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

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.

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

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)

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.

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 ageSerum K+ levels of 5.0 to 6.5 mmol per litWere able to undergo repeated blood draws.• Exclusion criterias:oPatients receiving dialysis had diabetic ketoacidosisoHad K+ levels > 6.5 mmol /litoHad cardiac arrhythmia that required immediate treatment oHad received organic polymer resins or phosphate binders

within one week before enrollment.

Study Design

• All concomitant medications were kept constant throughout the study, including diuretic agents , RAAS inhibitors, and antidiabetic therapy

• No dietary restrictions were imposed .

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).

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.

Enrollment and Outcome

Patient Characteristics at baseline

EfficacyInitial Phase

ZS-9, 1.25gm ZS-9, 2.5gm ZS-9, 5gm ZS-9, 10gm Placebo

0.11%0.16%

0.21%0.30%

0.09%

Mean exponential rates of change from baseline per hour were reduction of

Mean exponential rates of change from baseline per hour

ZS-9, 2.5gm

ZS-9, 5gm ZS-9, 10gm

Placebo0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.460.54

0.73

0.25

Absolute mean reduction in serum K+ at 48 hours

Absolute mean reduc-tion at 48 hours

EfficacyInitial Phase

Efficacy-Maintenance Phase

Adverse Events

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.)

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.

DiscussionResults 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.

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.

Advantage over current TherapiesInitial 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.

Hence there is need for new treatment option -

In patients with acute or chronic diseaseThat can be safely used in outpatient settings Have acceptable safety profile That cause rapid and sustained reduction serum K+ levels

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.@

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.

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.

References• 1. Khanagavi J, Gupta T, Aronow WS, et al. Hyperkalemia among

hospitalized patients and association between duration of hyperkalemia and outcomes. Arch Med Sci 2014;10:251-7.2. An JN, Lee JP, Jeon HJ, et al. Severe hyperkalemia requiring hospitalization: predictors of mortality. Crit Care 2012;16: R225.3. Jain N, Kotla S, Little BB, et al. Predictors of hyperkalemia and death in patients with cardiac and renal disease. Am J Cardiol 2012;109:1510-3.4. Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev 2009;3:CD007004.5. Svensson M, Gustafsson F, Galatius S, Hildebrandt PR, Atar D. How prevalent is hyperkalemia and renal dysfunction during treatment with spironolactone in patients with congestive heart failure? J Card Fail 2004;10:297-303.

• 6. Ahn SY, Ryu J, Baek SH, et al. Incident chronic kidney disease and newly developed complications related to renal dysfunction in an elderly population during 5 years: a community-based elderly population cohort study. PLoS One 2013;8(12):e84467.7. Tylicki L, Lizakowski S, Rutkowski B. Renin-angiotensin-aldosterone system blockade for nephroprotection: current evidence and future directions. J Nephrol 2012;25:900-10.8. Palmer BF, Fenves AZ. Optimizing blood pressure control in patients with chronic kidney disease. Proc (Bayl Univ Med Cent) 2010;23:239-45.9. Berl T. Review: renal protection by inhibition of the renin angiotensin-aldosterone system. J Renin Angiotensin Aldosterone Syst 2009;10:1-8.10. St Peter WL, Odum LE, Whaley-Connell AT. To RAS or not to RAS? The evidence for and cautions with renin-angiotensin system inhibition in patients with diabetic kidney disease. Pharmacotherapy 2013;33:496-514

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)

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)

• 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 severehyperkalemia

• (Ref: The New England Journal of Medicine , april 16, 2015, Sodium Zirconium Cyclosilicate for Urgent Therapyof Severe Hyperkalemia)

On-going trials1. 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)

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