HARMONIZE: ZS-9 reduced serum potassium in patients with hyperkalemia

CHICAGO — Treatment with sodium zirconium cyclosilicate was associated with rapid and sustained reductions in serum potassium compared with placebo in patients with hyperkalemia.

The phase 3, double blind, randomized, multicenter HARMONIZE trial included 258 patients with hyperkalemia (serum potassium ≥5.1 mEq/L). During the open-label phase, patients received a 10-mg dose of sodium zirconium cyclosilicate (ZS-9, ZS Pharma) three times daily for 48 hours. Patients who achieved normal serum potassium levels during this phase (n=237) were randomly assigned to once-daily placebo (n=85) or ZS-9 5 g (n=45), 10 g (n=51) or 15 g (n=56) during a 28-day maintenance phase.

The primary endpoint of HARMONIZE was mean serum potassium during days 8 to 29 of the randomized phase. Secondary endpoints included the proportion of patients achieving normal potassium levels during each phase, change in potassium levels and time to potassium normalization during the open-label phase, and incidence of adverse events.

The mean serum potassium level at baseline was 5.55 mEq/L. During the open-label phase of the trial, serum potassium was reduced to 4.5 mEq/L. Potassium declined by 0.2 mEq/L at 1 hour, 0.4 mEq/L at 2 hours and 0.5 mEq/L at 4 hours after administration of ZS-9 (P<.001). The median time to potassium normalization was 2.2 hours, according to data reported. Eighty-four percent of patients achieved normokalemia within 24 hours of ZS-9 administration, and 98% achieved normokalemia within 48 hours.

The decline in serum potassium levels observed during the open-label phase was consistent across all key evaluated subgroups, and was greater in patients with higher potassium at baseline.

During the maintenance phase, all patients assigned ZS-9 exhibited significantly lower serum potassium than patients treated with placebo. From days 8 to 29, serum potassium was 4.75 mEq/L in the 5-g group, 4.51 mEq/L in the 10-g group and 4.37 mEq/L in the 15-g group, compared with 5.06 mEq/L in the placebo group (P<.001 for all), according to data presented. Significantly more patients assigned ZS-9 maintained normokalemia: 80% of the 5-g group, 90% of the 10-g group and 94% of the 15-g group, compared with 46% of the placebo group (P<.001 for all).

Results observed during the randomized phase were consistent across all evaluated subgroups.

Mikhail N. Kosiborod

Adverse events occurred at a similar rate between patients assigned ZS-9 and placebo. No serious treatment-related adverse events were observed. Hypokalemia occurred more frequently in the ZS-9 10-g (10%) and 15-g (11%) groups; however, all cases were mild and resolved with dose adjustment.

“The results of the HARMONIZE study show that ZS-9 is effective in rapidly lowering potassium in patients with various degrees of hyperkalemia, and maintaining normal potassium levels for up to 4 weeks, with tolerability profile that is similar to placebo,” Mikhail N. Kosiborod, MD, cardiologist at Saint Luke’s Mid America Heart Institute, Kansas City, told Cardiology Today. “These data have the potential to shift the current paradigm for how hyperkalemia is managed among various at-risk patient groups.” – by Adam Taliercio

For more information:

Kosiborod M. Abstract #20737. Presented at: American Heart Association Scientific Sessions; Nov. 15-19, 2014; Chicago.

Kosiborod M. JAMA. 2014;doi:10.1001/jama.2014.15688.

Disclosure: Kosiborod reports serving as a consultant/advisory board member for ZS Pharma, which funded the HARMONIZE study.