Addressing the risk of

hyperkalaemia:

Is there a sweet spot for potassium

binding?

Peter van der Meer, MD

Groningen, The Netherlands

June 15, 2019 - Budapest, Hungary

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University Medical Center Groningen

Addressing the risk of hyperkalaemia: Is there a sweet spot for potassium binding?

Peter van der Meer, MD, PhD, FESC

cardiologistUniversity Medical Center Groningen

The Netherlands p.van.der.meer@umcg.nl

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Case

50 year old man

• No medical history

• No current medication

• Family: mother has “heart disease”

• No smoking, no alcohol use

Presents at ER with SOB

Works off-shore on oil plaform

Since 2 weeks progressive SOB

Can normally bike 60-70km Courtesy dr. Brugts

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Physical Examination

BMI: 31.4 BP: 150/82 mmHg, Heart: 78 bpm, systolic murmerLungs: crepitus basal both lungsExtremities: Trace peripheral edema, pulses & neuro intact

Lab values:Hemoglobin: 8.1 mmol/L NTproBNP: 2.058 ng/LCreatinin: 159 umol/L hsTroponin T: 38 ng/LeGFR: 43 ml/mn/1.73 TSH: 2.1 mE/L, fT4:16.2 pmol/LSodium:130 mmol/L Total cholesterol: 4.0 mmol/LPotassium: 5.3 mmol/L LDL-cholesterol: 2.7 mmol/L

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Echo cardiogram

- LVEF: ~25%

- Moderate MR and TR

- No regional wall motion abnormalities

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Cardiac MRI

No late enhancement (excludes myocarditis)

LVEF: 22%

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Therapeutic algorithm for a patient with symptomatic HF with reduced ejection fraction

Ponikowski, …, Van der Meer Eur Heart J 2016

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5 mg 5 mg 5 mg 5 mg 3 mgBumetanide

Ramipril

Carvedilol

Spironolactone

2,5 mg 5 mg 7,5 mg 10 mg 10 mg

- 25 mg 37,5 mg 50 mg 50 mg

- - 25 mg 25 mg 25 mgDaily

dose

Uptitration

Potassium(mmol/L)

5.3 5.1 5.3 5.5 5.6

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Hyperkalaemia is common with RAASi + renal failure

1. Brenner BM et al. N Engl J Med 2001;345:861–9; 2. Miao Y et al. Diabetologia 2011;54:44–50; 3. Lewis EJ et al. N Engl J Med 2001;345:851–60; 4. Ibesartan Highlights of Prescribing Information 2014. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020757s059s067lbl.pdf.

Accessed: January 2018;5. Pitt B et al. N Engl J Med 1999;341:709–17; 6. The RALES Investigators. Am J Cardiol 1996 15;78:902–7. 7. Pitt B et al. N Engl J Med 2003;348:1309–21; 8.

Pitt B et al. Circulation 2008;118:1643–50; 9. Zannad F et al. N Engl J Med 2011;364:11–21; 10. Eschalier R et al. J Am Coll Cardiol 2013 22;62:1585–93

Trial Treatments PopulationOutcome

(risk reduction)Hyperkalaemia rates

RALES5,6 Spironolactone vs

placeboModerate–severe HF 30%

2% >6.0 mEq/L;

13% >5.5 mEq/L

(25 mg in RALES pilot)

EPHESUS7,8 Eplerenone vs

placeboHF post-MI 15%

16% >5.5 mEq/L

5.5% >6.0 mEq/L

EMPHASIS-HF9,10 Eplerenone vs

placeboMild HF 37%

12% >5.5 mEq/L

2.5% >6.0 mEq/L

DM, diabetes mellitus; HF, heart failure; MI, myocardial

infarction; RAASi, renin–angiotensin–aldosterone system

inhibitor

1

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University Medical Center Groningen 1Tromp & Van der Meer, Eur Heart J. suppl 2019

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What are the risks associated with hyperkalaemia?

• Hyperkalaemia was associated with a higher incidence of mortality

• The benefit of spironolactone relative to placebo was maintained (P<0.0001)

Vardeny O et al. Incidence, predictors, and outcomes related to hypo- and hyperkalemia in patients with severe heart failure treated with a mineralocorticoid receptor antagonist, Circ Heart Fail 2014;7:573–9. Available at: http://circheartfailure.ahajournals.org/content/7/4/573.long

The RALES study

3 4 5 6

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00

pa

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ars

20

40

60

80

Week 4 K+ level (mmol/L)

Placebo Spironolactone

Shaded areas represent 95% CI

0

CI, confidence interval; K+, potassium

1

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Hyperkalemia in the real – world (outside RCTs)

1

Inclusion criteria

Previous documented admission with HF requiring diuretic treatment

Treated with furosemide >20 mg/day or equivalent

Not treated or <50% of target dose of ACEi/ARBs and/or beta-blockers

Anticipated uptitration of ACE inhibitors/ARBs and/or beta-blockers

Index : 2174

Validation:1707

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Hyperkalemia and HF across Europe – data from BIOSTAT

1EJHF 2018

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Independent associations with potassium – data from BIOSTAT

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University Medical Center Groningen 1Beusekamp 2018 EJHF

Increased mortality rates in HF patients who aren’t receiving the

recommended RAASi doses

BIOSTAT-CHF

Ouwerkerk W et al. Eur Heart J 2017;

100 200 300 400 500 600 700

0

5

10

15

20

25

30

Recommended ACEi/ARB dose (n=470)

Less than recommended dose owing to symptoms, side effects or

non-cardiac organ dysfunction (n=553)

Less than recommended doses for other reason (n=1077)

Survival time in days

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2 novel potassium binders:

• Patiromer

• ZS-9

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• N=104, chronic HF

• History of Hyper K+

• CKD: GFR<60 ml/min/1.73m2

• Patiromer vs Placebo

• Efficacy Endpoint: change in K+

• Safety endpoint: AE

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Efficacy & Safety

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Van der Meer et al. Eur Heart J 2011

© Vifor Pharma 21

A Multicenter, Double-blind, Placebo-controlled, Randomized Withdrawal,

Parallel Group Study of Patiromer for

the Management of Hyperkalemia in Subjects Receiving

Renin-Angiotensin-Aldosterone System Inhibitor (RAASi) Medications for

the Treatment of Heart Failure

Phase 3b study

ClinicalTrials.gov identifier: NCT03888066

© Vifor Pharma

DIAMOND STUDY DESIGN

22

Hyperkalemia (HK)

History of HK

Potassium Assessment Visit (within 2 weeks of patiromer/placebo

discontinuation) and/or

Follow-up Phone Call (at least 2 weeks after the EOS visit)§

*

*

†

†

‡ ‡ ‡

Objective: To determine if patiromer treatment of subjects who developed hyperkalemia while receiving RAASi medications will result in

continued use of RAASi medications in accordance with heart failure (HF) treatment guidelines and thereby decrease the occurrence of

the combined endpoint of cardiovascular (CV) death and CV hospitalization events compared with placebo treatment.

Primary Endpoint: Time to first occurrence of CV death or CV hospitalization (or equivalent in outpatient clinic)

ClinicalTrials.gov identifier: NCT03888066

© Vifor Pharma

2400 PATIENTS RANDOMIZED AT

APPROXIMATELY 418 SITES PLANNED

23

• Canada

• United States

• Argentina

• Mexico

• Brazil

• Denmark

• France

• Germany

• Italy

• Netherlands

• Spain

• Sweden

• United Kingdom

• Bulgaria

• Czech Republic

• Hungary

• Israel

• Poland

• Russia

• Serbia

• Ukraine

• Georgia

Countries

ClinicalTrials.gov identifier: NCT03888066

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- Received CRT device

- LVEF improved to ~40%

- Genetics: Titin mutation

- Unable to tolerate 50mg spiro

Follow up of the patient

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Conclusions

• Hyperkalemia is common in patients with Heart Failure

• Hyperkalemia is associated with disease severity, renal function and RAASi

• Not achieving recommended dose of RAASi is associated with worse outcome

• Hyperkalemia is associated with less RAASi

• Potassium binding drugs may enable MRA use

• Unclear whether this results in an improved outcome

• DIAMOND-HF will try to answer this question