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Vol. 43. Issue. 6.November - December 2023
Pages 663-806
Vol. 43. Issue. 6.November - December 2023
Pages 663-806
Letter to the Editor
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Reply to "Letter to the Editor — Consensus document on the management of hyperkalaemia"
Respuesta a «Carta al Director - Documento de consenso sobre el abordaje de la hiperpotasemia»
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Alberto Ortiza,
Corresponding author
aortiz@fjd.es

Corresponding author.
, Carmen del Arco Galánb, José Carlos Fernández-Garcíac, Jorge Gómez Cerezod, Rosa Ibán Ochoab, Julio Núñeze, Francisco Pita Gutiérrezc, Juan F. Navarro-Gonzáleza,
Corresponding author
jnavgon@gobiernodecanarias.org

Corresponding author.
a Sociedad Española de Nefrología (S.E.N.), Spain
b Sociedad Española de Medicina de Urgencias y Emergencias (SEMES), Spain
c Sociedad Española de Endocrinología y Nutrición (SEEN), Spain
d Sociedad Española de Medicina Interna (SEMI), Spain
e Sociedad Española de Cardiología (SEC), Spain
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Dear Editor,

We are grateful for the interest shown by Dr Lorente in the consensus document on the management of hyperkalaemia, which was open for public comment between December 2022 and January 2023.1 Dr Lorente made a number of comments, which we have summarised and responded to below.2

Boxes 1 and 2 refer to the acute treatment of severe hyperkalaemia, not to the mechanism of action of the interventions. In a section on the acute treatment of severe hyperkalaemia, it should be noted that the first measures are still: (1) Antagonise the effects of potassium on the cell membrane: calcium gluconate or calcium chloride; and (2) Introduce potassium into the cells, as shown in Box 1. Avoid giving the impression that the only measure to be applied is to increase digestive elimination. In this regard, ENERGIZE (NCT03337477) was a multicentre, double-blind, placebo-controlled, Phase 2 clinical trial evaluating the efficacy of sodium zirconium cyclosilicate (SZC) in the emergency treatment of hyperkalaemia, added to glucose and insulin, with the primary endpoint being the change in serum potassium.3 We have not found a similar clinical trial for patiromer (standard measures plus patiromer compared to standard measures plus placebo) with published results,4 so it was not possible to include patiromer in Boxes 1 and 2. However, the document notes that the PLATINUM study (NCT04443608), a multicentre, randomised, placebo-controlled clinical trial evaluating aspects relating to the use of patiromer in the context of hyperkalaemia in the emergency department, is currently underway. Although we agree with Dr Lorente that it seems reasonable to start chronic treatment as early as possible, Boxes 1 and 2 refer to a specific situation, which is the acute treatment of severe hyperkalaemia.

We also agree with Dr Lorente that the 2022 consensus document, "Recommendations for the management of hyperkalaemia in the emergency department", of the Spanisch Society of Emergency Medicine and Emergencies (SEMES) [Sociedad Española de Medicina de Urgencias y Emergencias], the Spanish Society of Cardiology (SEC) [Sociedad Española de Cardiología] and the Spanish Society of Nephrology (S.E.N) [Sociedad Española de Nefrología] mentions gastrointestinal cation exchangers in the algorithm for the treatment of hyperkalaemic emergency, without naming any one in particular.5 Moreover, we also agree that patiromer, SZC and ion exchange resins such as sodium or calcium polystyrene sulfonate are mentioned in the text. However, the text does not present evidence on the use of patiromer or ion exchange resins in this area. The only clinical trial cited in the setting of emergency hyperkalaemia is ENERGIZE,3 whose authors conclude that SZC with insulin and glucose may provide incremental benefit in the emergency treatment of hyperkalaemia over insulin and glucose alone. Therefore, our interpretation is that although the SEMES-SEC-S.E.N document does not mention any specific gastrointestinal cation exchanger in the algorithm for the treatment of hyperkalaemic emergency, the fact that it only presents evidence for one of them would clarify its position. We would have liked to be able to include patiromer in this area to avoid controversy, but we cannot do this arbitrarily, and we must to base the decision on the available evidence.

We agree with Dr Lorente that the "European Resuscitation Council Guidelines 2021: Cardiac arrest in special circumstances" include patiromer, SZC and calcium polystyrene sulfonate among the measures to remove potassium from the body in the emergency treatment of hyperkalaemia.6 The text explains that SZC takes effect within the first hour and lowers blood potassium by 1.1 mmol/l in the first 48 h, while the onset of patiromer action is slower, being evident at 4−7 h and lowering blood potassium by 0.36 mmol/l in 72 h.6 They consider the above-mentioned studies to be inconclusive.3,4

Dr Lorente points out that Box 3 gives a broad description of SZC, but not of patiromer. The extra information is that SZC contributes to the correction of metabolic acidosis. This statement is based on an exploratory analysis of three clinical trials, as reported in the text.1,7 Dr Lorente points out that patiromer also provides pleiotropic effects, such as lowering phosphorus levels. We agree with Dr Lorente that this may be an advantage for patients with chronic kidney disease (CKD) and hyperphosphataemia.

Unfortunately, the reference he provides is from July 2023,8 so it is outside the evidence review period. This information will be taken into account in subsequent updates of the document.

Dr Lorente asks on what studies we based the suggestion in the algorithm that SZC should be considered particularly in patients with CKD or metabolic acidosis. The rationale for considering SZC in patients with metabolic acidosis, a common and often undiagnosed condition in CKD patients, is that SZC can correct it.7 Given the high prevalence of undiagnosed metabolic acidosis in CKD, this was expressed as “CKD or metabolic acidosis”. However, in an ideal world where the acid-base status of CKD patients is regularly assessed, the term “CKD with metabolic acidosis” could preferably be used in addition to isolated metabolic acidosis.

Dr Lorente points out that in the meta-analysis cited above, there is a higher prevalence of CKD and other comorbidities expressed as a percentage among the 654 participants in the trials testing patiromer than among the 1102 participants in the trials testing SZC.9 Although this is a minor point, it is worth noting that the total number of patients with CKD and other comorbidities was higher in the trials testing CSZ than in those testing patiromer.

Dr Lorente points out that there is no mention in the consensus document that SZC has a European Medicines Agency (EMA) alert for intestinal perforations.

Indeed, the EMA states that, "The risk for intestinal perforation with the use of Lokelma is currently unknown. Since intestinal perforation has been reported with potassium binders including Lokelma, specific attention should be paid to signs and symptoms related to intestinal perforation".10 For patiromer, "Patients with a history of bowel obstruction or major gastrointestinal surgery, severe gastrointestinal disorders, or swallowing disorders were not included in the clinical studies. Gastrointestinal ischaemia, necrosis and/or intestinal perforation have been reported with other potassium binders. The benefits and risks of administering patiromer should be carefully evaluated in patients with current or history of severe gastrointestinal disorders, before and during treatment".11

Dr Lorente cites the EMA as stating that SZC should be separated by 2 h from tacrolimus administration because of a possible interaction with tacrolimus; this decision is dated 10 January 2023 and was therefore issued after the evidence review period.10 In any case, it is correct that the consensus document does not detail the drug-drug interactions of the drugs discussed. It is obvious that every prescribing physician should periodically review the conditions of use of the medicines he or she prescribes. In this regard, the EMA's “summary of product characteristics” for patiromer explains in the “Posology” section that “Administration of Veltassa should be separated by 3 hours from other oral medicinal products (see section 4.5, shown in the annex)”. Notably, it does not make an exception for tacrolimus, and the EMA does not include in vivo studies on patiromer and tacrolimus where the area under the tacrolimus curve is determined, such as the study that motivated the EMA recommendation for SZC, which analysed a dose of SZC (15 g) which is not among the presentations available in Europe (5 and 10 g).11 The "Posology" section of the EMA's "summary of product characteristics" for SZC has no limitations with respect to other drugs.10 However, in section 4.5, shown in the Annex, it states, “However, sodium zirconium cyclosilicate should be administered at least 2 hours before or 2 hours after oral medicinal products with clinically meaningful gastric pH dependent bioavailability”.

Finally, Dr Lorente suggests that the use of patiromer could be associated with a lower risk of heart failure hospitalisations compared to SZC in real clinical practice. However, the article he cites found no statistically significant differences in heart failure hospitalisations between SZC and patiromer.12

References
[1]
A. Ortiz, C. del Arco Galán, J.C. Fernández García, J. Gómez Cerezo, R. Ibán Ochoa, J. Núñez, et al.
Documento de consenso sobre el abordaje de la hiperpotasemia.
Nefrología, 43 (2023), pp. 765-782
[2]
A. Lorente.
Documento de consenso sobre el abordaje de la hiperpotasemia (respuesta).
Nefrología, 43 (2023), pp. 795-796
[3]
W.F. Peacock, Z. Rafique, K. Vishnevskiy, E. Michelson, E. Vishneva, T. Zvereva, et al.
Emergency potassium normalization treatment including sodium zirconium cyclosilicate: a phase II, randomized, double-blind, placebo-controlled study (ENERGIZE).
Acad Emerg Med, 27 (2020), pp. 475-486
[4]
Z. Rafique, M. Liu, K.A. Staggers, C.G. Minard, W.F. Peacock.
Patiromer for treatment of hyperkalemia in the emergency department: a pilot study.
Acad Emerg Med, 27 (2020), pp. 54-60
[5]
E. Álvarez-Rodríguez, A. Olaizola Mendibil, M.A. San Martín Díez, A. Burzako Sánchez, A. Esteban-Fernández, E. Sánchez Álvarez.
Recomendaciones para el manejo de la hiperpotasemia en urgencias.
Emergencias, 34 (2022), pp. 287-297
[6]
C. Lott, A. Truhlář, A. Alfonzo, A. Barelli, V. González-Salvado, J. Hinkelbein, et al.
ERC Special Circumstances Writing Group Collaborators. European Resuscitation Council Guidelines 2021: Cardiac arrest in special circumstances.
Resuscitation, 161 (2021), pp. 152-219
[7]
S.D. Roger, B.S. Spinowitz, E.V. Lerma, S. Fishbane, S.R. Ash, J.G. Martins, et al.
Sodium zirconium cyclosilicate increases serum bicarbonate concentrations among patients with hyperkalaemia: exploratory analyses from three randomized, multi-dose, placebocontrolled trials.
Nephrol Dial Transplant, 36 (2021), pp. 871-883
[8]
D.A. Bushinsky, J.J. Budden, P.A. Kalra, J. Yuan, C.M. Quinn, M. Epstein.
Patiromer treatment in patients with CKD, hyperkalemia, and hyperphosphatemia: a post hoc analysis of 3 clinical trials.
Am J Kidney Dis, 82 (2023), pp. 97-104
[9]
C.J. Meaney, M.V. Beccari, Y. Yang, J. Zhao.
Systematic review and meta-analysis of patiromer and sodium zirconium cyclosilicate: a new armamentarium for the treatment of hyperkalemia.
Pharmacotherapy, 37 (2017), pp. 401-411
[10]
Summary of product characteristics. (Accessed 29 June 2023). Available from: http://www.ema.europa.eu/en/documents/product-information/lokelma-epar-productinformation_en.pdf.
[11]
Summary of product characteristics. (Accessed 29 June 2023) Available from: http://www.ema.europa.eu/en/documents/product-information/veltassa-epar-productinformation_en.pdf.
[12]
M. Zhuo, S.C. Kim, E. Patorno, J.M. Paik.
Risk of hospitalization for heart failure in patients with hyperkalemia treated with sodium zirconium cyclosilicate versus patiromer.
J Card Fail, 28 (2022), pp. 1414-1423
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