Sodium zirconium cyclosilicate in hyperkalemia, an article from The New england journal of Medicine, dated January 15 , 2015.

1. SODIUM ZIRCONIUM
CYCLOSILICATE IN
HYPERKALEMIA
David K. Packham, Henrik S. Rasmussen,
Philip T. Lavin, Mohd. A. Elshahawy
The NEW ENGLAND JOURNAL of MEDICINE
January 15 , 2015
Presented by- Guide:
Dr. Ranjeet Dalvi Dr. Abhijeet Pal

2. Abstract
• Background:
Hyperkalemia ( serum potassium level, > 5.0
mmol per lit) (ICD-10 E-87.5)is associated with
increased mortality among patients with heart
failure, chronic kidney disease, or diabetes.
The study was done to find whether sodium
zirconium cyclosilicate (ZS-9), a novel selective
cation exchanger , could lower serum potassium
in patients with hyperkalemia.

3. Methods
• This was a multicenter , two staged, phase 3 trial.
• 753 patients with hyperkalemia received ZS-9 ( at
doses of 1.25g, 2.5 g, 5g , 0r 10g) or placebo
three times daily for 48 hours.
• Patients with normokalemia ( serum potassium
level, 3.5 to 4.9 mmol per liter) at 48 hours were
randomly assigned to receive either ZS-9 or
placebo once daily on days 3 to 14.
• The primary end point was the exponential rate of
change in the mean serum potassium level at 48
hours

4. Introduction
• Hyperkalemia is associated with serious cardiac
dysrhythmia and increased mortality.
• Patients with renal dysfunction and diabetes mellitus
are at increased risk of hyperkalemia.
• Therapies that inhibit RAAS are associated with
increased risk of hyperkalemia in patients with kidney
disease or heart failure.
• Use of existing polymers resins(e.g. sodium
polystyrene sulfonate) has poor side effect profile and
uncertain efficacy
• Thus there is a need for additional agent that can
safely treat hyperkalemia in both patients with acute
disease and chronic disease)

5. About Sodium Zirconium
Cyclosilicate
• Sodium Zirconium cyclosilicate (ZS-9) is a highly
selective cation exchanger that entraps potassium in
intestinal tracts in exchange for sodium and
hydrogen.
• In phase 2 study, ZS-9 as compared with placebo
was associated with significant reduction in serum
potassium levels within first 48 hours of treatment in
patients with stage 3 CKD (estimated GFR 30 to 60
ml per minute per 1.73 m2 and serum potassium
levels of 5 to 6 mmol per liter.

6. Methods
• Duration of study was from November 2012 through November
2013 , total 753 patients were recruited at 65 site in the USA,
Australia and South Africa .
• Eligible patients :
At least 18 years of age
Serum K+ levels of 5.0 to 6.5 mmol per lit
Were able to undergo repeated blood draws.
• Exclusion criterias:
oPatients receiving dialysis had diabetic ketoacidosis
oHad K+ levels > 6.5 mmol /lit
oHad cardiac arrhythmia that required immediate treatment
oHad received organic polymer resins or phosphate binders
within one week before enrollment.

7. Study Design

8. • All concomitant medications were kept constant
throughout the study, including diuretic agents , RAAS
inhibitors, and antidiabetic therapy
• No dietary restrictions were imposed .

9. Safety End Points
• Adverse events,
• Vital signs,
• Findings on electrocardiography,
• Hematologic analyses,
• Relevant laboratory analyses, including the incidence of
hypokalemia (serum potassium level, <3.5 mmol per liter)
and hypomagnesemia (serum magnesium level, <0.6 mmol
per liter).

10. Primary End Points
• Primary efficacy end point for initial phase : was the
between-group difference in the exponential rate of
change in the mean serum potassium level during
the first 48 hours of treatment .
• Efficacy end point for maintenance phase was the
between-group difference in the mean serum
potassium level during the 12 day treatment
interval, which was analysed separately for each of
the four dose groups in the initial phase , as
compared with the corresponding placebo group.

11. Enrollment and Outcome

12. Patient Characteristics at baseline

13. Efficacy
Initial Phase
0.11%
0.16%
0.21%
0.30%
0.09%
ZS-9, 1.25gm ZS-9, 2.5gm ZS-9, 5gm ZS-9, 10gm Placebo
Mean exponential rates of change from baseline
per hour were reduction of
Mean exponential rates of change from baseline per hour

14. 0.46
0.54
0.73
0.25
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
ZS-9,
2.5gm
ZS-9, 5gm ZS-9, 10gm Placebo
Absolute mean reduction in serum K+ at 48 hours
Absolute mean
reduction at 48 hours

15. Efficacy
Initial Phase

16. Efficacy-Maintenance Phase

17. Adverse Events

18. Adverse Events
ZS-9 group Placebo Group
Initial phase 12.9% 10.8%
Maintenance Phase 25.1% 24.5%
The most common adverse event at all dose levels was diarrhea
( frequency in initial phase being 1.8% in ZS-9 group and 2.5% in
placebo group and in maintenance phase 1.7% and 2.2% resp.)

19. Adverse Events(cont.)
• An increase in QTc was observed in ZS-9 group during
initial phase - consistent with decrease in Potassium level.
• Dose dependant
• Mean increase in QTc : 0.03 msec to 7.61 msec on day 2
and 0.38 msec to 10.3 msec on day 3
• Clinically non-significant increase was noted in mean QTc
in each ZS-9 dose group on Day 15.

20. Discussion
Results Indicate that ZS-9 is a potent, selective potassium
trap that corrects hyperkalemia within 48 hours.
A clinically significant effect was observed within 1 hour
after administration.
The decrease in serum potassium level was rapid and
dose dependant, starting at dose 2.5 g three times a day.

21. Reduction in sr. K+ was most pronounced with the highest
K+ level at base line.
ZS-9 effectively normalizes K+ levels in patients receiving
RAAS inhibitors for treatment of heart failure or CKD.#
Drug was equally effective in various subgroups ,
including in patients with a combination of heart failure,
renal failure and diabetes.

22. Advantage over current Therapies
Initial treatment ( insulin, beta-2 agonists and sod.
bicarbonate)- simply promote translocation of
potassium from extracellular space to the
intracellular space- provide relief for 1 to 4 hours.
Nonspecific polymeric exchange resins(Na+ or Ca+
polystyrene sulfonate) - have uncertain efficacy and
poor side-effect profile and associated with serious
GI adverse events ( esp. with Sorbitol)
Low potassium diet- it is restrictive and deprives
patient of many food choices that are otherwise
associated with improved renal outcomes.
Hyperkalemia often prevents therapy with RAAS
inhibitors at the full target dose.

23. Hence there is need for new treatment option -
In patients with acute or chronic disease
That can be safely used in outpatient settings
Have acceptable safety profile
That cause rapid and sustained reduction serum K+ levels

24. About Sodium Zirconium
Cyclosilicate
• Potassium lowering action is based on size
selective micropores in the zirconium silicate
crystal structure.
• The pores trap K+ ions in intestinal tract in
exchange for protons(H+) and sodium(Na+).
• Potassium binding ability is 9 times that of organic
polymer resins.
• Potassium binding of ZS-9 is more selective by a
factor of > 125 for potassium over calcium.
• Zs-9 is insoluble ,does not swell on contact with
water, and is not absorbed systemically.#
• Binding to K+ is throughout the intestinal tract.@

25. Safety of ZS-9
• Overall safety profile of ZS-9 was similar to that of
placebo.
• There was no case of decrease in serum potassium level
more than 3.0mmol/lit.

26. Limitations of the Study
• Patients having serum K+ levels > 6.5mmol/lit or ECG
changes associated with Hyperkalemia were excluded.
• Short term nature of the study.
• Study was conducted among ambulatory patients ,
excludes hospitalised patients and those receiving
dialysis.

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29. Other articles
• Among ambulatory patients with hyperkalemia,
open-label administration of sodium zirconium
cyclosilicate reduced serum potassium levels
to the normal range within 48 hours, and in the
randomized phase, compared with placebo,
administration of all 3 doses of zirconium
cyclosilicate resulted in lower potassium levels
and a higher proportion of patients with normal
potassium levels for up to 28 days
(Ref: Journal of the American Medical
Association Volume Dec 3, 2014 -Effect of Sodium
Zirconium Cyclosilicate on Potassium Lowering for 28 Days
Among Outpatients With Hyperkalemia: The HARMONIZE
Randomized Clinical Trial)

30. Other Articles
• The results demonstrate that oral ingestion of ZS-9 with
meals significantly lowered s-K+ in patients with stage 3 CKD.
The 10-g dose of ZS-9 rapidly and substantially reduced
mean s-K+: levels were 0.92 mEq/l below baseline after 38 h
of treatment (P<0.001).
• (Ref: Kidney international ,4 Feb 2015, The treatment of
hyperkalemia in patients with chronic kidney disease suggests that the
selective potassium trap, ZS-9, is safe and efficient)

31. • In patients with severe hyperkalemia at baseline, treatment
with a single 10-g dose of ZS-9 resulted in a rapid and
significant reduction in the serum potassium level as early
as 1 hour after administration. These findings suggest that
ZS-9 may be a therapeutic option in the urgent treatment of
patients with severe
hyperkalemia
• (Ref: The New England Journal of Medicine , april 16, 2015,
Sodium Zirconium Cyclosilicate for Urgent Therapy
of Severe Hyperkalemia)

32. On-going trials
1. Open-label Safety and Efficacy of Sodium Zirconium
Cyclosilicate for up to 12 Months Including
Randomized Withdrawal (Estimated study completion
date August 2016)
2. Open-label Safety & Efficacy of ZS (Sodium
Zirconium Cyclosilicate)10g qd to Extend Study ZS-
004 in Hyperkalemia. ( Estimated study completion date
Nov 2015)

33. THANK YOU!