The beneficial effect of spironolactone compared

importance of hyperkalemia when augmenting RAASi

with placebo was maintained at all levels of hyper- or

and the need for careful monitoring of electrolytes.

hypokalemia, showing a U-shaped relationship be-

Hyperkalemia risk is increased with concomitant

tween potassium levels and mortality, with higher

CKD in HF patients. In 105,388 HF patients enrolled in

mortality rates in patients randomized to placebo at all

the ADHERE (Acute Decompensated Heart Failure

potassium levels (p < 0.0001) (34). The use of spi-

National Registry) study, more than 60% of patients

ronolactone increased after the RALES trial; however,

had kidney disease (35). In patients with CKD, the

the hospitalizations attributed to hyperkalemia also

prevalence of hyperkalemia can be up to 20% and is

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Hyperkalemia in HF

F I G U R E 2 Hyperkalemia in Heart Failure Patients Increases as Renal Function Declines

35 Rate of Hyperkalemia (% of Patients)

30.2 30 25.6 25 18.2

20 15.4

15 10

13.3 8.5

6.0

6.7

5 0

Baseline eGFR ≥60

No WRF

Baseline eGFR <60

Baseline Renal Function

WRF

Intra-study Change in Renal Function

Placebo

Spironolactone

Impaired renal function increases the risk of hyperkalemia in both the patients taking placebo and the MRA-treated patients. Modified with permission from Go et al. (23). eGFR ¼ estimated glomerular filtration rate; MRA ¼ mineralocorticoid receptor antagonist; WRF ¼ worsening renal function.

associated with the risk of mortality and major

potassium should be stopped or used judiciously

adverse cardiovascular events and discontinuation

under supervision. It may be preferable to use lower

of RAASi (36). The use of RAASi in patients with

doses of both RAASi and MRAs rather than higher

cardiovascular

myocardial

doses of one and not to use the other class of drugs

infarction, HF, diabetes, and CKD, can reduce adverse

altogether. Higher doses of ACEi and ARBs are asso-

long-term consequences (37). However, most trials

ciated with better outcomes in HF with reduced

excluded patients with moderate or severe CKD,

ejection fraction (38,39). However, this benefit is

which is common in HF, especially at advanced stages

modest, and lower doses were better tolerated. Thus,

(37).

lower doses of RAASi are better than avoiding these

diseases,

including

The use of effective and safe potassium binders

drugs. In case of worsening renal function, the risk of

now provides an opportunity to assess RAASi in such

hyperkalemia and the rate of decline in renal function

patients. In the meantime, several steps can be taken

should be assessed. There are no specific guidelines,

to attempt RAASi therapy in such patients. First,

but generally, ACEi or ARB doses may be reduced

potassium supplements or salt substitutes containing

or stopped, either temporarily or permanently, with

F I G U R E 3 Prevalence of Heart Failure and Diabetes Mellitus in Relation to Chronic Kidney Disease

Heart Failure

Diabetes

35

31.1 28.2

30 Prevalence (%)

1578

25

20.8

19.6

18.5

20 15

12.6

12.3 8.6

10 5.2 5 0

N=

1.0 >60

45-59

30-44 15-29 >15 eGFR mL/min/1.73m2 924,136 153,426 34,275 7085 1373

>60

45-59

30-44

15-29

>15

924,136 153,426 34,275

7085

1373

Prevalence of heart failure and diabetes mellitus may increase the risk of hyperkalemia on the basis of disease and concomitant therapies. Modified with permission from Go et al. (23). eGFR ¼ estimated glomerular filtration rate.

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Hyperkalemia in HF

MAINTENANCE. In addition to dietary potassium

T A B L E 1 Treatment Options for Hyperkalemia

Severity

intake restriction, lowering the dose of drugs that

Treatment

impair potassium excretion or administering them

Emergent

Calcium gluconate Insulin Beta-adrenoreceptor agonists

every other day or totally discontinuing them is often

Intermediate

Dialysis Loop diuretic agents Thiazide diuretic agents Sodium bicarbonate in patients with metabolic acidosis.

dietary and herbal supplements and salt substitutes

Maintenance

needed (11). This should include a review of all as well. Potassium-binding resins can also be used; however, until recently, the only approved ionexchange resin was sodium polystyrene sulfonate,

Review of medication list and dietary supplements Low-potassium diet Reduce dose of renin-angiotensin-converting enzyme inhibitors. Stop offending medications Potassium-binding resins

which was not well tolerated and may cause colonic necrosis and intestinal injury (43). Patiromer has recently become available for use, expanding the armamentarium of therapies available for the management of these patients. However, chronic therapy targeting prevention of hyperkalemia

estimated glomerular filtration rate (eGFR) <15 to 30

and subsequent optimization of RAASi needs further

ml/min, whereas they can be used in dialysis patients

studies.

with careful monitoring. Currently, MRAs are contraindicated in patients with eGFR <30 ml/min. In

PATHOPHYSIOLOGY OF

hospitalized patients receiving intravenous diuretic

HYPERKALEMIA IN HF

agents who have rapid changes in renal function with or without hypotension, holding or lowering RAASi is

A close association exists between serum potassium

common. However, this decision should be individ-

and plasma renin concentration in HF (44). Renin

ualized, and currently, evidence for what to do in

elevation due to renal hypoperfusion in HF causes the

such a situation is not available.

excretion of potassium by stimulating the synthesis of

According to the Health Care Cost and Utilization

aldosterone, whereas high potassium concentrations

Project database, in 2011, the estimated total annual

can directly inhibit the RAAS (45). ACEi block the

charges for Medicare admissions with hyperkalemia

stimulatory effect of angiotensin II on aldosterone

as the primary diagnosis were $697 million, the

secretion, whereas ARBs prevent angiotensin II from

average Medicare length of stay was 2 to 3 days with

binding to its adrenal receptors (45). In addition, these

mean charges of $24,085 per day, and one-third of the

drugs may interfere with angiotensin I produced

patients were discharged to another short-term hos-

locally within the adrenal glands (14). RAASi, such as

pital or home health care (40).

ACEi, ARBs, MRAs, and direct renin inhibitors, are

CURRENT MANAGEMENT OF HYPERKALEMIA The treatment of hyperkalemia depends on the severity and cause (Table 1).

associated with an increased risk of hyperkalemia, particularly when administered in combination (46). This risk is increased in patients with stage 3 or higher CKD; hence, dual RAAS blockade is of concern in this scenario (47). Hyperkalemia can also develop sec-

EMERGENT MANAGEMENT. In patients with electro-

ondary to decreased sodium delivery to the distal

cardiographic

nephron, aldosterone deficiency, and abnormal func-

changes

and/or

potassium

levels

>7.0 mmol/l, intravenous calcium is administered to

tioning of the cortical collecting tubule (11). These

prevent arrhythmia (41). To rapidly lower potassium

abnormalities can result from the effects of other

levels, insulin and beta-2 adrenoreceptor agonists are

drugs or from underlying diseases.

used to redistribute potassium from the extracellular

In normal circumstances, the serum aldosterone

to the intracellular space; however, this is a tempo-

concentration varies inversely with delivery of

rary measure (11).

sodium to the distal nephron, so that potassium

INTERMEDIATE MANAGEMENT. Dialysis can be used

excretion remains independent of changes in extrafluid

in patients with poor kidney function or in those who

cellular

are unresponsive to other treatments. In patients

increased aldosterone causes increased absorption of

with CKD and metabolic acidosis, sodium bicarbonate

sodium

therapy is an effective strategy to minimize increases

decreased delivery to the distal nephrons, which in

in the potassium concentration (42). Loop diuretic

turn, results in decreased potassium excretion. The

agents are effective in excretion of potassium by the

use of RAASi in the presence of tubulointerstitial

delivery of sodium in the collecting duct (11).

renal disease increases the risk of hyperkalemia by

in

volume

proximal

(9–11). tubules,

However, resulting

in in

HF, its

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Hyperkalemia in HF

T A B L E 2 Comparison of Sodium Polystyrene Sulfonate, Patiromersorbitex Calcium (RLY5016), and Sodium Zirconium Cyclosilicate (ZS-9)

Characteristic

Sodium Polystyrene Sulfonate

Patiromersorbitex Calcium

Sodium Zirconium Cyclosilicate

FDA approval

Approved as Kayexalate

Approved as Veltassa

Under review

Structure

Benzene, diethenyl-polymer, with ethenylbenzene, sulfonated, sodium salt, organic polymer

100-mm bead, organic polymer

Octahedral, micropore ring 3Å diameter, inorganic crystal

Mechanism of action

Binds Naþ, Kþ, Ca2þ, or Mg2 High selectivity for Caþ2 (68) Works mostly in colon (68)

Ca2+ loaded polymer and Ca2+-K+ exchanger Binds K+, Na+, Ca2+, or Mg2 Works mostly in colon (68)

Selectivity for Kþ Works in entire GI tract (68)

Administration

15-60 g, up to 4 times daily (85)

8.4 g once daily and can be advanced to 16.8 g to 25.2 g at weekly intervals (60)

5–15 g, once daily, oral (71)

Storage temperature

Room temperature (43)

2 C–8 C (60)

Room temperature (71)

Normalize serum Kþ

Variable and not known

48 to 72 h (60)

2.2 h (mean) (69)

Normokalemia maintained

Variable and not known

52 weeks (so far known) (61)

52 weeks (so far known) (79)

Efficacy

Safety Edema

Not known

None

1.3% (14 days) (69), 7.9% (28 days) (69)

Worsening of CKD

Not known

6.3% (over 52 weeks) (61)

Not known

Mild to moderate GI AE

Variable (53)

15% (52 weeks) (61)

5.3% (open-label phase) (69) 1.8% (maintenance phase) (69)

Severe GI AE

Colonic necrosis: case reports (43,86) None

None

Hypomagnesemia

Reported (85)

7.2%–24% (56,60,61)

None

Hypokalemia/increased QTc Reported (87)

3%–5.6% (61,63)

0%–11% (69), dose-dependent

Calcium

Reported hypercalcemia (85)

Possible hypocalcemia (88), rare

None

Phosphosphate

Not known

None to minimal (56,63)

None

AE ¼ adverse events; Ca2þ ¼ calcium ion; CKD ¼ chronic kidney disease; FDA ¼ Food and Drug Administration; GI ¼ gastrointestinal; Kþ ¼ potassium ion; Mg2þ ¼ magnesium ion; Naþ ¼ sodium ion; QTc ¼ QT interval corrected for heart rate.

promoting the development of resistance to already

PATIROMER

reduced RAASi-induced aldosterone levels (11,13). Many of the diseases that affect tubular function also

Patiromer, is a nonabsorbed polymer designed to

impair the release of renin and result in hypo-

bind potassium in the gastrointestinal tract and

reninemic hypoaldosteronism and impaired tubular

reduce serum potassium levels, which was recently

function (11).

approved by the U.S. Food and Drug Administration

NEW TREATMENTS FOR HYPERKALEMIA

(FDA) (56). STRUCTURE

AND

MECHANISM

OF

ACTION.

Sodium polystyrene sulfonate has significant limita-

Patiromer (Figure 4) is synthesized as a 100- m m bead

tions for chronic use and has not been evaluated in

with optimized flow and viscosity properties and is

large randomized trials (48–50). Its use in HF is limited,

made in a high-yield 2-step process with polymeri-

as it may worsen edema by exchanging sodium for

zation followed by hydrolysis (57). Patiromer pre-

potassium ions (51). In addition, it is poorly tolerated

dominantly uses calcium as the exchange cation,

and associated with severe and even fatal gastroin-

instead of sodium (57). Patiromer is administered as

testinal complications (50,52). In a small single-center

once daily with food and promotes ionization of the

randomized controlled trial in 33 outpatients with CKD

polymeric potassium-binding moiety under pH con-

and mild hyperkalemia (5.0 to 5.9 mmol/l), a sodium

ditions present along the extent of the gastrointes-

polystyrene sulfonate dosage of 30 g orally once daily

tinal tract, predominantly in the colon (43). As a

for 7 days achieved normokalemia in 73% of the pa-

result of this structure, patiromer exchanges mono-

tients versus 38% of patients in the placebo group (53–

valent (sodium ion [Naþ]) and divalent (calcium ion

55). Patiromer (patiromersorbitex calcium/RLY5016;

[Ca2þ] and magnesium ion [Mg2þ]) cations through

Veltassa; Relypsa, Red Wood City, California) and so-

the length of the gastrointestinal tract and preferen-

dium zirconium cyclosilicate (ZS-9) (AstraZeneca,

tially binds potassium in the colon, where the con-

Cheltenham, Pennsylvania) are 2 new and promising

centration of this cation is substantially higher than

potassium-lowering compounds (Table 2 and Central

that of Na þ, Ca2þ, or Mg2þ (58). The net effect is a

Illustration).

reduction in serum potassium under hypokalemic

Sarwar et al.

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Hyperkalemia in HF

C ENTR AL I LL U STRA T I O N Novel Agents for the Management of Hyperkalemia: Characteristics and Considerations

NEW TREATMENTS FOR HYPERKALEMIA: Patiromer (RLY5016) and Sodium zirconium cyclosilicate (ZS-9)

K

• Normalizes and maintains potassium levels

• Drug-drug interactions • Edema (at high doses of ZS-9)

• Reduces aldosterone levels and blood pressure

• Constipation, diarrhea, nausea • Hypomagnesemia • Hypokalemia

Evidence gaps: • Prevention of hyperkalemia • Limitation of RAASi optimization due to hypotension or worsening renal function RAASi in patients excluded from previous trials RAASi than used in previous trials Sarwar, C.M.S. et al. J Am Coll Cardiol. 2016;68(14):1575–89.

This figure shows the advantages, concerns, and clinical scenarios that have been tested and those that need to be addressed with patiromer and sodium zirconium cyclosilicate for the treatment of hyperkalemia in heart failure population. RAASi ¼ renin-angiotensin aldosterone system.

conditions in the colon, where increased potassium

followed by an 8-week randomized withdrawal

secretion through big potassium channels represents

phase, in which patients were randomly assigned to

an adaptive response to elevated serum potassium

continue the initial dose or were switched to placebo.

(59). Hypomagnesemia is reported in clinical trials of

Seventy-six percent of patients achieved normal po-

patiromer;

significant

tassium levels in 4 weeks. During the withdrawal

neuromuscular or cardiac abnormalities noted with

phase, the hyperkalemia incidence was 15% in the

treatment (56,60–62).

treatment arm and 60% in the placebo group. The

CLINICAL

however,

there

TRIALS WITH

were

no

PATIROMER

(RLY5016).

AMETHYST-DN (Patiromer in the Treatment of

Patiromer has been evaluated in 3 clinical trials

Hyperkalemia in Patients With Hypertension and

(Table 3).

Diabetic Nephropathy) study (61) was a multicenter,

E f fi c a c y . OPAL-HK (Study Evaluating the Efficacy

open-label, dose-ranging, randomized trial with a

and Safety of Patiromer for the Treatment of Hyper-

total of 306 patients with diabetes mellitus, CKD

kalemia) included 237 CKD patients with potassium

(eGFR: 15 to <60 ml/min/1.73 m2), and serum potas-

levels of 5.1 to 6.4 mmol/l, who were taking RAASi

sium level >5.0 mmol/l. All patients received RAASi

(60). There were 2 phases: a 4-week phase in which

before and during study treatment. Treatment with

patients received patiromer 4.2 g or 8.4 g twice a day,

patiromer in both the mild and the moderate

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Hyperkalemia in HF

hypomagnesemia (8%), and hypokalemia (3%). Mag-

F I G U R E 4 Chemical Structure of Patiromer

nesium replacement therapy was initiated in 4% of subjects during the initial phase. In the withdrawal

Chemical structure of active ingredient

phase, constipation, diarrhea, and nausea (4% each) were the most common gastrointestinal events reported with patiromer, whereas these events

OH OH Calcium-sorbitol counterion

[Ca2+( HO

occurred in none of the patients with placebo (63). In OH )0.5]0.5

the PEARL-HF trail, the most common adverse events

OH OH -O

were gastrointestinal complaints (12%, n ¼ 21: flatuH2O

O

lence, diarrhea, constipation, or vomiting) (56).

* * F Patiromer anion

n

m

Hypokalemia is an important concern in HF (64).

p

When used as preventive measure for hyperkalemia, patiromer in PEARL-HF resulted in hypokalemia

*

(<3.5 mmol/l) in 6% of patients versus 0% of placebo n*

patients (p ¼ 0.094) (56). In addition, hypomagnese-

* p

*

mia (<1.8 mg/dl) was observed in 24% of the patients in the treatment group versus 2.1% in the placebo group. Adverse events resulting in patient with-

m = number of 2-fluoro-2-proprenoate groups n, p = number of crosslinking groups H2O = associated water *Indicates an extended polymeric network

m = 0.91 n + p = 0.09

drawal were similar in both groups (56). DRUG–DRUG

INTERACTION

WITH

PATIROMER.

Initial in vitro study data showed patiromer binding of >30% in 14 of 28 drugs tested, including 30% to 50%

From patiromer (Veltassa) prescribing information (Relypsa, Inc., Red Wood City, California). Ca ¼ calcium; F ¼ fluorine; O ¼ oxygen; OH ¼ hydroxide.

binding

to

clopidogrel,

furosemide,

metformin,

warfarin, metoprolol, verapamil, and lithium, whereas there was >50% binding to amlodipine, cinacalcet, ciprofloxacin, levothyroxine, quinidine, thiamine, and trimethoprim (65). In addition, a 30% reduction

hyperkalemia groups resulted in a reduction from baseline level at 4 weeks, which was maintained through 52 weeks. It is important to note that in both the OPAL-HK and the AMETHYST-DN trials, patients were able to maintain RAASi therapy. E f fi c a c y i n H F . A subgroup analysis of the OPAL-HK trial studied the effects of patiromer in HF patients (63). Of the 102 patients in the first 4 weeks, 76% achieved a serum potassium level of 3.8 mmol/l to 5.0 mmol/l. In the second withdrawal phase, hyperkalemia occurred in 52% (n ¼ 22) of patients taking placebo and 8% (n ¼ 27) of those taking patiromer (p < 0.001). The PEARL-HF (Evaluation of Patiromer in Heart Failure Patients) trial studied patiromer in patients with chronic HF (56). Patients either had eGFR <60 ml/min or a history of hyperkalemia resulting in discontinuation of a RAASi. A total of 155 patients were started on 25 mg/day of spironolactone and were randomized to double-blind treatment with 30 g/day of patiromer or placebo for 4 weeks. At 4 weeks, the

was seen in the availability of valsartan and rosiglitazone in preclinical coadministration studies in rats (56). Of 14 drugs tested initially for drug–drug interactions, 12 were tested in healthy volunteers (phase 1) in randomized, open-label studies, using a 3-way crossover design, according to FDA recommendations. The results released by the manufacturer showed no clinically meaningful reduction in absorption and no impact on peak concentration (Cmax) of lithium, trimethoprim, verapamil, and warfarin. There was also no clinically meaningful reduction in absorption, although there was some reduction in Cmax , of amlodipine, cinacalcet, clopidogrel, furosemide, and metoprolol and reduced absorption and C max of ciprofloxacin, levothyroxine, and metformin. Quinidine and thiamine were not tested (66). Meanwhile, the manufacturer, on the basis of in vitro studies, recommends taking these medications at least 6 h before or 6 h after patiromer, whereas the data from in vivo studies are being reviewed by the FDA (67).

patiromer treatment group had lowered potassium levels (7.3% vs. 24.5%, respectively; p ¼ 0.015) and was

SODIUM ZIRCONIUM CYCLOSILICATE

more likely to have spironolactone increased to 50 mg/day (91% vs. 74%, respectively; p ¼ 0.019).

Sodium zirconium cyclosilicate (ZS-9) is an inorganic,

S a f e t y a n d t o l e r a b i l i t y . The most common side

orally administered potassium-binding compound

effect in the initial phase of the OPAL-HK trial was

that has recently been investigated in phase II and III

constipation

clinical trials.

(11%),

followed

by

diarrhea

(8%),

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T A B L E 3 Clinical Trials With Patiromer

Trial, First Author, Year (Ref. #)

Type

Number of Patients

Intervention

Endpoints

Results

OPAL-HK Weir et al., 2015 (60)

RCT

237 CKD patients on RAASi with hyperkalemia þ (K 5.1–6.5 mmol/l)

Phase 1: 4–week initial treatment Change in median Kþ The mean Kþ level at baseline was 5.6  0.5 with 4.2 or 8.4 g twice daily levels in first 4 weeks mmol/l (5.3  0.6 mmol in patients with mild Phase 2: 8-week randomized of each phase hyperkalemia and 5.7  0.4 mmol in those withdrawal phase. Patients with moderate-to-severe hyperkalemia). þ who had decreased K to 3.8– At 4 weeks, mean  SE change in Kþ levels from 5.1 mmol/l, received treatment baseline was 1.01  0.03 mmol/l (95% CI: vs. placebo 1.07 to 0.95; p < 0.001). The change in patients with mild hyperkalemia was 0.65  0.05 mmol/l (95% CI: 0.74 to 0.55), and the change in those with moderate-to-severe hyperkalemia was 1.23  0.04 mmol/l (95% CI: 1.31 to 1.16). In the withdrawal phase at week 8, 60% of patients in the placebo group had recurrence of hyperkalemia (Kþ >5.5 mmol/l) vs. 15% in the treatment group (p < 0.001). At the end of phase 2, 55% of HF patients on placebo and 100% of treatment group patients were receiving RAASi.

OPAL-HK (Substudy) Pitt et al., 2015 (63)

RCT

102 patients with CKD and HF

Change in median Kþ Phase 1 at 4 weeks: the mean SE change in serum Phase 1: 4-week treatment with levels in first 4 weeks Kþ from baseline was 1.06  0.05 mmol/l 4.2 or 8.4 g twice daily of each phase (95% CI: 1.16 to 0.95; p < 0.001). Phase 2: 8-week withdrawal phase In withdrawal phase at 8 weeks, 52% of patients in patients with Kþ to 3.8–5.1 mmol/l, received treatment vs. in the placebo group had a recurrence of placebo hyperkalemia (Kþ >5.5 mmol/l) vs. 8% in the treatment group (p < 0.001). At the end of phase 2, 55% of HF patients on placebo and 100% of treatment group patients were receiving RAASi.

PEARL-HF Pitt et al., 2011 (56)

RCT

105 HF patients on standard therapy and spironolactone

Patient randomized to 3 g/day of treatment vs. placebo for 4 weeks

Change in median Kþ levels at 4 weeks

Treatment group normalized Kþ in 24 % (12 of 49 patients) vs. 7% (4 of 55 patients) in placebo (p ¼ 0.015) 91% in the treatment group were able to reach the target dosage of spironolactone (50 mg/day at 4 weeks, increased from 25 mg/day). A greater number of patients in the treatment group were able to have their spironolactone dose increased vs. the placebo group (91% vs. 74%; p ¼ 0.019).

AMETHYST-DN Bakris et al., 2015 (61)

RCT

306 diabetic patients on RAASi with Kþ >5.0 mmol/l

Varying patiromer twice-daily dosing in: 1. Mild hyperkalemia group, dose of 4.2, 8.4, or 12.6 g 2. Moderate hyperkalemia group, dose of 8.4, 12.6, or 16.8 g Dose titrated to keep Kþ <5.0 mmol/l

Change in median Kþ levels at 4 weeks or before dose titration. Adverse events up to 52 weeks

1. Mild hyperkalemia group: Kþ at 4 weeks was 0.35 (95% CI: 0.22–0.48) mmol/l for the 4.2-g twice-daily starting-dosage group, 0.51 (95% CI: 0.38–0.64) mmol/l for the 8.4-g twice-daily starting-dosage group, and 0.55 (95% CI: 0.42–0.68) mmol/l for the 12.6 g twice-daily starting-dosage group. 2. Moderate hyperkalemia group: Kþ reduction at 4 weeks was 0.87 (95% CI: 0.60–1.14) mmol/l for the 8.4 g twice-daily starting-dosage group, 0.97 (95% CI: 0.70–1.23) mmol/l for the 12.6 g twice-daily starting-dosage group, and 0.92 (95% CI: 0.67–1.17) mmol/l for the 16.8 g twice-daily starting-dosage group (p < 0.001 for all groups). This effect was maintained through week 52, where mean daily patiromer dosages were similar to those at week 4 through week 8 (19.4 g/day vs. 27.2 g/day) in patients with mild vs. moderate hyperkalemia, respectively. Adverse events: hypomagnesemia (8.6%), mild to moderate constipation, and hypokalemia (<3.5 mmol/l) occurred in 5.6% of patients.

AMETHYST-DN ¼ Patiromer in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy; CI ¼ confidence interval; HF ¼ heart failure; OPAL-HK ¼ Study Evaluating the Efficacy and Safety of Patiromer for the Treatment of Hyperkalemia; PEARL-HF ¼ Evaluation of Patiromer in Heart Failure Patients; RAASi ¼ angiotensin-converting enzyme inhibitors; RCT ¼ randomized controlled trial; other abbreviations as in Table 1.

STRUCTURE AND MECHANISM OF ACTION. ZS-9 is

physiological potassium channels and selectively

administered as a once-daily dose, and its physio-

captures potassium cations. This is accomplished by

logical ion channels filter ions on the basis of their

the use of a selectivity filter (62). In order to pass

differing diameters. ZS-9 has a structure that mimics

through the channel, an ion must shed its hydration

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F I G U R E 5 ZS-9 Pore Detail

The ZS-9 pore is shown with a potassium ion (A), a sodium ion (B), and a calcium ion (C). The specificity for potassium is likely due to the size and binding sites of the pores. Adapted with permission from Stavros et al. (68). Abbreviations as in Figures 1 and 4.

sphere and only then can it interact with the carbonyl

shedding its water coat has a diameter of 1.44  A (72).

oxygens in the channel. Both sodium and potassium

This diameter is energetically unfavorable for Mg þ2 to

are of the size that would fit in the ZS-9 structure ring,

interact with the oxygen bonds in the ZS-9 structural

but after shedding their hydration shells, only K þ has

ring (68).

a size sufficient to fit into the ZS-9 pore size (68) CLINICAL TRIALS WITH ZS-9. Sodium zirconium

(Figure 5). ZS-9 is not absorbed in the gastrointestinal tract

cyclosilicate has been evaluated in 4 clinical trials

and is available as insoluble, free-floating, odorless,

(Table 4).

tasteless, white crystalline powder. It is an inorganic

E f fi c a c y . The effect of ZS-9 over 14 days, including at

compound, unlike sodium polystyrene sulfonate, and

the 48-h acute phase was demonstrated in the ZS-003

specifically

and

trial (71). Overall, 753 patients with potassium levels

ammonium) over divalent cations (like Ca 2þ or Mg 2þ).

between 5.0 and 6.4 mmol/l were given various doses

Because it is not systemically absorbed, the risk of

of ZS-9, and the exponential rate of change in serum

systemic toxicity is low (69–71). The potassium ex-

potassium levels at 48 h was measured. A dose-

change capacity of ZS-9 was studied using a simulated

related reduction in potassium levels was observed.

gastrointestinal tract medium with various concen-

A similar short-term phase II study by Ash et al. (70),

trations of ZS-9 doses and medium pH (68). It was

using lower various doses of ZS-9 provided favorable

observed that in the simulated gastric fluid (pH w1.2),

results with significant reductions in potassium

there is an initial drop in potassium concentration,

levels, even at lower doses, with only mild con-

which reverses soon afterward. In the small intestine

stipation reported (70).

traps

monovalent

(potassium

(pH w4.5), there is an immediate uptake of potas-

The

HARMONIZE

(Hyperkalemia

Randomized

sium, followed by a small release, with equilibrium

Intervention Multi-Dose ZS-9 Maintenance Another)

reached in approximately 20 min. In the large intes-

trial (69) enrolled ambulatory patients with hyper-

tine (pH 6.8), there is a rapid uptake of potassium

kalemia (>5.1 mmol/l). In the first 48 h, the patients

during the first 10 min, followed by continued but

(n ¼ 258) received 10 g of ZS-9 3 times a day, which

slower uptake over the next hour with no further in-

resulted in lowering of potassium levels from 5.6

crease thereafter. It was also observed that the bind-

mmol/l to 4.5 mmol/l. The median time to normali-

ing capacity of ZS-9 increased proportionately with

zation was 2.2 h. At 24 h, 84% of patients were nor-

increasing concentration >0.5 to 50 mg/ml. These

mokalemic, and by 48 h, 98% were normokalemic.

results led to the conclusion that, in environments

This was followed by the maintenance phase, in

mimicking the human gastrointestinal tract and in

which patients who achieved normokalemia were

the presence of ZS-9, potassium equilibrium was

randomized to receive ZS-9, 5 g (n ¼ 45), 10 g (n ¼ 51), or

reached relatively quickly (<20 min) (68). Mg2þ after

15 g (n ¼ 56), or placebo (n ¼ 85) daily for 28 days.

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T A B L E 4 Clinical Trials With Sodium Zirconium Cyclosilicate

Trial, First Author, Year (Ref #)

Type of Study

Number of Patients (n)

Intervention

Endpoints

Results

ZS-003 Packham et al., 2015 (71)

RCT Double-blinded Phase III

Potassium levels Reduction of 0.46, 0.54, and 0.73 in the 2.5-, 5-, Patients were randomly 753 patients with Kþ through 48 h and 10-g groups, respectively, and 0.25 mmol/l assigned to thrice-daily: 5.0-6.5 mmol/l with placebo. At 1 h, a significant reduction was 1. ZS-9 treatment with 1.25, 561 patients had seen after the 10-g dose (-0.11 vs. þ0.01 mmol/l 2.5, 5.0, or 10 g or eGFR <60 ml/min/ 2 in placebo; p ¼ 0.009). At 48 h, 99% of patients 1.73 m , 502 patients 2. placebo for 48 h. þ treated with 10 g t.i.d. and 94% with 5 g t.i.d. had diabetes, and 300 Patients with K 3.5–4.9 mmol/l at 48 h were achieved normal Kþ. In the maintenance phase, patients had history the patients who received 5 g and 10 g ZS-9, randomly assigned to of HF serum Kþ levels were maintained at 4.76 mmol/l once-daily ZS-9 or and 4.58 mmol/l, respectively, compared with placebo on days 3–14. >5.10 mmol/l in the placebo group (p < 0.01) after ZS-9 withdrawal. Adverse events: Initial phase (ZS-9 group 12.9% and placebo group 10.8%). Maintenance phase (ZS-9 group 25.1% and placebo group 24.5%).

ZS-002 Ash et al., 2015 (70)

RCT Double-blinded Phase II

90 patients with Kþ 5.0-6.5 mmol/l

Potassium levels Mean baseline serum Kþ was 5.1 mmol/l. Serum Kþ Patients were randomly assigned to thrice-daily: through 48 h was significantly decreased by 0.92  1. ZS-9 treatment with 0.3 0.52 mmol/l at 38 h. Urinary potassium excretion (n ¼ 12), 3.0 (n ¼ 24) or significantly decreased with 10-g ZS-9 as 10 g (n ¼ 24) or compared with placebo at day 2 (þ15.8  21.8 2. Placebo (n ¼ 30) for 48 h mmol/l/24 h vs. þ8.9  22.9 mmol/l/24 h). Mild GI adverse events in 20% patients in treatment group vs. 10% in placebo group. Only 90 patients in study.

258 patients with Kþ >5.0 mmol/l

All patients treated with Potassium levels thrice-daily 10 g ZS-9 through 8 to for 48 h. Patients with 29 days in normokalemia (3.5–5.0 each group mmol/l) at 48 h were randomly assigned to receive once-daily 5, 10, or 15 g of ZS-9 or placebo for 28 days

In the open-label phase, mean Kþ levels decreased from 5.6 to 4.5 mmol/l at 48 h. Median time to normalization was 2.2 h, 84% achieved normokalemia by 24 h and 98% by 48 h. In the randomized phase, Kþ level declined though days 8-29 with all ZS-9 doses vs. placebo (4.8 mmol/l, 4.5 mmol/l, and 4.4 mmol/l for 5 g, 10 g, and 15 g, respectively; 5.1 mmol/l for placebo. The proportion of patients with mean Kþ <5.1 mmol/l during days 8-29 was higher in all treatment groups vs. placebo (80%, 90%, and 94% for the 5-, 10-, and 15-g groups, respectively, vs. 46% with placebo. Edema was more common in the ZS-9, 15-g group (2%, 2%, 6%, and 14% in placebo, 5-g, 10-g, and 15-g groups, respectively). Hypokalemia developed in 10% and 11% in the 10-g and 15-g treatment groups, respectively, vs. none in the 5-g or placebo group.

94 patients with Kþ >5.0 mmol/l; 60 receiving RAASi

All patients treated with thrice-daily 10 g ZS-9 for 48 h. Patients with normokalemia (3.5–5.0 mmol/l) at 48 h were randomly assigned to receive once-daily 5 g, 10 g, or 15 g of ZS-9 or placebo for 28 days

87 (93%) achieved normokalemia after 48 h. In the randomized phase, despite constant RAASi doses, Kþ level declined though days 8-29 with all ZS-9 doses vs. placebo (4.7 mmol/l, 4.5 mmol/l, and 4.4 mmol/l for 5 g, 10 g, and 15 g, respectively; 5.2 mmol/l for placebo. The proportion of patients with mean Kþ <5.1 mmol/l during days 8-29 was higher in all treatment groups vs. placebo (83%, 89%, and 92% for the 5-g, 10-g, and 15-g dose groups, respectively, vs. 40% with placebo. Edema was more common in the maintenance phase, occurring in 1, 2, and 5 patients in the 5-g, 10-g, and 15-g dose groups, respectively, vs. 1 patient in the placebo group.

ZS-004 or HARMONIZE RCT Kosiborod et al., Double-blinded 2014 (69) Phase III

HARMONIZE HF subgroup Anker et al., 2015 (73)

Double-blinded Phase III

Potassium levels through 8 to 29 days in each group

eGFR ¼ estimated glomerular filtration rate; HARMONIZE ¼ Hyperkalemia Randomized Intervention Multi-Dose ZS-9 Maintenance Another; t.i.d. ¼ 3 times a day; ZS-9 ¼ sodium zirconium cyclosilicate; other abbreviations as in Tables 1 and 2.

Maintenance of normokalemia was observed with

E f fi c a c y i n H F . The effect of ZS-9 on the subgroup

once-daily doses of ZS-9 at 5, 10, and 15 g, with serum

population of HF patients (n ¼ 94) from the

potassium levels of 4.8, 4.5, and 4.4 mmol/l, respec-

HARMONIZE trial showed that all 3 doses of ZS-9 were

tively, versus placebo (5.1 mmol/l). It was also demon-

effective in lowering and maintaining normal potas-

strated that patients with higher baseline potassium

sium levels, including those taking RAASi therapy

levels experienced greater absolute reductions.

with similar safety profiles (73) (Table 4).

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Hyperkalemia in HF

S a f e t y a n d t o l e r a b i l i t y . In the ZS-003 trial, the

hypertension in 7% (48 of 684) patients (79). More

rates of adverse events were similar to those in the

prospective data are needed to further explore the

ZS-9 group (12.9%) and the placebo groups (10.8%),

effect of patiromer on blood pressure.

with diarrhea being the most common complication in both groups (1.7% in ZS-9 vs. 2.2% in placebo). In HARMONIZE, adverse events occurred in 53%, 29%, and 44% of patients receiving ZS-9 doses of 5, 10, and 15 g, respectively, compared with 32% in patients who received placebo. Edema was more common in the 15-g group. Gastrointestinal side effects were similar to those in the placebo group (14% placebo vs. 7%, 2%, and 9% for the 5-, 10-, and 15-g groups, respectively) (70).

EFFECT ON ALDOSTERONE Renal hypoperfusion in HF activates the RAAS, which increases norepinephrine and angiotensin II, causing vasoconstriction and release of aldosterone through alpha-adrenergic and angiotensin II type 1 receptors (74). RAAS stimulation contributes to salt and water retention, renal potassium excretion, and activation of the sympathetic nervous system (75). RAASi inhibit aldosterone, resulting in decreased potassium excretion (11,76). Weir et al. (77) analyzed the effect of

CHRONIC USE FOR PREVENTION OF HYPERKALEMIA The treatment of acute hyperkalemia is well recognized. It is equally important to develop treatments for chronic use by both previously hyperkalemic patients and those who are at risk of developing hyperkalemia. The utility of this approach will require long-term data for the safety of these compounds, as well as the efficacy of such an approach to optimize RAASi use. This will require both clinical outcomes and quality-of-life data comparing patients’ willingness to continue the therapy versus using other approaches, such as dietary potassium restrictions in patients who are already on a lowcarbohydrate and low-salt diet. Also, in case of noncompliance and abrupt discontinuation of therapy by patients, the risk of rebound hyperkalemia in patients optimized to RAASi therapy in HF needs to be studied.

ONGOING TRIALS FOR PATIROMER AND ZS-9

patiromer on serum aldosterone levels in patients with CKD in the OPAL-HK trial. A reduction in plasma

The TOURMALINE (Patiromer With or Without Food

aldosterone levels and in the urine aldosterone-to-

for the Treatment of Hyperkalemia) study is an

creatinine ratio at 4 and 8 weeks of patiromer use

ongoing trial to determine patiromer’s efficacy and

was observed. Similarly, a reduction in systolic (SBP)

safety when used once daily with or without food,

and diastolic (DBP) blood pressure and in the urinary

focusing more on African American and Hispanic pa-

albumin to creatinine ratio was also observed. Data

tients (NCT02694744) (80). ZS-9 has an ongoing trial

from HARMONIZE showed a 30% reduction in serum

(ZS-005) to evaluate the safety and efficacy of 10 g

aldosterone with ZS9 after 28 days of treatment. It is

3 times a day for 24 to 72 h, followed by a long-term

important to study the clinical relevance of this

maintenance phase once daily for up to 12 months

finding.

(NCT02163499) (81).

EFFECT ON BLOOD PRESSURE

FUTURE DIRECTION

Treating hyperkalemia with patiromer, in addition to

According to HF guidelines, MRAs should not be used

maintenance of RAASi therapy, may improve blood

in patients with eGFR <30 ml/min or serum potas-

pressure control. A subgroup analysis from the

sium levels >5.0 mmol/l (5,6). This leads to the

AMETHYST-DN trial in a cohort of 79 of 306 patients

exclusion of a significant group of HF patients (18% to

with diabetic kidney disease and resistant hyperten-

40%) with reduced ejection fraction who are not

sion (defined as systolic blood pressure [SBP] >140

prescribed MRAs (82,83). Similarly, the use of ACEi or

mm Hg in 4 or more classes of antihypertensive

ARBs is seen only in 55% to 63 % of patients with CKD

drugs), who were treated with patiromer for hyper-

in primary care; however, there is a lack of published

kalemia and continued with RAASi therapy, showed

data quantifying the role of hyperkalemia that results

decreases in SBP and diastolic blood pressure (DBP)

in lack of use of RAASi in this population (84).

of 18  17 mm Hg and 9.0  13 mm Hg, respec-

It is evident that there is a need for better therapies

tively, at the end of 52 weeks of therapy (78). The

for

interim analysis of the 711 patients enrolled in

shown by patiromer and ZS-9 may have a favorable

hyperkalemia. The promising

initial results

an ongoing ZS-9 study (ZS005) to evaluate the long-

impact on this paradigm. Although both compounds

term (52-week) efficacy and safety of ZS-9 showed

have demonstrated positive short- and longer-term

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Hyperkalemia in HF

efficacy and tolerability, the long-term optimization of RAASi with the use of potassium binders needs to

not known. Additionally, in this high-risk group, the efficacy of novel binders may be different.

be evaluated. In addition, further data for their safety

3. Assessing higher doses of RAASi than previously

also need to be considered. This will also provide the

used, for example, a high dose in the setting of

opportunity to study those groups of patients who

acute HF.

were excluded from clinical trials due to hyperkalemia. Although subgroup analysis of HF patients supported the ability of these agents to continue RAASi use in HF, further studies of up-titration to optimal dosing of RAASi in HF are needed (73). On the basis of these evidence gaps, there are 3 proposed areas for future research, as follows:

No trials are ongoing to assess the highlighted gaps in evidence in order to optimize long-term management of HF patients. It also needs to be determined whether these evidence gaps would require largescale morbidity and mortality trials or whether only short-term safety and tolerability trials would suffice by implicitly accepting the fact that if the newer

1. Prevention of hyperkalemia and the ability to

potassium-lowering agents reduced hyperkalemia,

optimize RAASi. We don’t know if this is possible,

then use of RAASi would improve outcomes in pop-

even if hyperkalemia is prevented, as patients may

ulations where they have not been tested specifically.

still be intolerant on the basis of hypotension or REPRINT REQUESTS AND CORRESPONDENCE: Dr.

worsening renal function. 2. Broadening the use of RAASi to patients with eGFR

Javed Butler, Cardiology Division, Stony Brook Uni-

<30 ml/min, who have generally been excluded

versity Health Sciences Center, T-16, Room 080,

from previous trials. These patients may benefit

SUNY at Stony Brook, New York 11794. E-mail: javed.

more from RAASi due to their higher risk, but it is

[email protected].

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KEY WORDS angiotensin-converting enzyme inhibitors, angiotensin-receptor

based decision finding in the treatment of heart failure: REFLECT-HF. Clin Res Cardiol 2014;103: 665–73.

blockers, chronic kidney disease, mineralocorticoid receptor antagonist, patiromer, sodium zirconium cyclosilicate

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