use of adjuncts in ahf potassium binders

Use of adjuncts in AHF: potassium binders

Alexandre MebazaaDepartment of Anesthesiology and Critical Care

University Hospital Saint Louis – LariboisièreUniversity Paris 7; INSERM – UMR 942

Conflicts of interestHonoraria for lectures:• Orion, AbbVie, Alere, Edwards, Novartis,

Roche, Vifor

Consultancy:• Cardiorentis, Novartis, Sphingotec

Hyperkalemia

• Is increasingly present in cardiovascular area

• Increasing number of diabetes, chronic kidney disease

• Use of RAAS inhibitors

Packham DK et al NEJM 2014

K+K+K+

ZS-9 PROPERTIES

u Unique microporous zirconium silicate compound

u Designed to be selective for K+ trapping

u Insoluble and highly stable

u Non-systemically absorbed

u Builds on long history of Zr use in dialysis and other biomedical applications

ZS-9 Crystal Structure

Average Width of Micropore

Opening 3Å

ZS-9 Selective Potassium Trap

Acute effect of Sodium Zirconiumcyclosilicate

Packham DK et al NEJM 2014Patients: CKD, DM, HF, RAASi

Effect of ZS-9 withdrawal

Packham DK et al NEJM 2014

Kosiborod et al, JAMA 2014

HARMONIZE: Open label phase (1)Rapid drop in serum potassium


10Confidential and Proprietary |

Open Label Phase:Consistent Efficacy in All Subgroups

-0.8

-1.5

*P value <0.0001

Error bars represent ±95 confidence intervals Kosiborod et al, JAMA 2014

Harmonize: Randomized phase (2)


Adverse events need to be still followed in the future


Pitt B et al Eur Heart J 2011

14

Patiromer: Physical & Chemical Properties

Patiromer

Free-flowing powder of small, spherical beads (~100 µm).

Active moiety is a Ca2+ exchange polymer that binds K+ and increases fecal K+ excretion.

Site of action is the lumen of the colon:- K+ is the most abundant cation;- Residence time of the polymer is

the longest.

Light Microscopy Image

Electron Microscopy Image

KayexalatePatiromer

15

Prevention of Hyperkalemia:Patiromer - PEARL-HF Study Design

Spiro 50 mg

1° : Change serum K+

2° : Incidence K+ > 5.5 Spironolactone dose titration

Tolerability/safety

If K+ ≤ 5.1 (day 15)

4-w

eeks

Spiro 25 mg

Subjects with chronic HF, aged 18 or older, clinically indicated to receive spironolactone

1. CKD (eGFR <60 mL/min) and on ≥ 1 ACEI or ARB or βB; or2. Documented Hx hyperK+ < 6 mo*3. K+ > 4.3 – 5.1 mEq/L

* Leading to d/c of RAASi or BB.** No patiromer dose titration.

Placebon ≈ 50

Patiromer 30 g/day**n ≈ 50

4-w

eeks


16

PEARL-HF Primary Efficacy Endpoint: Change From Baseline in Serum K+ (LOCF) by Study Visit

Spironolactone increased to 50 mg/day on Day 15 if K ≤ 5.1

Spironolactone initiated at 25 mg/d on Day 1

*P < 0.01**P < 0.001

***

**** ** **

N=49

N=55

3


17

PEARL-HF: Proportion of Subjects With Serum K > 5.5 mEq/L by eGFR

Pitt B, Anker SD, Bushinsky DA, et al. Eur Heart J. 2011;32(7):820-828.Pitt B. Paper presented at: HFSA Annual Scientific Meeting; September 12-15, 2010; San Diego, CA.

0.250.19

0.390000000000002

0.56

0.07 0.07 0.07

0

mean eGFR =81mL/min

mean eGFR ≥60mL/min

0%

10%

20%

30%

40%

50%

60%

Placebo

N=104 n=76 n=28 n=16

P=0.015P=0.125

P=0.041

P<0.05*

% o

f Sub

ject

s


Weir et al. NEJM 2015

Patients with chronic kidney disease who were receiving RAAS inhibitors with serum K 5.1-6.5 mEq/L

Baseline characteristics


20

Relypsa Partiromer: 4-w initial treatment phase

4.0

4.2

4.4

4.6

4.8

5.0

5.2

5.4

5.6

5.8

6.0

Mea

n Se

rum

K+

(mEq

/L)

Mild HK

Moderate/Severe HK

All Subjects

Baseline Week 4Week 2

Secondary Efficacy Endpoint:76% of subjects had serum K+ in the target range

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


8-w withdrawal phase: secondary efficacy endpoint


Adverse events in the initial phase


Treatment of severe hyperkaliemia ?

Kosiborod M et al NEJM 2015

In summary

• Hyper K is frequent in cardiovascular conditions

• Two novels compounds are very active to reduce serum K and to prevent any increase under RAASi

• Indications: CKD, HF, optimisation of RAASi ?

use of adjuncts in ahf potassium binders

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