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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

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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 can be life threateningbecause of the associated risk for arrhyth-mias and conduction system abnormalities

(1,2). Generally, a serum potassium level higher than5.0 mmol/l is defined as hyperkalemia (1). Among pa-tients hospitalized for any cause, the prevalence ofhyperkalemia has been estimated at 1% to 10% (3). Pa-tients with chronic kidney disease (CKD), heart fail-ure (HF), and diabetes mellitus and those usingrenin-angiotensin-aldosterone system inhibitors

m the aCardiology Division, Stony Brook University, Stony Brook, New Yo

bor, Michigan; cCardiology Division, Albert Einstein College of Medicine;

nique 9501 and Unité 961, Centre Hospitalier Universitaire, and the Depart

rraine, Nancy, France; eInnovative Clinical Trials, Department of Cardio

ttingen, Germany; and the fCenter for Cardiovascular Drug Development

ool of Medicine, Chicago, Illinois. Dr. Pitt is a compensated board memb

ehringer-Ingelheim, GE Healthcare, Relypsa, BG Medicine, Nile Therapeu

eived grant support from Forest Laboratories and Novartis; and holds sto

rasenc. Dr. Piña is a consultant for the U.S. Food and Drug Administration;

a compensated board member for Boston Scientific; consultant for Novar

althcare, Relypsa, Servier, Boston Scientific, Bayer, Johnson & Johnson, an

d AstraZeneca. Dr. Anker has received honoraria from and is a consulta

althCare AG, ZS Pharma, Relypsa, Novartis Pharma AG, and Vifor Pharma

ies, Astellas, AstraZeneca, Bayer HealthCare AG, CorThera, Cytokineti

ithKline, Ikaria, Johnson & Johnson, Medtronic, Merck, Novartis Pharma

ricor Therapeutics, Protein Design Laboratories, Sanofi, Sigma Tau, So

vena Therapeutics. Dr. Butler has received research support from the Na

d is a consultant for Amgen, Bayer, Boehringer-Ingelheim, Cardiocell, C

nsun. All other authors have reported that they have no relationships rele

nuscript received June 20, 2016; accepted June 28, 2016.

(RAASi) are at 2 to 3 times higher risk for hyperkale-mia (4–6). In hospitalized patients admitted withworsening HF, despite aggressive diuresis, increasesin serum potassium levels are observed (7). Withgrowing numbers of CKD and HF patients takingRAASi and mineralocorticoid receptor antagonists(MRAs), hyperkalemia has become a more commonconcern. Angiotensin-converting enzyme inhibitors(ACEi), angiotensin-receptor blockers (ARBs), andMRAs have proven benefit in patients who are also

rk; bCardiology Division, University of Michigan, Ann

Bronx, New York; dINSERM, Centre d’Investigation

ment of Cardiology, Nancy University, Université de

logy and Pneumology, University Medical Center,

and Innovation, Northwestern University Feinberg

er for Novartis; consultant for Takeda, AstraZeneca,

tics, Merck, Forest Laboratories, and Novartis; has

ck in Relypsa, BG Medicine, Nile Therapeutics, and

and is on the advisory board of Novartis. Dr. Zannad

tis, Takeda, AstraZeneca, Boehringer-Ingelheim, GE

d Resmed; and is a compensated speaker with Pfizer

nt for ThermoFisher Scientific, Cardiorentis, Bayer

. Dr. Gheorghiade has consulted for Abbott Labora-

cs, DebioPharm SA, Errekappa Terapeutici, Glaxo-

AG, Otsuka Pharmaceuticals, Palatin Technologies,

lvay Pharmaceuticals, Takeda Pharmaceutical, and

tional Institutes of Health and the European Union;

elladon, Novartis, Trevena, Relypsa, Z Pharma, and

vant to the contents of this paper to disclose.

ABBR EV I A T I ON S

AND ACRONYMS

ACEi = angiotensin-converting

enzyme inhibitor

ARB = angiotensin receptor

blocker

CKD = chronic kidney disease

eGFR = estimated glomerular

filtration rate

HF = heart failure

MRA = mineralocorticoid

receptor antagonist

RAASi = renin-angiotensin-

aldosterone system inhibitor

ZS-9 = sodium zirconium

cyclosilicate

Sarwar et al. J A C C V O L . 6 8 , N O . 1 4 , 2 0 1 6

Hyperkalemia in HF O C T O B E R 4 , 2 0 1 6 : 1 5 7 5 – 8 9

1576

at high risk for hyperkalemia (8). Even morechallenging is the fact that many patientshave several of these comorbidities simulta-neously and are attempting to use 1 or moreRAASi together. Thus, many patients inneed for these therapies are unable totolerate them, or if these medicines are pre-scribed, they are prescribed at less thanoptimal dosages. RAASi discontinuation forhyperkalemia represents an undesirable clin-ical compromise. Importantly, many clinicaltrials have excluded patients with advancedCKD and those with or at risk for hyperkale-mia, leaving a critical evidence gap in phar-macotherapy for these high-risk patients.

POTASSIUM HOMEOSTASIS

Under normal circumstances, the kidneys areresponsible for excreting 90% of the potassium that isconsumed daily (9). Most of the potassium is freelyfiltered by the glomerulus and is absorbed in theproximal tubule and loop of Henle, and only 10%reaches the distal tubule (10,11). Principal cells in therenal collecting duct are responsible for secretingexcess potassium from the circulation into thetubular lumen and excreting it in the urine. Luminalmembrane potassium channels that respond to theelectrochemical gradient for potassium generated bythe basolateral membrane sodium-potassium adeno-sine triphosphatase (Naþ/Kþ-ATPase) and a luminalmembrane sodium channel accomplish this secretion.In states of potassium depletion, potassium secretionby the principal cells is inhibited, and the luminalmembrane hydrogen-potassium adenosine triphos-phatase (Hþ/Kþ-ATPase) is activated in the interca-lated cells to reabsorb the potassium (Figure 1) (12).Secretion of potassium by the collecting duct isregulated by the serum aldosterone and sodiumconcentration in the distal tubule (11). Aldosterone isregulated by the renin-angiotensin-aldosterone sys-tem (RAAS) and by serum potassium levels (13). InHF, when the renal perfusion pressure falls, juxta-glomerular cells secrete renin, which convertsangiotensinogen to angiotensin II, in conjunctionwith angiotensin-converting enzyme (ACE) (14).Angiotensin II acts on zona glomerulosa of the adre-nal glands and stimulates aldosterone secretion. Highserum potassium is also a stimulator of aldosterone,which lowers serum potassium by stimulating potas-sium excretion from distal tubule (13,15).

Increased potassium intake increases kaliuresis,and it is postulated that potassium receptorsalso reside in gastrointestinal tract, enterohepatic

circulation, and liver (12). A role for the pituitarygland in potassium homeostasis has been shown inrats where renal potassium excretion was impairedpost-hypophysectomy (16,17). In human subjects,hourly increased renal and gastrointestinal potassiumexcretion after 35 mmol of oral potassium persistedfollowing aldosterone blockade, suggesting agastrointestinal-renal kaliuretic signaling axis that isindependent of the changes in serum potassiumconcentration and aldosterone (18).

HYPERKALEMIA IN PATIENTS WITH HF:

ROLE OF RENAL DISEASE AND THERAPY

Approximately 26million people globally haveHF (19).These patients, by virtue of their disease, comorbid-ities, and medical therapy, are at risk for hyper-kalemia. Hyperkalemia can be classified into 2 types:

1. Inherent hyperkalemia: includes hormonal disor-ders (e.g., Addison’s disease, hyporeninemichypoaldosteronism), diabetes mellitus, CKD, anddiseases with cell membrane instability that cancause intracellular and extracellular potassiumshifts (20,21); and

2. Treatment-related hyperkalemia: medications(e.g., RAASi, MRA, nonsteroidal anti-inflammatorydrugs, diuretic agents, heparin).

In addition, excess dietary intake of foods high inpotassium or sodium supplements containing highpotassium content can cause hyperkalemia (22–24)(Figures 2 and 3). MRAs or RAASi increase the risk ofhyperkalemia (25). As the use of RAASi has increased,especially in higher doses and in combination (26–29),hyperkalemia has become more common. The use ofACEi is attributed to the development of hyper-kalemia in 10% to 38% of hospitalized patients (3,30),whereas hyperkalemia develops in up to 10% of theoutpatient population within 1 year of prescribingRAASi (31). Patients with impaired renal function andthose with diabetes are at higher risk of hyperkalemia(11). In the PARADIGM-HF (Prospective comparison ofARNI with ACEI to Determine Impact on Global Mor-tality and morbidity in Heart Failure) trial, despiterenal function, potassium-based eligibility criteria,and a run-in period, approximately 15% of patients inboth the LCZ696 and the enalapril arms developedhyperkalemia (32). In a recent HF study (n ¼ 19,194),11.3% of patients had hyperkalemia over a meanfollow-up of 3.9 � 3.2 years, yielding an incidence of2.90/100 person-years (95% confidence interval [CI]:2.78 to 3.02) (33).

Similarly, in RALES (Randomized AldactoneEvaluation Study), although the beneficial effect of

FIGURE 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∼67% of filtered K

Low K: Reabsorbs∼3% of filtered K

DT

Glom ProximalTubule

CollectingDuct

CCD

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

Low K: Reabsorbs∼25% of filtered K

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

Low K: Reabsorbs∼10% of filtered K

MTAL

OMCD

Loop ofHenle IMCD

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

Low K: Reabsorbs∼1% of filtered K

Lumen

Secretion

Blood

Principal cell

Na+

K+

K+ 2K+

3Na+

ATPADP+Pi

ADP+Pi ADP+Pi

ADP+Pi

ATP ATP

ATP

3Na+

K+

K+

2K+

H+ H+

Blood

Lumen

Intercalated cell

Reabsorption

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.

J A C C V O L . 6 8 , N O . 1 4 , 2 0 1 6 Sarwar et al.O C T O B E R 4 , 2 0 1 6 : 1 5 7 5 – 8 9 Hyperkalemia in HF

1577

spironolactone continued in the treatment groupversus placebo, despite higher potassium levels in thetreatment group (4.54 � 0.49 mmol/l vs. 4.28 � 0.50mmol/l, respectively; p < 0.001), a higher mortalityrisk was observed when potassium levels increasedto more than 5.5 mmol/l in the spironolactone group(34). The beneficial effect of spironolactone comparedwith placebo was maintained at all levels of hyper- orhypokalemia, showing a U-shaped relationship be-tween potassium levels and mortality, with highermortality rates in patients randomized to placebo at allpotassium levels (p < 0.0001) (34). The use of spi-ronolactone increased after the RALES trial; however,the hospitalizations attributed to hyperkalemia also

increased to 11 of 1,000 patients in 2001 comparedwith 2.4 of 1,000 patients in 1994 (p < 0.001) (8).Additionally, the rate of in-hospital hyperkalemia-associated death in HF patients increased from 0.10 of1,000 patients in 1994 to 0.39 of 1,000 patients in 2001(p < 0.001) (8). These data underscore both theimportance of hyperkalemia when augmenting RAASiand the need for careful monitoring of electrolytes.

Hyperkalemia risk is increased with concomitantCKD in HF patients. In 105,388 HF patients enrolled inthe ADHERE (Acute Decompensated Heart FailureNational Registry) study, more than 60% of patientshad kidney disease (35). In patients with CKD, theprevalence of hyperkalemia can be up to 20% and is

FIGURE 2 Hyperkalemia in Heart Failure Patients Increases as Renal Function Declines

35

30

25

20

15

10

5

0Baseline eGFR ≥60 Baseline eGFR <60 No WRF WRF

Baseline Renal Function Intra-study Change in Renal Function

6.0

15.4

8.5

25.6

6.7

18.2

13.3

30.2

Rate

of H

yper

kale

mia

(% o

f Pat

ient

s)

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.

Sarwar et al. J A C C V O L . 6 8 , N O . 1 4 , 2 0 1 6

Hyperkalemia in HF O C T O B E R 4 , 2 0 1 6 : 1 5 7 5 – 8 9

1578

associated with the risk of mortality and majoradverse cardiovascular events and discontinuationof RAASi (36). The use of RAASi in patients withcardiovascular diseases, including myocardialinfarction, HF, diabetes, and CKD, can reduce adverselong-term consequences (37). However, most trialsexcluded patients with moderate or severe CKD,which is common in HF, especially at advanced stages(37).

The use of effective and safe potassium bindersnow provides an opportunity to assess RAASi in suchpatients. In the meantime, several steps can be takento attempt RAASi therapy in such patients. First,potassium supplements or salt substitutes containing

FIGURE 3 Prevalence of Heart Failure and Diabetes Mellitus in Rela

35

30

25

20

15

10

5

0

Prev

alen

ce (%

)

>60 45-59 30-44 15-29 >15eGFR mL/min/1.73m2

N= 924,136 153,426 34,275 7085 1373

1.0

5.2

12.6

20.818.5

Heart Failure

Prevalence of heart failure and diabetes mellitus may increase the risk o

Modified with permission from Go et al. (23). eGFR ¼ estimated glomer

potassium should be stopped or used judiciouslyunder supervision. It may be preferable to use lowerdoses of both RAASi and MRAs rather than higherdoses of one and not to use the other class of drugsaltogether. Higher doses of ACEi and ARBs are asso-ciated with better outcomes in HF with reducedejection fraction (38,39). However, this benefit ismodest, and lower doses were better tolerated. Thus,lower doses of RAASi are better than avoiding thesedrugs. In case of worsening renal function, the risk ofhyperkalemia and the rate of decline in renal functionshould be assessed. There are no specific guidelines,but generally, ACEi or ARB doses may be reducedor stopped, either temporarily or permanently, with

tion to Chronic Kidney Disease

>60 45-59 30-44 15-29 >15

924,136 153,426 34,275 7085 1373

8.612.3

19.6

28.231.1

Diabetes

f hyperkalemia on the basis of disease and concomitant therapies.

ular filtration rate.

TABLE 1 Treatment Options for Hyperkalemia

Severity Treatment

Emergent Calcium gluconateInsulinBeta-adrenoreceptor agonists

Intermediate DialysisLoop diuretic agentsThiazide diuretic agentsSodium bicarbonate in patients with metabolic

acidosis.

Maintenance Review of medication list and dietary supplementsLow-potassium dietReduce dose of renin-angiotensin-converting enzyme

inhibitors. Stop offending medicationsPotassium-binding resins

J A C C V O L . 6 8 , N O . 1 4 , 2 0 1 6 Sarwar et al.O C T O B E R 4 , 2 0 1 6 : 1 5 7 5 – 8 9 Hyperkalemia in HF

1579

estimated glomerular filtration rate (eGFR) <15 to 30ml/min, whereas they can be used in dialysis patientswith careful monitoring. Currently, MRAs are con-traindicated in patients with eGFR <30 ml/min. Inhospitalized patients receiving intravenous diureticagents who have rapid changes in renal function withor without hypotension, holding or lowering RAASi iscommon. However, this decision should be individ-ualized, and currently, evidence for what to do insuch a situation is not available.

According to the Health Care Cost and UtilizationProject database, in 2011, the estimated total annualcharges for Medicare admissions with hyperkalemiaas the primary diagnosis were $697 million, theaverage Medicare length of stay was 2 to 3 days withmean charges of $24,085 per day, and one-third of thepatients were discharged to another short-term hos-pital or home health care (40).

CURRENT MANAGEMENT OF HYPERKALEMIA

The treatment of hyperkalemia depends on theseverity and cause (Table 1).

EMERGENT MANAGEMENT. In patients with electro-cardiographic changes and/or potassium levels>7.0 mmol/l, intravenous calcium is administered toprevent arrhythmia (41). To rapidly lower potassiumlevels, insulin and beta-2 adrenoreceptor agonists areused to redistribute potassium from the extracellularto the intracellular space; however, this is a tempo-rary measure (11).

INTERMEDIATE MANAGEMENT. Dialysis can be usedin patients with poor kidney function or in those whoare unresponsive to other treatments. In patientswith CKD and metabolic acidosis, sodium bicarbonatetherapy is an effective strategy to minimize increasesin the potassium concentration (42). Loop diureticagents are effective in excretion of potassium by thedelivery of sodium in the collecting duct (11).

MAINTENANCE. In addition to dietary potassiumintake restriction, lowering the dose of drugs thatimpair potassium excretion or administering themevery other day or totally discontinuing them is oftenneeded (11). This should include a review of alldietary and herbal supplements and salt substitutesas well. Potassium-binding resins can also be used;however, until recently, the only approved ion-exchange resin was sodium polystyrene sulfonate,which was not well tolerated and may cause colonicnecrosis and intestinal injury (43).

Patiromer has recently become available for use,expanding the armamentarium of therapies availablefor the management of these patients. However,chronic therapy targeting prevention of hyperkalemiaand subsequent optimization of RAASi needs furtherstudies.

PATHOPHYSIOLOGY OF

HYPERKALEMIA IN HF

A close association exists between serum potassiumand plasma renin concentration in HF (44). Reninelevation due to renal hypoperfusion in HF causes theexcretion of potassium by stimulating the synthesis ofaldosterone, whereas high potassium concentrationscan directly inhibit the RAAS (45). ACEi block thestimulatory effect of angiotensin II on aldosteronesecretion, whereas ARBs prevent angiotensin II frombinding to its adrenal receptors (45). In addition, thesedrugs may interfere with angiotensin I producedlocally within the adrenal glands (14). RAASi, such asACEi, ARBs, MRAs, and direct renin inhibitors, areassociated with an increased risk of hyperkalemia,particularly when administered in combination (46).This risk is increased in patients with stage 3 or higherCKD; hence, dual RAAS blockade is of concern in thisscenario (47). Hyperkalemia can also develop sec-ondary to decreased sodium delivery to the distalnephron, aldosterone deficiency, and abnormal func-tioning of the cortical collecting tubule (11). Theseabnormalities can result from the effects of otherdrugs or from underlying diseases.

In normal circumstances, the serum aldosteroneconcentration varies inversely with delivery ofsodium to the distal nephron, so that potassiumexcretion remains independent of changes in extra-cellular fluid volume (9–11). However, in HF,increased aldosterone causes increased absorption ofsodium in proximal tubules, resulting in itsdecreased delivery to the distal nephrons, which inturn, results in decreased potassium excretion. Theuse of RAASi in the presence of tubulointerstitialrenal disease increases the risk of hyperkalemia by

TABLE 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, withethenylbenzene, 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+

exchangerBinds 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 beadvanced to 16.8 g to 25.2 gat weekly intervals (60)

5–15 g, once daily, oral (71)

Storage temperature Room temperature (43) 2�C–8�C (60) Room temperature (71)

Efficacy

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)

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 magnesiumion; Naþ ¼ sodium ion; QTc ¼ QT interval corrected for heart rate.

Sarwar et al. J A C C V O L . 6 8 , N O . 1 4 , 2 0 1 6

Hyperkalemia in HF O C T O B E R 4 , 2 0 1 6 : 1 5 7 5 – 8 9

1580

promoting the development of resistance to alreadyreduced RAASi-induced aldosterone levels (11,13).Many of the diseases that affect tubular function alsoimpair the release of renin and result in hypo-reninemic hypoaldosteronism and impaired tubularfunction (11).

NEW TREATMENTS FOR HYPERKALEMIA

Sodium polystyrene sulfonate has significant limita-tions for chronic use and has not been evaluated inlarge randomized trials (48–50). Its use inHF is limited,as it may worsen edema by exchanging sodium forpotassium ions (51). In addition, it is poorly toleratedand associated with severe and even fatal gastroin-testinal complications (50,52). In a small single-centerrandomized controlled trial in 33 outpatients with CKDand mild hyperkalemia (5.0 to 5.9 mmol/l), a sodiumpolystyrene sulfonate dosage of 30 g orally once dailyfor 7 days achieved normokalemia in 73% of the pa-tients versus 38% of patients in the placebo group (53–55). Patiromer (patiromersorbitex calcium/RLY5016;Veltassa; Relypsa, Red Wood City, California) and so-dium zirconium cyclosilicate (ZS-9) (AstraZeneca,Cheltenham, Pennsylvania) are 2 new and promisingpotassium-lowering compounds (Table 2 and CentralIllustration).

PATIROMER

Patiromer, is a nonabsorbed polymer designed tobind potassium in the gastrointestinal tract andreduce serum potassium levels, which was recentlyapproved by the U.S. Food and Drug Administration(FDA) (56).

STRUCTURE AND MECHANISM OF ACTION.

Patiromer (Figure 4) is synthesized as a 100-mm beadwith optimized flow and viscosity properties and ismade in a high-yield 2-step process with polymeri-zation followed by hydrolysis (57). Patiromer pre-dominantly uses calcium as the exchange cation,instead of sodium (57). Patiromer is administered asonce daily with food and promotes ionization of thepolymeric potassium-binding moiety under pH con-ditions present along the extent of the gastrointes-tinal tract, predominantly in the colon (43). As aresult of this structure, patiromer exchanges mono-valent (sodium ion [Naþ]) and divalent (calcium ion[Ca2þ] and magnesium ion [Mg2þ]) cations throughthe length of the gastrointestinal tract and preferen-tially binds potassium in the colon, where the con-centration of this cation is substantially higher thanthat of Naþ, Ca2þ, or Mg2þ (58). The net effect is areduction in serum potassium under hypokalemic

CENTRAL ILLUSTRATION Novel Agents for the Management of Hyperkalemia: Characteristicsand Considerations

K

• Normalizes and maintainspotassium levels

• Reduces aldosterone levels and blood pressure

Evidence gaps:• Prevention of hyperkalemia• Limitation of RAASi optimization due to

hypotension or worsening renal function

in patients excluded from previous trials

than used in previous trials

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

nausea• Hypomagnesemia• Hypokalemia

NEW TREATMENTS FOR HYPERKALEMIA:Patiromer (RLY5016) and

Sodium zirconium cyclosilicate (ZS-9)

RAASi

RAASi

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.

J A C C V O L . 6 8 , N O . 1 4 , 2 0 1 6 Sarwar et al.O C T O B E R 4 , 2 0 1 6 : 1 5 7 5 – 8 9 Hyperkalemia in HF

1581

conditions in the colon, where increased potassiumsecretion through big potassium channels representsan adaptive response to elevated serum potassium(59). Hypomagnesemia is reported in clinical trials ofpatiromer; however, there were no significantneuromuscular or cardiac abnormalities noted withtreatment (56,60–62).CLINICAL TRIALS WITH PATIROMER (RLY5016).

Patiromer has been evaluated in 3 clinical trials(Table 3).Efficacy . OPAL-HK (Study Evaluating the Efficacyand Safety of Patiromer for the Treatment of Hyper-kalemia) included 237 CKD patients with potassiumlevels of 5.1 to 6.4 mmol/l, who were taking RAASi(60). There were 2 phases: a 4-week phase in whichpatients received patiromer 4.2 g or 8.4 g twice a day,

followed by an 8-week randomized withdrawalphase, in which patients were randomly assigned tocontinue the initial dose or were switched to placebo.Seventy-six percent of patients achieved normal po-tassium levels in 4 weeks. During the withdrawalphase, the hyperkalemia incidence was 15% in thetreatment arm and 60% in the placebo group. TheAMETHYST-DN (Patiromer in the Treatment ofHyperkalemia in Patients With Hypertension andDiabetic Nephropathy) study (61) was a multicenter,open-label, dose-ranging, randomized trial with atotal of 306 patients with diabetes mellitus, CKD(eGFR: 15 to <60 ml/min/1.73 m2), and serum potas-sium level >5.0 mmol/l. All patients received RAASibefore and during study treatment. Treatment withpatiromer in both the mild and the moderate

FIGURE 4 Chemical Structure of Patiromer

Chemical structure of active ingredient

Calcium-sorbitolcounterion

Patiromeranion

OH OH

OH OH[Ca2+(HO OH)0.5]0.5

H2O-O O

**

Fm n p

*

n**

*p

m = number of 2-fluoro-2-proprenoate groupsn, p = number of crosslinking groupsH2O = associated water*Indicates an extended polymeric network

m = 0.91n + p = 0.09

From patiromer (Veltassa) prescribing information (Relypsa, Inc., Red Wood

City, California). Ca ¼ calcium; F ¼ fluorine; O ¼ oxygen; OH ¼ hydroxide.

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hyperkalemia groups resulted in a reduction frombaseline level at 4 weeks, which was maintainedthrough 52 weeks. It is important to note that in boththe OPAL-HK and the AMETHYST-DN trials, patientswere able to maintain RAASi therapy.Efficacy in HF. A subgroup analysis of the OPAL-HKtrial 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 to5.0 mmol/l. In the second withdrawal phase, hyper-kalemia occurred in 52% (n ¼ 22) of patients takingplacebo and 8% (n ¼ 27) of those taking patiromer (p <

0.001). The PEARL-HF (Evaluation of Patiromer inHeart Failure Patients) trial studied patiromer in pa-tients with chronic HF (56). Patients either hadeGFR <60 ml/min or a history of hyperkalemia result-ing in discontinuation of a RAASi. A total of 155 patientswere started on 25 mg/day of spironolactone and wererandomized to double-blind treatment with 30 g/dayof patiromer or placebo for 4 weeks. At 4 weeks, thepatiromer treatment group had lowered potassiumlevels (7.3% vs. 24.5%, respectively; p¼0.015) andwasmore likely to have spironolactone increased to50 mg/day (91% vs. 74%, respectively; p ¼ 0.019).Safety and tolerab i l i ty . The most common sideeffect in the initial phase of the OPAL-HK trial wasconstipation (11%), followed by diarrhea (8%),

hypomagnesemia (8%), and hypokalemia (3%). Mag-nesium replacement therapy was initiated in 4% ofsubjects during the initial phase. In the withdrawalphase, constipation, diarrhea, and nausea (4% each)were the most common gastrointestinal eventsreported with patiromer, whereas these eventsoccurred in none of the patients with placebo (63). Inthe PEARL-HF trail, the most common adverse eventswere gastrointestinal complaints (12%, n ¼ 21: flatu-lence, diarrhea, constipation, or vomiting) (56).

Hypokalemia is an important concern in HF (64).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 placebopatients (p ¼ 0.094) (56). In addition, hypomagnese-mia (<1.8 mg/dl) was observed in 24% of the patientsin the treatment group versus 2.1% in the placebogroup. Adverse events resulting in patient with-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%binding to clopidogrel, furosemide, metformin,warfarin, metoprolol, verapamil, and lithium, whereasthere was >50% binding to amlodipine, cinacalcet,ciprofloxacin, levothyroxine, quinidine, thiamine,and trimethoprim (65). In addition, a 30% reductionwas seen in the availability of valsartan and rosiglita-zone in preclinical coadministration studies in rats(56). Of 14 drugs tested initially for drug–drug in-teractions, 12 were tested in healthy volunteers (phase1) in randomized, open-label studies, using a 3-waycrossover design, according to FDA recommenda-tions. The results released by the manufacturershowed no clinically meaningful reduction in absorp-tion and no impact on peak concentration (Cmax) oflithium, trimethoprim, verapamil, andwarfarin. Therewas also no clinically meaningful reduction in ab-sorption, although there was some reduction in Cmax,of amlodipine, cinacalcet, clopidogrel, furosemide,and metoprolol and reduced absorption and Cmax ofciprofloxacin, levothyroxine, and metformin. Quini-dine and thiamine were not tested (66). Meanwhile,the manufacturer, on the basis of in vitro studies,recommends taking these medications at least 6 hbefore or 6 h after patiromer, whereas the data fromin vivo studies are being reviewed by the FDA (67).

SODIUM ZIRCONIUM CYCLOSILICATE

Sodium zirconium cyclosilicate (ZS-9) is an inorganic,orally administered potassium-binding compoundthat has recently been investigated in phase II and IIIclinical trials.

TABLE 3 Clinical Trials With Patiromer

Trial, First Author,Year (Ref. #) Type Number of Patients Intervention Endpoints Results

OPAL-HKWeir et al., 2015 (60)

RCT 237 CKD patients onRAASi withhyperkalemia

(Kþ 5.1–6.5 mmol/l)

Phase 1: 4–week initial treatmentwith 4.2 or 8.4 g twice daily

Phase 2: 8-week randomizedwithdrawal phase. Patientswho had decreased Kþ to 3.8–5.1 mmol/l, received treatmentvs. placebo

Change in median Kþ

levels in first 4 weeksof each phase

The mean Kþ level at baseline was 5.6 � 0.5mmol/l (5.3 � 0.6 mmol in patients with mildhyperkalemia and 5.7 � 0.4 mmol in thosewith moderate-to-severe hyperkalemia).

At 4 weeks, mean � SE change in Kþ levels frombaseline was �1.01 � 0.03 mmol/l (95% CI:�1.07 to �0.95; p < 0.001).

The change in patients with mild hyperkalemiawas �0.65 � 0.05 mmol/l (95% CI: �0.74 to�0.55), and the change in those withmoderate-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% ofpatients in the placebo group had recurrenceof hyperkalemia (Kþ >5.5 mmol/l) vs. 15% inthe treatment group (p < 0.001).

At the end of phase 2, 55% of HF patients onplacebo and 100% of treatment grouppatients were receiving RAASi.

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

RCT 102 patients with CKDand HF

Phase 1: 4-week treatment with4.2 or 8.4 g twice daily

Phase 2: 8-week withdrawal phasein patients with Kþ to 3.8–5.1mmol/l, received treatment vs.placebo

Change in median Kþ

levels in first 4 weeksof each phase

Phase 1 at 4 weeks: the mean SE change in serumKþ from baseline was �1.06 � 0.05 mmol/l(95% CI: �1.16 to �0.95; p < 0.001).

In withdrawal phase at 8 weeks, 52% of patientsin the placebo group had a recurrence ofhyperkalemia (Kþ >5.5 mmol/l) vs. 8% in thetreatment group (p < 0.001). At the end ofphase 2, 55% of HF patients on placebo and100% of treatment group patients werereceiving RAASi.

PEARL-HFPitt et al., 2011 (56)

RCT 105 HF patients onstandard therapy andspironolactone

Patient randomized to 3 g/day oftreatment vs. placebo for4 weeks

Change in median Kþ

levels at 4 weeksTreatment 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 toreach the target dosage of spironolactone(50 mg/day at 4 weeks, increased from25 mg/day). A greater number of patients inthe treatment group were able to have theirspironolactone dose increased vs. the placebogroup (91% vs. 74%; p ¼ 0.019).

AMETHYST-DNBakris et al.,

2015 (61)

RCT 306 diabetic patients onRAASi with Kþ

>5.0 mmol/l

Varying patiromer twice-dailydosing in:

1. Mild hyperkalemia group, doseof 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 <5.0mmol/l

Change in median Kþ

levels at 4 weeks orbefore dose titration.

Adverse events up to 52weeks

1. Mild hyperkalemia group: Kþ at 4 weeks was0.35 (95% CI: 0.22–0.48) mmol/l for the4.2-g twice-daily starting-dosage group, 0.51(95% CI: 0.38–0.64) mmol/l for the 8.4-gtwice-daily starting-dosage group, and 0.55(95% CI: 0.42–0.68) mmol/l for the 12.6 gtwice-daily starting-dosage group.

2. Moderate hyperkalemia group: Kþ reduction at4 weeks was 0.87 (95% CI: 0.60–1.14) mmol/lfor the 8.4 g twice-daily starting-dosagegroup, 0.97 (95% CI: 0.70–1.23) mmol/l forthe 12.6 g twice-daily starting-dosage group,and 0.92 (95% CI: 0.67–1.17) mmol/l for the16.8 g twice-daily starting-dosage group(p<0.001 for all groups). This effect wasmaintained through week 52, where meandaily patiromer dosages were similar to thoseat week 4 through week 8 (19.4 g/day vs.27.2 g/day) in patients with mild vs. moderatehyperkalemia, respectively.

Adverse events: hypomagnesemia (8.6%), mild tomoderate 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-HK¼ Study Evaluating the Efficacyand 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 controlledtrial; other abbreviations as in Table 1.

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STRUCTURE AND MECHANISM OF ACTION. ZS-9 isadministered as a once-daily dose, and its physio-logical ion channels filter ions on the basis of theirdiffering diameters. ZS-9 has a structure that mimics

physiological potassium channels and selectivelycaptures potassium cations. This is accomplished bythe use of a selectivity filter (62). In order to passthrough the channel, an ion must shed its hydration

FIGURE 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.

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sphere and only then can it interact with the carbonyloxygens in the channel. Both sodium and potassiumare of the size that would fit in the ZS-9 structure ring,but after shedding their hydration shells, only Kþ hasa size sufficient to fit into the ZS-9 pore size (68)(Figure 5).

ZS-9 is not absorbed in the gastrointestinal tractand is available as insoluble, free-floating, odorless,tasteless, white crystalline powder. It is an inorganiccompound, unlike sodium polystyrene sulfonate, andspecifically traps monovalent (potassium andammonium) over divalent cations (like Ca2þ or Mg2þ).Because it is not systemically absorbed, the risk ofsystemic toxicity is low (69–71). The potassium ex-change capacity of ZS-9 was studied using a simulatedgastrointestinal tract medium with various concen-trations of ZS-9 doses and medium pH (68). It wasobserved that in the simulated gastric fluid (pH w1.2),there is an initial drop in potassium concentration,which reverses soon afterward. In the small intestine(pH w4.5), there is an immediate uptake of potas-sium, followed by a small release, with equilibriumreached in approximately 20 min. In the large intes-tine (pH 6.8), there is a rapid uptake of potassiumduring the first 10 min, followed by continued butslower uptake over the next hour with no further in-crease thereafter. It was also observed that the bind-ing capacity of ZS-9 increased proportionately withincreasing concentration >0.5 to 50 mg/ml. Theseresults led to the conclusion that, in environmentsmimicking the human gastrointestinal tract and inthe presence of ZS-9, potassium equilibrium wasreached relatively quickly (<20 min) (68). Mg2þ after

shedding its water coat has a diameter of 1.44 �A (72).This diameter is energetically unfavorable for Mgþ2 tointeract with the oxygen bonds in the ZS-9 structuralring (68).

CLINICAL TRIALS WITH ZS-9. Sodium zirconiumcyclosilicate has been evaluated in 4 clinical trials(Table 4).Efficacy . The effect of ZS-9 over 14 days, including atthe 48-h acute phase was demonstrated in the ZS-003trial (71). Overall, 753 patients with potassium levelsbetween 5.0 and 6.4 mmol/l were given various dosesof ZS-9, and the exponential rate of change in serumpotassium levels at 48 h was measured. A dose-related reduction in potassium levels was observed.A similar short-term phase II study by Ash et al. (70),using lower various doses of ZS-9 provided favorableresults with significant reductions in potassiumlevels, even at lower doses, with only mild con-stipation reported (70).

The HARMONIZE (Hyperkalemia RandomizedIntervention Multi-Dose ZS-9 Maintenance Another)trial (69) enrolled ambulatory patients with hyper-kalemia (>5.1 mmol/l). In the first 48 h, the patients(n ¼ 258) received 10 g of ZS-9 3 times a day, whichresulted in lowering of potassium levels from 5.6mmol/l to 4.5 mmol/l. The median time to normali-zation was 2.2 h. At 24 h, 84% of patients were nor-mokalemic, and by 48 h, 98% were normokalemic.This was followed by the maintenance phase, inwhich patients who achieved normokalemia wererandomized to receive ZS-9, 5 g (n¼45), 10 g (n¼ 51), or15 g (n ¼ 56), or placebo (n ¼ 85) daily for 28 days.

TABLE 4 Clinical Trials With Sodium Zirconium Cyclosilicate

Trial, First Author,Year (Ref #) Type of Study Number of Patients (n) Intervention Endpoints Results

ZS-003Packham et al.,

2015 (71)

RCTDouble-blindedPhase III

753 patients with Kþ

5.0-6.5 mmol/l561 patients had

eGFR <60 ml/min/1.73 m2, 502 patientshad diabetes, and 300patients had historyof HF

Patients were randomlyassigned to thrice-daily:

1. ZS-9 treatment with 1.25,2.5, 5.0, or 10 g or

2. placebo for 48 h.Patients with Kþ 3.5–4.9mmol/l at 48 h wererandomly assigned toonce-daily ZS-9 orplacebo on days 3–14.

Potassium levelsthrough 48 h

Reduction of 0.46, 0.54, and 0.73 in the 2.5-, 5-,and 10-g groups, respectively, and 0.25 mmol/lwith placebo. At 1 h, a significant reduction wasseen after the 10-g dose (-0.11 vs. þ0.01 mmol/lin placebo; p ¼ 0.009). At 48 h, 99% of patientstreated with 10 g t.i.d. and 94% with 5 g t.i.d.achieved normal Kþ. In the maintenance phase,the patients who received 5 g and 10 g ZS-9,serum Kþ levels were maintained at 4.76 mmol/land 4.58 mmol/l, respectively, compared with>5.10 mmol/l in the placebo group (p < 0.01)after ZS-9 withdrawal.

Adverse events: Initial phase (ZS-9 group 12.9% andplacebo group 10.8%). Maintenance phase (ZS-9group 25.1% and placebo group 24.5%).

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

RCTDouble-blindedPhase II

90 patients with Kþ

5.0-6.5 mmol/lPatients were randomly

assigned to thrice-daily:1. ZS-9 treatment with 0.3

(n ¼ 12), 3.0 (n ¼ 24) or10 g (n ¼ 24) or

2. Placebo (n ¼ 30) for 48 h

Potassium levelsthrough 48 h

Mean baseline serum Kþ was 5.1mmol/l. Serum Kþ

was significantly decreased by 0.92 �0.52mmol/l at 38h. Urinary potassium excretionsignificantly decreased with 10-g ZS-9 ascompared with placebo at day 2 (þ15.8 � 21.8mmol/l/24 h vs. þ8.9 � 22.9 mmol/l/24 h).

Mild GI adverse events in 20% patients in treatmentgroup vs. 10% in placebo group. Only 90patients in study.

ZS-004 or HARMONIZEKosiborod et al.,

2014 (69)

RCTDouble-blindedPhase III

258 patients with Kþ

>5.0 mmol/lAll patients treated with

thrice-daily 10 g ZS-9for 48 h. Patients withnormokalemia (3.5–5.0mmol/l) at 48 h wererandomly assigned toreceive once-daily 5, 10,or 15 g of ZS-9 orplacebo for 28 days

Potassium levelsthrough 8 to29 days ineach group

In the open-label phase, mean Kþ levels decreasedfrom 5.6 to 4.5 mmol/l at 48 h. Median time tonormalization was 2.2 h, 84% achievednormokalemia by 24 h and 98% by 48 h.

In the randomized phase, Kþ level declined thoughdays 8-29 with all ZS-9 doses vs. placebo (4.8mmol/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 alltreatment groups vs. placebo (80%, 90%, and94% 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). Hypokalemiadeveloped in 10% and 11% in the 10-g and 15-gtreatment groups, respectively, vs. none in the5-g or placebo group.

HARMONIZEHF subgroupAnker et al., 2015 (73)

Double-blindedPhase III

94 patients with Kþ

>5.0 mmol/l;60 receiving RAASi

All patients treated withthrice-daily 10 g ZS-9for 48 h. Patients withnormokalemia (3.5–5.0mmol/l) at 48 h wererandomly assigned toreceive once-daily 5 g,10 g, or 15 g of ZS-9 orplacebo for 28 days

Potassium levelsthrough 8 to29 days ineach group

87 (93%) achieved normokalemia after 48 h.In the randomized phase, despite constant RAASi

doses, Kþ level declined though days 8-29 withall ZS-9 doses vs. placebo (4.7 mmol/l, 4.5mmol/l, and 4.4 mmol/l for 5 g, 10 g, and 15 g,respectively; 5.2 mmol/l for placebo. Theproportion of patients with mean Kþ <5.1 mmol/lduring days 8-29 was higher in all treatmentgroups vs. placebo (83%, 89%, and 92% for the5-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 patientin the placebo 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-9¼ sodium zirconium cyclosilicate; otherabbreviations as in Tables 1 and 2.

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Maintenance of normokalemia was observed withonce-daily doses of ZS-9 at 5, 10, and 15 g, with serumpotassium levels of 4.8, 4.5, and 4.4 mmol/l, respec-tively, versus placebo (5.1 mmol/l). It was also demon-strated that patients with higher baseline potassiumlevels experienced greater absolute reductions.

Efficacy in HF. The effect of ZS-9 on the subgrouppopulation of HF patients (n ¼ 94) from theHARMONIZE trial showed that all 3 doses of ZS-9 wereeffective in lowering and maintaining normal potas-sium levels, including those taking RAASi therapywith similar safety profiles (73) (Table 4).

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Safety and to lerab i l i ty . In the ZS-003 trial, therates of adverse events were similar to those in theZS-9 group (12.9%) and the placebo groups (10.8%),with diarrhea being the most common complicationin both groups (1.7% in ZS-9 vs. 2.2% in placebo). InHARMONIZE, adverse events occurred in 53%, 29%,and 44% of patients receiving ZS-9 doses of 5, 10, and15 g, respectively, compared with 32% in patientswho received placebo. Edema was more common inthe 15-g group. Gastrointestinal side effects weresimilar 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, whichincreases norepinephrine and angiotensin II, causingvasoconstriction and release of aldosterone throughalpha-adrenergic and angiotensin II type 1 receptors(74). RAAS stimulation contributes to salt and waterretention, renal potassium excretion, and activationof the sympathetic nervous system (75). RAASi inhibitaldosterone, resulting in decreased potassium excre-tion (11,76). Weir et al. (77) analyzed the effect ofpatiromer on serum aldosterone levels in patientswith CKD in the OPAL-HK trial. A reduction in plasmaaldosterone levels and in the urine aldosterone-to-creatinine ratio at 4 and 8 weeks of patiromer usewas observed. Similarly, a reduction in systolic (SBP)and diastolic (DBP) blood pressure and in the urinaryalbumin to creatinine ratio was also observed. Datafrom HARMONIZE showed a 30% reduction in serumaldosterone with ZS9 after 28 days of treatment. It isimportant to study the clinical relevance of thisfinding.

EFFECT ON BLOOD PRESSURE

Treating hyperkalemia with patiromer, in addition tomaintenance of RAASi therapy, may improve bloodpressure control. A subgroup analysis from theAMETHYST-DN trial in a cohort of 79 of 306 patientswith diabetic kidney disease and resistant hyperten-sion (defined as systolic blood pressure [SBP] >140mm Hg in 4 or more classes of antihypertensivedrugs), who were treated with patiromer for hyper-kalemia and continued with RAASi therapy, showeddecreases in SBP and diastolic blood pressure (DBP)of �18 � 17 mm Hg and �9.0 � 13 mm Hg, respec-tively, at the end of 52 weeks of therapy (78). Theinterim analysis of the 711 patients enrolled inan ongoing ZS-9 study (ZS005) to evaluate the long-term (52-week) efficacy and safety of ZS-9 showed

hypertension in 7% (48 of 684) patients (79). Moreprospective data are needed to further explore theeffect of patiromer on blood pressure.

CHRONIC USE FOR PREVENTION

OF HYPERKALEMIA

The treatment of acute hyperkalemia is well recog-nized. It is equally important to develop treatmentsfor chronic use by both previously hyperkalemic pa-tients and those who are at risk of developinghyperkalemia. The utility of this approach willrequire long-term data for the safety of these com-pounds, as well as the efficacy of such an approach tooptimize RAASi use. This will require both clinicaloutcomes and quality-of-life data comparing pa-tients’ willingness to continue the therapy versususing other approaches, such as dietary potassiumrestrictions in patients who are already on a low-carbohydrate and low-salt diet. Also, in case ofnoncompliance and abrupt discontinuation of ther-apy by patients, the risk of rebound hyperkalemia inpatients optimized to RAASi therapy in HF needs tobe studied.

ONGOING TRIALS FOR PATIROMER AND ZS-9

The TOURMALINE (Patiromer With or Without Foodfor the Treatment of Hyperkalemia) study is anongoing trial to determine patiromer’s efficacy andsafety when used once daily with or without food,focusing more on African American and Hispanic pa-tients (NCT02694744) (80). ZS-9 has an ongoing trial(ZS-005) to evaluate the safety and efficacy of 10 g3 times a day for 24 to 72 h, followed by a long-termmaintenance phase once daily for up to 12 months(NCT02163499) (81).

FUTURE DIRECTION

According to HF guidelines, MRAs should not be usedin patients with eGFR <30 ml/min or serum potas-sium levels >5.0 mmol/l (5,6). This leads to theexclusion of a significant group of HF patients (18% to40%) with reduced ejection fraction who are notprescribed MRAs (82,83). Similarly, the use of ACEi orARBs is seen only in 55% to 63 % of patients with CKDin primary care; however, there is a lack of publisheddata quantifying the role of hyperkalemia that resultsin lack of use of RAASi in this population (84).

It is evident that there is a need for better therapiesfor hyperkalemia. The promising initial resultsshown by patiromer and ZS-9 may have a favorableimpact on this paradigm. Although both compoundshave demonstrated positive short- and longer-term

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efficacy and tolerability, the long-term optimizationof RAASi with the use of potassium binders needs tobe evaluated. In addition, further data for their safetyalso need to be considered. This will also provide theopportunity to study those groups of patients whowere excluded from clinical trials due to hyper-kalemia. Although subgroup analysis of HF patientssupported the ability of these agents to continueRAASi use in HF, further studies of up-titration tooptimal dosing of RAASi in HF are needed (73). On thebasis of these evidence gaps, there are 3 proposedareas for future research, as follows:

1. Prevention of hyperkalemia and the ability tooptimize RAASi. We don’t know if this is possible,even if hyperkalemia is prevented, as patients maystill be intolerant on the basis of hypotension orworsening renal function.

2. Broadening the use of RAASi to patients with eGFR<30 ml/min, who have generally been excludedfrom previous trials. These patients may benefitmore from RAASi due to their higher risk, but it is

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

3. Assessing higher doses of RAASi than previouslyused, for example, a high dose in the setting ofacute HF.

No trials are ongoing to assess the highlighted gapsin evidence in order to optimize long-term manage-ment of HF patients. It also needs to be determinedwhether these evidence gaps would require large-scale morbidity and mortality trials or whether onlyshort-term safety and tolerability trials would sufficeby implicitly accepting the fact that if the newerpotassium-lowering agents reduced hyperkalemia,then use of RAASi would improve outcomes in pop-ulations where they have not been tested specifically.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Javed Butler, Cardiology Division, Stony Brook Uni-versity Health Sciences Center, T-16, Room 080,SUNY at Stony Brook, New York 11794. E-mail: javed.butler@stonybrookmedicine.edu.

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KEY WORDS angiotensin-convertingenzyme inhibitors, angiotensin-receptorblockers, chronic kidney disease,mineralocorticoid receptor antagonist,patiromer, sodium zirconium cyclosilicate