Letter to the editor regarding ‘Patiromer for the treatment of hyperkalemia’

The recent review by Colbert and colleagues [1] evaluates the role of potassium binders, particularly patiromer, in the treatment of hyperkalemia of chronic kidney disease (CKD). Although informative, there are several inaccuracies that need to be addressed, particularly related to sodium zirconium cyclosilicate (SZC).

First, the following statement concerning SZC is potentially misleading: ‘Drug approval studies have shown edema as a problem in up to 16.1% of patients and are mentioned in the package label for clinicians to monitor,’ as this refers to mild-to-moderate edema only observed with the 15-g dose of SZC. Although the authors mention the SZC package label, it is not cited [2]; the full information in the product label states that in placebo-controlled trials in which patients received once-daily SZC for up to 28 days, the incidence of edema was 4.4%, 5.9%, and 16.1% with SZC 5 g, 10 g, and 15 g, respectively, compared with 2.4% with placebo [2]. Further, longer-term uncontrolled trials, in which most patients were maintained on SZC doses of <15 g once daily, reported edema (edema, generalized edema, and peripheral edema) in 8%–11% of patients [2]. Edema was generally mild-to-moderate in severity, and in up to 47% of patients, resolved without treatment [2,3]. The remainder were managed with diuretic initiation or diuretic dose adjustment. Thus, the authors’ general statement that edema is ‘a problem in up to 16.1% of patients’ is misleading.

Second, the authors erroneously imply short-term sodium loading, as well as long-term tolerability issues, based on the sodium content of SZC in their statement: ‘ … the exposure to large sodium dosing, up to 2400 mg on three times a day initiation, makes tolerability for long-term dosing yet to be determined.’ SZC preferentially captures potassium in exchange for hydrogen and sodium [2,3]. The amount of sodium released and subsequently absorbed per a given dose of SZC (400 mg Na+ per 5 g SZC) has not been quantified.

Data from randomized trials suggests that only a small fraction of the elemental sodium contained within SZC is released. In two studies of patients with hyperkalemia, urinary sodium excretion did not significantly increase with SZC versus placebo, during either the correction or maintenance treatment phase [4,5], indicating that sodium loading with SZC is not a significant issue. Moreover, after initial treatment with SZC 10 g three times daily for up to 48 hours during the correction phase, patients then receive maintenance therapy with SZC 10 g once daily, which has a total sodium content of 800 mg [2]. It is also inaccurate for the authors to imply that the long-term tolerability of SZC is yet to be determined. Long-term, international phase 3 clinical trials with SZC maintenance therapy have shown good tolerability for up to 12 months among patients with multiple comorbidities, including CKD, heart failure, and diabetes mellitus [6,7], as well as in patients with mild, moderate, severe, or end-stage CKD [8]. All of these studies were published within the search period of this review.

Third, the statement ‘[w]hile we have a small trial showing patiromer is safe and effective in dialysis patients [43], dedicated trials in hemodialysis patients and those with a kidney transplant would be a tremendous value … ’ refers to a 2-week, phase 2 study in six hemodialysis patients, which did not claim to demonstrate the efficacy or safety of patiromer [9]. The authors cite the value of having data in hemodialysis patients, but fail to mention DIALIZE, a phase 3b, randomized, double-blind, placebo-controlled, multicenter study of SZC in 196 patients on maintenance hemodialysis [10]. In DIALIZE, SZC demonstrated effective reductions in serum potassium concentrations over the 4-week treatment period and was well-tolerated, with a similar safety profile to that previously observed in non-hemodialysis patients [10]. Based on the DIALIZE study results, SZC is now the only potassium binder indicated for use in patients undergoing maintenance hemodialysis according to the US and EU package labels [2,3]. Please also note that reference 43 cited for the patiromer data in this statement is missing from the reference list.

Fourth, the information related to the dosing of SZC within the text and in Table 3 is inadequate, lacks proper citation of the United States (US) [2] or European Union (EU) [3] package labels, and may be misleading as it only reports the starting dose in patients not receiving hemodialysis. For patients not on hemodialysis, the recommended initial SZC dose is 10 g three times a day for up to 48 hours (in the US) and 72 hours (in the EU) and the recommended maintenance dose ranges from a minimum of 5 g every other day to a maximum of 10 g (in the EU) [3] or 15 g (in the US) [2] once daily, based on regularly monitored serum potassium levels. In patients on chronic hemodialysis, both the US and EU labels recommend a starting dose of SZC 5 g once daily on non-dialysis days, with a maintenance dose range of 5 g to 15 g once daily on non-dialysis days [2,3].

Finally, the statement in Table 3 that SZC has an onset of action from 1–6 hours is incorrect. All studies that measured serum potassium at 1 hour after the first dose of SZC demonstrated significant reductions from baseline in serum potassium compared with placebo [4,5,11]; thus, the 6-hour time-to-onset value is inaccurate.

Declaration of interest

The author is a shareholder and employee of AstraZeneca. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Acknowledgments

Editorial support was provided by inScience Communications, Springer Healthcare, (New York, NY) funded by AstraZeneca.

Additional information

Funding

This letter was funded by AstraZeneca.