Two new investigational drugs show promise for the treatment of hyperkalemia, a condition associated with increased mortality in some high-risk patients, according to researchers.

In separate studies of patients with hyperkalemia, sodium zirconium cyclosilicate (ZS-9) decreased serum potassium levels significantly compared with placebo. In a study of hyperkalemic patients with chronic kidney disease (CKD) receiving renin-angiotensin-aldosterone system (RAAS) inhibitors, patiromer decreased serum potassium levels, and, compared with placebo, was associated with a significant reduction in the recurrence of hyperkalemia.

David K. Packham, MD, of Melbourne Renal Research Group in Australia, and colleagues conducted a multicenter, double-blind phase 3 trial in which they randomly assigned 753 patients with hyperkalemia (serum potassium level higher than 5 mmol/L) to receive either ZS-9 at doses of 1.25 2.5, 5, or 10 grams or placebo 3 times daily for 48 hours.

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At 48 hours, the mean serum potassium level had decreased from 5.3 mmol/L at baseline to 4.9 mmol/L in the patients who received 2.5 grams of ZS-9, 4.8 mmol/L in the 5-gram group, and 4.6 mmol/L in the 10-gram group, for mean reductions of 0.5, 0.5, and 0.7 mmol/L, respectively, according to an online report in The New England Journal of Medicine (NEJM). The mean potassium level declined to 5.1 mmol/L in the 1.25-gram group and the placebo group, for a mean reduction of 0.3 mmol/L.

Additionally, in patients who received 5 grams of ZS-9 and those who received 10 grams of ZS-9, serum potassium levels were maintained at 4.7 and 4.5 mmol/L, respectively, during days 3–15, compared with a level of more than 5.0 mmol/L in the placebo group. Adverse rates were similar among the ZS-9 and placebo recipients.

In another ZS-9 study, 258 hyperkalemic patients received 10 grams of ZS-9 3 times daily in an initial 48-hour open-label phase. Then, 237 patients achieving normokalemia (3.5–5.0 mEq/L) were randomized to receive 5, 10, or 15 grams of ZS-9 or placebo daily for 28 days.

In the open-label phase, serum potassium levels declined from 5.6 mEq/L at baseline to 4.5 mEq/L at 48 hours, Mikhail Kosiborod, MD, of Saint Luke’s Mid America Heart Institute in Kansas City, Mo., and collaborators reported online in the Journal of the American Medical Association. The median time to normalization was 2.2 hours, with 84% of patients achieving normokalemia by 24 hours and 98% by 48 hours.

In the randomized phase, serum potassium was significantly lower during days 8-29 with all 3 ZS-9 doses compared with placebo: 4.8, 4.5, and 4.4 mEq/L for the 5, 10, and 15 gram doses versus 5.1 mEq/L for placebo. Furthermore, the proportion of patients with mean potassium levels below 5.1 mEq/L during days 8-29 was significantly higher in all ZS-9 groups compared with placebo: 80%, 90%, and 94% for the 5- 10-, and 15-gram groups versus 46% of placebo recipients.

The patiromer trial, led by Matthew R. Weir, MD, of the University of Maryland Medical Center in Baltimore, consisted of an initial treatment phase and a randomized withdrawal phase. Among 237 patients receiving patiromer in the initial treatment phase and who had at least 1 potassium measurement at a scheduled visit after day 3, the mean serum potassium level decreased by a significant 1.01 mmol/L, Dr. Weir’s group reported online in NEJM.

At week 4, 76% of patients had achieved the target potassium level of at least 3.8 but less than 5.1 mmol/L. In the subsequent randomized withdrawal phase, the investigators assigned 107 patients to receive either patiromer (55 patients) or placebo (52 patients). The median increase in the potassium level from baseline of that phase was significantly greater in the placebo than patiromer arm.

In addition, 60% of the placebo arm experienced a recurrence of hyperkalemia (potassium level of 5.5 mmol/L or higher) through week 8 compared with 15% in the patiromer arm, a significant difference between the groups.