Managing Hyperkalemia-Potential Impact on the Use of

RAAS Inhibitors

Barry Greenberg MDDistinguished Professor of Medicine

Director Advanced Heart Failure Treatment ProgramUniversity of California, San Diego

25th Annual San Diego Heart Failure SymposiumJune 28-29, 2019

La Jolla, CA

Case Presentation

• 63 yo female with longstanding NICM admitted for weight gain of 23 lbs, SOB and ankle swelling.

• PMH- diabetes, CKD stage II-III

• Outpatient cardiac meds:- carvedilol 25 mg bid- sacubitril/valsartan 49/51 mg bid- spironolactone 12.5 mg daily- bumetanide 1 mg bid- KCl 20 meq daily

Physical Examination

• BP 126/84 mmHg, pulse 86 reg, RR 24, O2

sat 94%

• SOB but able to speak in full sentences

• JVP 15 cm, bibasilar rales, S3, 2-3 + LE

edema

• Labs – Na+ 134, K+ 4.8, Cr 1.56, BUN 43

Course in the Hospital• Patient is given 2 mg bumetanide IV and

supplemental nasal oxygen.

• She has a urine output of 2.3 L over the first 24 hours with only 1 L input. She feels less SOB.

• Diuresis continues over the next 3 days with progressive improvement in her symptoms.

• Weight is down 7 lbs from admission.

However….

• Labs on the morning of day 4 in the hospital show a creatinine and BUN that are both slightly elevated from baseline at 1.66/49. Her K+ is 5.4.

• What are your next steps?

Hyperkalemia in Patients During Heart Failure Hospitalization

Formiga F. Eu J Int Med. 2019 Feb;60:24-30

5.0 meq/l

Factors Associated With Hyperkalemia

Shah KB et al, JCF Volume 46, Issue 5, 2005, 845–849

Association Between Renal Function and Hyperkalemia in HF Patients

Drug-Induced Hyperkalemia

• ACEi’s, ARB’s and sacubitril-valsartan combination• K+-sparing diuretics, spironolactone

• Bactrim (trimethoprim), pentamidine• NSAIDs

• Beta blocker (both non-selective and B2 selective)

• Heparin• Digoxin (supratherapetuic levels)

• Succinylcholine (intubation in ICU, Surgery)* • Calcineurin inhibitors (cyclosporine, tacrolimus [FK506])

Modified from Palmer BF. N Engl J Med. 2004;351(6):585-592.

Medications Associated with Hyperkalemia

2016 ACC/AHA/HFSA Heart Failure Guideline Update

Pharmacological Treatment for Stage C HFrEF

ARNI = angiotensin receptor blocker and neprilysin inhibitor; COR = class of recommendation; LOE = level of evidence.

Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e147-239.

1. Granger CB, et al. Lancet. 2003;362:772-776. 2. The SOLVD Investigators. N Engl J Med. 1991;325:293-302. 3. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.

Impact of ACEIs, ARBs and ARNIs on Mortalityin Patients with HFrEF

10

20

30

ACEInhibitor2

AngiotensinReceptorBlocker1

0

Dec

reas

e in

Mor

talit

y (%

)

18%

20%

AngiotensinNeprilysinInhibitor3

15%

2013 AHA/ACC/HFSA Guidelines

Aldosterone receptor antagonists are recommended in patients with NYHA class II-IV, LVEF of ≤35%,to reduce morbidity and mortality.

I IIa IIb III

Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e147-239.

554/3,319 478/3,313 .85 .008(.75, .96)

Hazard Log-rankPlacebo

Aldosterone

Antagonist Ratio P Value

Primary Endpoint: All-Cause Mortality

EPHESUSPost-MI

284/822386/841 .70 <.001(.60, .82)

RALESAdvanced HF

Trial

Pitt B. N Engl J Med. 2003;348:1309-1321. Pitt B. N Engl J Med. 1999;341:709-717.

Zannad F, et al. N Engl J Med. 2011;364:11-21

Trials With Mineralicorticoid

Receptor Antagonists

EMPHASISMilder HF

.76(.62, .93)

.008356/1373 249/1364

Admitted 2011-2013 withWorsening of Chronic HF

(n=1250)

>1 year Follow-Up(n=444)

Not Candidates for MRA Based on

Inclusion/ Exclusion Criteria (n=173)

Fulfilled Criteria for MRA Use(n=271)

<1 Year Follow Up(n=806)

No MRA on Admission

(n=210)

MRA on Admission(n=61)

Discharged without MRA

(n=164)MRA Initiated at DC

(n=46)

Receiving an MRA at Time of Hospital Discharge(n=105)

MRA Maintained during

Hospitalization (n=59)

MRA Discontinued

(n=2)

Only 105 of 271 (39%) Eligible Patients Were Taking anMRA at Hospital Discharge

DC with MRA

(n=105) (-) OFF MRA(n=35)

(+) ON MRA(n=70)

• (+) ON MRA (n = 70)– MRA Tx to discharge, LVAD or OHT– Without interruption– With 1 or fewer drug discontinuations and

tolerated therapy for > 180 days (6 months)

• (-) OFF MRA (n = 35)– 2 or more discontinuations– 1 discontinuation without restart and tx

duration < 180 days (6 months)

A

0

5

10

15

0

2

4

6

8

10

0

2

4

6

8

All-Cause Hospitalizations

+ -

p = 0.0010

Cardiovascular Hospitalizations

+ -

p = 0.0032

Heart Failure Hospitalizations

+ -

p = 0.0019 (+) ON MRA (-) OFF MRA

0.0

0.5

1.0

1.5

2.0

2.5

Episodes of Hyperkalemia/Patient

p = 0.0006+

-

0 500 1000 1500 20000

50

100

Days

Perc

ent S

urvi

val

(%)

p < 0.02 (+) ON MRA(-) OFF MRA

Survival

DC with MRA

(n=105) (-) OFF MRA(n=35)

(+) ON MRA(n=70)

• (+) ON MRA (n = 70)– MRA Tx to discharge, LVAD or OHT– Without interruption– With 1 or fewer drug discontinuations and

tolerated therapy for > 180 days (6 months)

• (-) OFF MRA (n = 35)– 2 or more discontinuations– 1 discontinuation without restart and tx

duration < 180 days (6 months)

A

0

5

10

15

0

2

4

6

8

10

0

2

4

6

8

All-Cause Hospitalizations

+ -

p = 0.0010

Cardiovascular Hospitalizations

+ -

p = 0.0032

Heart Failure Hospitalizations

+ -

p = 0.0019 (+) ON MRA (-) OFF MRA

0.0

0.5

1.0

1.5

2.0

2.5

Episodes of Hyperkalemia/Patient

p = 0.0006+

-

0 500 1000 1500 20000

50

100

Days

Perc

ent S

urvi

val

(%)

p < 0.02 (+) ON MRA(-) OFF MRA

Survival

Stopping an MRA is associated with worse outcomesincluding increased mortality

Use of GDMT in HFrEF – Results of the CHAMP-HF Registry

McMurray et al., NEJM. 2014.

Patients Excluded Due to Elevated K+ Levels During Run-in Period Veils Number of Patients with Elevated K+ Due to Treatment

Hyperkalemia Was Common in PARADIGM-HF

Long-Term Hyperkalemia Management Strategies

Strategy Limitation

Dietary K+ restriction of 40-60 mmol/day

Potassium is common ingredient in many foodsRestricts consumption of healthy foodsLow K+ diet often expensive

KayexalateWarnings related to serious gastrointestinal (GI) adverse eventsPrecaution related to sodium

RAASi reduction Limiting the prescription of drugs known to be effective in these populations

Low K+ Diet Is the First Step in Chronic Management, but

Compliance Is Difficult

Potassium-Rich Foods

KAYEXALATE (Sodium Polystyrene Sulfonate) Is Not

the Answer • Can cause colonic necrosis (particularly when used with

sorbitol).

• Should not be used in patients who do not have normal bowel function or in patients at risk of developing constipation or impaction.

• Administration presents patient with obligatory salt and water load (e.g. each g of SPS contains 100 mg of Na+ and the average daily dose of SPS is 15-60 g/day).

FDA: Food and Drug AdministrationReferences: http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm186845.htm accessed 12/10/2014Kayexalate PI December 2010. Sterns 2010; J Am Soc Nephrol 21: 733–735, 2010.; Kayexalate is a registered trademark of Sanofi Aventis

Changes in RAAS Inhibitor Dose In Response to Hyperkalemia

Epstein M et al. Am J Manag Care. 2015;21:S212-S220

52%41%

16% 21%

22%

26%

0%

15%

30%

45%

60%

75%

Perc

ent o

f Hyp

erka

lem

ia E

vent

s Maintained Dose Down-titrated Dose Discontinued

Moderate-to-Severe Hyperkalemia

47%

Among Patients on RAAS Inhibitor at Maximum Dose

Mild Hyperkalemia (Potassium 5.1-5.4 mEq/L)

(23,556 events) (11,608 events)

38%

Percent Mortality by Prior RAAS Inhibitor Dose

Epstein M et al. Am J Manag Care. 2015;21:S212-S220

9.8%13.7%

5.0% 4.1%

20%

27%

10% 8.2%

22.4%

30.1%

13.1%11.0%

0%

10%

20%

30%

40%

CKD Stages 3-4(N = 43,288

total patients acrossdose categories)

Heart Failure(N = 20,529

total patients acrossdose categories)

Diabetes(N = 79,087

total patients acrossdose categories)

Total Population(N = 201,655

total patients acrossdose categories)

% P

atie

nts

Maximum Dose Submaximum Dose Discontinued

Hyperkalemia in Heart Failure

• Unmet need for a safe and effective chronic therapy for prevention and treatment of hyperkalemia in HF patients on ACE-I, ARBs, MRA, and ARNI therapies.

Characteristics of New Potassium

Binding AgentsCharacteristic Patiromer Zirconium Cyclosilicate (ZS-9)

GI Absorption Non-absorbable Non-absorbable

Molecular structure Organic polymer

Mechanism of Action Ca-K exchange Na-K exchange

Relative K Affinity - 25-fold > Na

Site of Action Colon Upper/Lower GI tract

K selectivity relative to SPSS - 120-fold

Onset of [K]p lowering 7 hours 2 hours

crystalline inorganic cation exchange compound

Baseline serum K+ 5.1-<5.5 mEq/L(Mild Hyperkalemia)

Baseline serum K + 5.5-<6.5 mEq/L(Moderate/Severe Hyperkalemia)

Part A: 4-week Treatment Phase (Single-Blind)

Primary endpoint:• Mean change in serum potassium

from Baseline to Week 4

Secondary endpoint:• Proportion of patients with serum

potassium level of 3.8 mEq/L to < 5.1 mEq/L at Week 4

Subjects with CKD* on RAASi

(n=243)

8.4g per day(total daily dose)†

(n=92)

16.8g per day (total daily dose)†

(n=151)

Week 4 Part A Baseline Part A

Starting Patiromer Dose

All patients were on stable dose of at least one RAAS inhibiting agents*estimated glomerular filtration rate 15-60 ml/min/1.73m2

† dose titrated as needed to maintain target serum K+ 3.8 mEq/L to < 5.1 mEq/L

Patiromer:OPAL-HK

1. VELTASSA [package insert]. Redwood City, CA. Relypsa, Inc. 2015. 2. Weir M, et al. N Engl J Med. 2015;372(3):211-21.

OPAL-HK Study Part A:Efficacy Results

Patiromer Starting DoseBaseline K+ [Mean (SD)]: 5.31 mEq/L (0.57)

(n=90)

5.74 mEq/L (0.40)

(n=147)

Overall Population*5.58 mEq/L (0.51)

(n=237)

-0.65

-1.23

-1.01

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

Cha

nge

in

Seru

m P

otas

sium

(mEq

/L)

(95% CI -0.74, -0.55)

(95% CI -1.31, -1.16)

(95% CI -1.07, -0.95)

Mild HKModerate/Severe HKTotal

Primary Endpoint:

Weir M, et al. N Engl J Med. 2015;372(3):211-221.

OPAL-HK: Primary and Secondary Efficacy Endpoints

Weir MR, et al. N Engl J Med. 2015;372(3):211-221.

Base-line

Mea

n Se

rum

K+

(mEq

/L)

Secondary Efficacy Endpoint:

76% of subjects had serum K+ in the target

range (3.8 to <5.1 mEq/L) at week 4

Study included 243 patientswith CKD who were takinga RAAS blocker

Phase 3 Part B: Exploratory Endpoints

0%

20%

40%

60%

80%

100%

Placebo

Patiromer62%

16%

44%

94%

Requiring any adjustment of RAASi (ie, down-titration or discontinuation) or

patiromer dose increase due to

hyperkalemia at any time during Part B

Receiving any dose of a RAASi at the

end of Part B

Pro

po

rtio

n o

f S

ub

ject

s (%

)P<0.001* P<0.001*

Weir MR, et al. N Engl J Med. 2015;372(3):211-221.

Mean Change in Serum PotassiumOver 1 Year (AMETHYST-DN)

Mean (95% CI) Serum Potassium over 52 weeks

Bakris GL, et al. JAMA 2015;314(2):151-161.

Mea

n (9

5% C

I) Se

rum

Pot

assi

um (m

Eq/L

)

Study Visit (week) Follow-Up (day)

Baseline Serum K+ ˃5.0 – 5.5 mEq/L

Baseline Serum K+ ˃5.5 – ˂6.0 mEq/L

BL 2 4 6 8 12 16 20 24 28 32 36 40 44 48 52 14 28

N= 301 (start of study)

N= 173 (study end)

ZS-9: A Novel First-in-Class Inorganic Crystalline Compound Designed

Specifically to Trap K+

Adapted from: Stavros F, et al. PLoS One. 2014;9(12):e114686.

In Vitro, ZS-9 is More Selective for Potassium than Kayexalate (SPS)

Adapted from: Stravos et al. PLOSONE 2014

ZS-9 Lowers K+ in Hyperkalemic Patients

Kosiborod M, et al. JAMA. 2014;312(21):2223-2233.

Effect of Sodium Zirconium Cyclosilicate on Potassium Lowering for 28 Days Among Outpatients With Hyperkalemia: The HARMONIZE Randomized Clinical Trial JAMA. 2014;312(21):2223-2233.

Mean Serum Potassium Levels Over 48 Hours With ZS-9

Dose-Dependent Serum K+ Reduction Over 48 Hours in HF Patients on RAASi

Source: El-Shahawy M, et al. Oral Presentation During a Late-Breaking Clinical Trial Session at the Heart Failure Society of America (HFSA) 18th Annual Scientific Meeting, Sep 15, 2014,

New Therapies For Hyperkalemia

• Hyperkalemia is common in patients with HF, CKD and/or

diabetes.

• High levels of potassium may lead to dose reduction or

discontinuation of RAAS inhibitors.

• Current treatments for hyperkalemia have limitations.

• Both patiromer and ZS-9 are newly available agents that

are safe and effective to treat hyperkalemia.

• Use of these new agents are likely to become important

adjuncts to heart failure therapy.