Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial.
OBJECTIVE
Hyperkalemia is a common electrolyte abnormality that may be difficult to manage because of a lack of effective therapies. Sodium zirconium cyclosilicate is a nonabsorbed cation exchanger that selectively binds potassium in the intestine.


OBJECTIVE
To evaluate the efficacy and safety of zirconium cyclosilicate for 28 days in patients with hyperkalemia.


METHODS
HARMONIZE was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial evaluating zirconium cyclosilicate in outpatients with hyperkalemia (serum potassium ≥5.1 mEq/L) recruited from 44 sites in the United States, Australia, and South Africa (March-August 2014).


METHODS
Patients (n = 258) received 10 g of zirconium cyclosilicate 3 times daily in the initial 48-hour open-label phase. Patients (n = 237) achieving normokalemia (3.5-5.0 mEq/L) were then randomized to receive zirconium cyclosilicate, 5 g (n = 45 patients), 10 g (n = 51), or 15 g (n = 56), or placebo (n = 85) daily for 28 days.


METHODS
The primary end point was mean serum potassium level in each zirconium cyclosilicate group vs placebo during days 8-29 of the randomized phase.


RESULTS
In the open-label phase, serum potassium levels declined from 5.6 mEq/L at baseline to 4.5 mEq/L at 48 hours. Median time to normalization was 2.2 hours, with 84% of patients (95% CI, 79%-88%) achieving normokalemia by 24 hours and 98% (95% CI, 96%-99%) by 48 hours. In the randomized phase, serum potassium was significantly lower during days 8-29 with all 3 zirconium cyclosilicate doses vs placebo (4.8 mEq/L [95% CI, 4.6-4.9], 4.5 mEq/L [95% CI, 4.4-4.6], and 4.4 mEq/L [95% CI, 4.3-4.5] for 5 g, 10 g, and 15 g; 5.1 mEq/L [95% CI, 5.0-5.2] for placebo; P < .001 for all comparisons). The proportion of patients with mean potassium <5.1 mEq/L during days 8-29 was significantly higher in all zirconium cyclosilicate groups vs placebo (36/45 [80%], 45/50 [90%], and 51/54 [94%] for the 5-g, 10-g, and 15-g groups, vs 38/82 [46%] with placebo; P < .001 for each dose vs placebo). Adverse events were comparable between zirconium cyclosilicate and placebo, although edema was more common in the 15-g group (edema incidence: 2/85 [2%], 1/45 [2%], 3/51 [6%], and 8/56 [14%] patients in the placebo, 5-g, 10-g, and 15-g groups). Hypokalemia developed in 5/51 (10%) and 6/56 patients (11%) in the 10-g and 15-g zirconium cyclosilicate groups, vs none in the 5-g or placebo groups.


CONCLUSIONS
Among outpatients with hyperkalemia, open-label sodium zirconium cyclosilicate reduced serum potassium to normal levels within 48 hours; compared with placebo, 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. Further studies are needed to evaluate the efficacy and safety of zirconium cyclosilicate beyond 4 weeks and to assess long-term clinical outcomes.


BACKGROUND
clinicaltrials.gov Identifier: NCT02088073.
Saint Luke's Mid America Heart Institute, Kansas City, Missouri2University of Missouri-Kansas City.
Mikhail
M
Kosiborod
ZS Pharma, Coppell, Texas.
Henrik S
HS
Rasmussen
Boston Biostatistics Research Foundation, Framingham, Massachusetts.
Philip
P
Lavin
University of Texas Health Science Center at San Antonio.
Wajeh Y
WY
Qunibi
Weill Medical College of Cornell University, New York, New York.
Bruce
B
Spinowitz
Melbourne Renal Research Group and Department of Medicine, University of Melbourne, Melbourne, Australia.
David
D
Packham
Renal Research, Gosford, Australia.
Simon D
SD
Roger
Xelay Acumen, Belmont, California.
Alex
A
Yang
University of Illinois at Chicago College of Medicine, Chicago11Advocate Christ Medical Center, Oak Lawn, Illinois.
Edgar
E
Lerma
ZS Pharma, Coppell, Texas.
Bhupinder
B
Singh
D000328:Adult; D004311:Double-Blind Method; D004487:Edema / Q000139:chemically induced; D005260:Female; D006801:Humans; D006947:Hyperkalemia / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010045:Outpatients; D011188:Potassium / Q000097:blood*; D017640:Silicates / Q000009:adverse effects / Q000627:therapeutic use*; D015040:Zirconium / Q000009:adverse effects / Q000627:therapeutic use*
D017640:Silicates; D015040:Zirconium; C000597310:sodium zirconium cyclosilicate; D011188:Potassium