Renal potassium excretion is severely reduced in patients with end-stage renal disease (ESRD), requiring hemodialysis or peritoneal dialysis to maintain normal serum potassium levels. However, despite receiving dialysis, many patients experience persistent predialysis hyperkalemia, a condition that is potentially life-threatening and associated with cardiac arrhythmias and death. There is an association between a serum potassium concentration of ≥5.6 mmol/L and increased risk of all-cause and cardiac death. In addition, the unadjusted hazard ratio between different serum potassium categories is U-shaped; the best survival is in patients with serum potassium concentrations of 4.6 to 5.6 mmol/L.
Patients with ESRD receiving hemodialysis require additional strategies for the management of hyperkalemia. Options for treatment include potassium binding resins such as sodium polystyrene sulfonate (SPS), patiromer, and sodium zirconium cyclosilicate (SZC; AstraZeneca AB, Södertälje, Sweden).
SZC is an orally administered, insoluble, nonabsorbed, inorganic crystalline compound that selectively captures potassium ions in exchange for hydrogen and sodium ions in the gastrointestinal lumen. The free concentration of serum potassium is reduced and fecal excretion of potassium is increased, resolving hyperkalemia. SZC is approved in Europe and the United States for the treatment of hyperkalemia in adults.
Steven Fishbane, MD, and colleagues reported results of the phase 3b DIALIZE study (NCT03303521) that sought to examine the safety and efficacy of SZC in stable patients with ESRD who were being managed by adequate hemodialysis. The study results were reported in the Journal of the American Society of Nephrology [2019;30(9);1723-1733].
The study randomized adults with ESRD who were receiving hemodialysis three times a week and had predialysis hyperkalemia to receive placebo or SZC 5 g once daily on nondialysis day and titrated toward maintaining normokalemia over 4 weeks, in increments of 5 g to a maximum of 15 g.
The primary efficacy end point of interest was the proportion of patients during the 4-week stable-dose evaluation period who maintained predialysis serum potassium of 4.0 to 5.0 mmol/L during at least three of four hemodialysis treatments after the long interdialytic interval. The secondary efficacy end point was the proportion of patients who required any urgent rescue intervention to reduce serum potassium in the setting of severe hyperkalemia (>6.0 mmol/L). Safety outcomes of interest were assessment of adverse events (AEs), laboratory parameters/vital signs, electrocardiogram, and interdialytic weight gain.
Of the 443 patients screened, 247 were excluded, primarily for not meeting inclusion criteria. A total of 97 patients were randomized to the SZC group and 96 were randomized to the placebo group. With the exception of one patient in the SZC group, all patients received treatment. A total of 188 patients (95.9%) completed the study; rates of study completion were balanced between the two groups (SZC, 92/97, 94.8%; placebo, 96/99; 97.0%).
Of the total study cohort, 58.7% were men, mean age was 58.1 years, and mean weight was 71.0 kg. Fifty-two percent were white, 33.7% were Asian, and 9.7% were black or African American. With the exception of a small difference in age distribution, patient characteristics were balanced between the groups; patients in the SZC group were younger compared with the placebo group (mean age=55.7 vs 60.4 years, respectively). Dialysis adequacy parameters were comparable between the two groups.
Following the dose titration period, 37%, 43%, and 19% of patients in the SZC group received SZC 5, 10, and 15 g, respectively, and 8%, 8%, and 83% of the placebo group received 5, 10, and 15 g, respectively. The mean rate of patient compliance was high during the overall treatment period (98.7%), and was balanced between the groups (SZC, 98.9%; placebo, 98.4%). The mean rate of patient compliance with treatment during the evaluation period was also high (99.0%) and balanced between the groups (SZC, 98.6%; placebo, 99.4%).
In the primary efficacy outcome, the proportion of patients during the 4-week stable dose evaluation period who maintained predialysis serum potassium of 4.0-5.0 mmol/L during at least three of four hemodialysis treatments, there was a significantly higher proportion of responders in the SZC group than in the placebo group: 41.2% (n=40/97) versus 1.0% (n=1/99); odds ratio [OR], 68.8; 95% confidence interval [CI], 10.9-2810.9; P<.001). Results of sensitivity analysis were consistent with those of the primary analysis: there was a higher proportion of responders in the SZC group than in the placebo group (42.3% [n=41/97] vs 2.0% [n=2/99]; OR, 35.5; 95% CI, 8.5-309.5; P<.001).
Analysis of the secondary efficacy outcome, the need for rescue therapy, found comparable and low proportions of patients in the SZC group and the placebo group needed rescue therapy to reduce serum potassium level during the overall treatment period: SZC, 2.1% (n=2/97); placebo, 5.1% (n=5/99).
Forty patients (41.7%) in the SZC group had an AE compared with 46 patients (46.5%) in the placebo group. Most AEs were mild or moderate; the most common were gastrointestinal disorders (19 in the SZC group and 17 in the placebo group). Twelve patients in the SZC group reported infections; nine in the placebo group reported infections
Serious AEs occurred in 7.3% of the SZC group and 8.1% of the placebo group. Angina pectoris was the most common serious AE in the SZC group (2.1%; n=2). The most common serious AEs in the placebo group were hyperkalemia requiring rescue therapy (3.0%; n=3) and fluid overload (2.0%; n=2). All serious AEs were considered non-study related by the investigator. Interdialytic weight gain was comparable between the two groups.
Possible study limitations included the relatively short duration; additional studies are needed to determine the long-term efficacy and safety of SZC in patients receiving chronic hemodialysis. In addition, while treatment compliance was high, the findings may not be generalizable to all patients in a real world setting.
The researchers said, “In conclusion, in the phase 3b DIALIZE study, SZC was effective in reducing serum potassium levels in patients on hemodialysis. The safety profile of SZC observed in patients managed by hemodialysis was similar to that known in the nondialysis population and raised no new concerns. The results indicate that SZC is an option for the management of hyperkalemia in this setting.”
The study was supported by AstraZeneca.
- Researchers reported results of the phase 3b DIALIZE study that examined sodium zirconium cyclosilicate (SZC) in the management of hyperkalemia in patients with end-stage renal disease on maintenance hemodialysis.
- Patients were randomized to receive SZC (n=97) or placebo (n=99). The primary end point was the proportion of patients during the 4-week stable dose evaluation period who maintained predialysis serum potassium of 4.0-5.0 mmol/L during at least three of four hemodialysis treatments.
- The safety profile of SZC was acceptable, and similar to that known in nondialysis patients.