Use of adjuncts in ahf potassium binders.

Acute Heart Failure , Use of adjuncts in ahf potassium binders.

1. Use of adjuncts in AHF: potassium binders
Alexandre Mebazaa
Department of Anesthesiology and Critical Care
University Hospital Saint Louis – Lariboisière
University Paris 7; INSERM – UMR 942

2. Conflicts of interest
Honoraria for lectures:
•Orion, AbbVie, Alere, Edwards, Novartis,
Roche, Vifor
Consultancy:
•Cardiorentis, Novartis, Sphingotec

3. Hyperkalemia
•Is increasingly present in cardiovascular
area
•Increasing number of diabetes, chronic
kidney disease
•Use of RAAS inhibitors

4. Packham DK et al NEJM 2014

5. K
+
K
+
K
+
ZS-9 PROPERTIES
uUnique microporous
zirconium silicate compound
uDesigned to be selective for
K
+
trapping
uInsoluble and highly stable
uNon-systemically absorbed
uBuilds 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

6. Acute effect of Sodium Zirconium
cyclosilicate
Packham DK et al NEJM 2014
Patients: CKD, DM, HF, RAASi

7. Effect of ZS-9 withdrawal
Packham DK et al NEJM 2014

8. Kosiborod et al, JAMA 2014

9. HARMONIZE: Open label phase (1)
Rapid drop in serum potassium
Kosiborod et al, JAMA 2014

10. 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

11. Harmonize: Randomized phase (2)
Kosiborod et al, JAMA 2014

12. Adverse events need to be still followed
in the future
Kosiborod et al, JAMA 2014

13. Pitt B et al Eur Heart J 2011

14. 14
Patiromer: Physical & Chemical Properties
Patiromer
Free-flowing powder of small,
spherical beads (~100 µm).
Active moiety is a Ca
2+

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. 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-weeks
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; or
2.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.
Placebo
n ≈ 50
Patiromer 30 g/day**
n ≈ 50
4-weeks
Pitt B et al Eur Heart J 2011

16. 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
Pitt B et al Eur Heart J 2011

17. 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.
0.25
0.19
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=0.015
P=0.125
P=0.041
P<0.05*
% of Subjects
Pitt B et al Eur Heart J 2011

18. Weir et al. NEJM 2015
Patients with chronic kidney disease who were receiving RAAS inhibitors
with serum K 5.1-6.5 mEq/L

19. Baseline characteristics
Weir et al. NEJM 2015

20. 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
M
e
a
n

S
e
r
u
m

K
+

(
m
E
q
/
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
Weir et al. NEJM 2015

21. 8-w withdrawal phase: secondary efficacy
endpoint
Weir et al. NEJM 2015

22. Adverse events in the initial phase
Weir et al. NEJM 2015

23. Treatment of severe hyperkaliemia ?
Kosiborod M et al NEJM 2015

24. 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 ?