Hyperkalemia Randomized Intervention Multidose ZS-9 - HARMONIZE

Nov 17, 2014
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
ZS Pharma
Date Presented:
01/01/2014
Date Published:
01/01/2014
Date Updated:
11/17/2014
Original Posted Date:
11/17/2014
References

Description:

Hyperkalemia is a commonly encountered medical problem. The current trial sought to study the safety and efficacy of sodium zirconium cyclosilicate (ZS) in patients with hyperkalemia.

Hypothesis:

ZS would be superior to placebo in reducing serum potassium (K) levels compared with placebo in a dose-dependent fashion.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Serum K ≥5.1 mEq/L
  • Ability to undergo repeat blood draws

    Number of screened applicants: 425
    Number of enrollees: 237
    Duration of follow-up: 28 days
    Mean patient age: 65 years
    Percentage female: 40%

Exclusions:

  • Dialysis requirement
  • Cardiac arrhythmias requiring immediate treatment
  • Active treatment with polymeric exchange resins (SPS)
  • Life expectancy <3 months
  • Pregnancy

Primary Endpoints:

  • Mean serum K on days 8-29

Drug/Procedures Used:

Patients with K ≥5.1 mEq/L received 10 g of ZS TID. Those who responded (subsequent K values <5.1 mEq/L) were randomized in a 1:1:1:1.7 fashion to receive ZS 5 g daily, 10 g daily, 15 g daily, or placebo daily.

Principal Findings:

A total of 237 patients were randomized, 45 to 5 g ZS, 51 to 10 g ZS, 56 to 15 g ZS, and 85 to placebo. Approximately 50% of the patients had serum K <5.5 mEq/L; 40% had levels between 5.5 and 6 mEq/L. Approximately 40% had congestive heart failure (CHF) and 65% had chronic kidney disease (CKD). Renin-angiotensin-aldosterone system (RAAS) inhibitors were being used in greater than two thirds of all patients.

Mean K levels were reduced in a dose-dependent fashion with ZS (4.75 vs. 4.51 vs. 4.37 vs. 5.06 mEq/L, p < 0.001 for each group vs. placebo) for 5 g, 10 g, 15 g, and placebo, respectively. Similarly, the proportion of patients with K <5.1 mEq/L during days 8-29 was higher in a dose-dependent fashion (80% vs. 90% vs. 94% vs. 46%, p < 0.05). Efficacy was similar in all subgroups tested, including CKD, CHF, diabetes mellitus, and use of RAAS inhibitors. Effect was observed as early as 1 hour; the median time to normalize K was 2.2 hours in the ZS arm.

Edema was higher with the 15 g ZS dose (2% vs. 6% vs. 14% vs. 2%), as was hypokalemia (0% vs. 10% vs. 11% vs. 0%).

Interpretation:

The results of this trial indicate that ZS may be safe and efficacious in the treatment of asymptomatic hyperkalemia. A dose-dependent relationship was observed, with higher doses achieving greater normalization of hyperkalemia, but with a greater propensity for side effects including hypokalemia.

ZS is an inorganic crystalline compound that exchanges potassium ions for hydrogen and sodium ions in the intestine. It is not systemically absorbed, and has a 125-fold greater selectiveness for K trapping than sodium polystyrene sulfonate (kayexelate), which is commonly used for this condition. Long-term safety and efficacy studies with ZS are planned.

References:

Kosiborod M, Rasmussen HS, Lavin P, et al. Effect of Sodium Zirconium Cyclosilicate on Potassium Lowering for 28 Days Among Outpatients With Hyperkalemia: The HARMONIZE Randomized Clinical Trial. JAMA 2014;Nov 17:[Epub ahead of print].

Presented by Dr. Mikhail Kosiborod at the American Heart Association Scientific Sessions, Chicago, IL, November 17, 2014.

Keywords: Polystyrenes, Potassium, Zirconium, Sodium, Hypokalemia, Heart Failure, Renin-Angiotensin System, Hyperkalemia, Edema, Intestines, Ions, Renal Insufficiency, Chronic, Hydrogen, Diabetes Mellitus, AHA Annual Scientific Sessions


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