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Meta-Analysis
. 2020 Jun 26;6(6):CD013165.
doi: 10.1002/14651858.CD013165.pub2.

Potassium binders for chronic hyperkalaemia in people with chronic kidney disease

Patrizia Natale  1   2 , Suetonia C Palmer  3 , Marinella Ruospo  1   2 , Valeria M Saglimbene  1   2 , Giovanni Fm Strippoli  1   2   4
Affiliations
Meta-Analysis

Potassium binders for chronic hyperkalaemia in people with chronic kidney disease

Patrizia Natale et al. Cochrane Database Syst Rev. .

Abstract

Background: Hyperkalaemia is a common electrolyte abnormality caused by reduced renal potassium excretion in patients with chronic kidney diseases (CKD). Potassium binders, such as sodium polystyrene sulfonate and calcium polystyrene sulfonate, are widely used but may lead to constipation and other adverse gastrointestinal (GI) symptoms, reducing their tolerability. Patiromer and sodium zirconium cyclosilicate are newer ion exchange resins for treatment of hyperkalaemia which may cause fewer GI side-effects. Although more recent studies are focusing on clinically-relevant endpoints such as cardiac complications or death, the evidence on safety is still limited. Given the recent expansion in the available treatment options, it is appropriate to review the evidence of effectiveness and tolerability of all potassium exchange resins among people with CKD, with the aim to provide guidance to consumers, practitioners, and policy-makers.

Objectives: To assess the benefits and harms of potassium binders for treating chronic hyperkalaemia among adults and children with CKD.

Search methods: We searched the Cochrane Kidney and Transplant Register of Studies up to 10 March 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria: Randomised controlled trials (RCTs) and quasi-randomised controlled studies (quasi-RCTs) evaluating potassium binders for chronic hyperkalaemia administered in adults and children with CKD.

Data collection and analysis: Two authors independently assessed risks of bias and extracted data. Treatment estimates were summarised by random effects meta-analysis and expressed as relative risk (RR) or mean difference (MD), with 95% confidence interval (CI). Evidence certainty was assessed using GRADE processes.

Main results: Fifteen studies, randomising 1849 adult participants were eligible for inclusion. Twelve studies involved participants with CKD (stages 1 to 5) not requiring dialysis and three studies were among participants treated with haemodialysis. Potassium binders included calcium polystyrene sulfonate, sodium polystyrene sulfonate, patiromer, and sodium zirconium cyclosilicate. A range of routes, doses, and timing of drug administration were used. Study duration varied from 12 hours to 52 weeks (median 4 weeks). Three were cross-over studies. The mean study age ranged from 53.1 years to 73 years. No studies evaluated treatment in children. Some studies had methodological domains that were at high or unclear risks of bias, leading to low certainty in the results. Studies were not designed to measure treatment effects on cardiac arrhythmias or major GI symptoms. Ten studies (1367 randomised participants) compared a potassium binder to placebo. The certainty of the evidence was low for all outcomes. We categorised treatments in newer agents (patiromer or sodium zirconium cyclosilicate) and older agents (calcium polystyrene sulfonate and sodium polystyrene sulfonate). Patiromer or sodium zirconium cyclosilicate may make little or no difference to death (any cause) (4 studies, 688 participants: RR 0.69, 95% CI 0.11, 4.32; I2 = 0%; low certainty evidence) in CKD. The treatment effect of older potassium binders on death (any cause) was unknown. One cardiovascular death was reported with potassium binder in one study, showing that there was no difference between patiromer or sodium zirconium cyclosilicate and placebo for cardiovascular death in CKD and HD. There was no evidence of a difference between patiromer or sodium zirconium cyclosilicate and placebo for health-related quality of life (HRQoL) at the end of treatment (one study) in CKD or HD. Potassium binders had uncertain effects on nausea (3 studies, 229 participants: RR 2.10, 95% CI 0.65, 6.78; I2 = 0%; low certainty evidence), diarrhoea (5 studies, 720 participants: RR 0.84, 95% CI 0.47, 1.48; I2 = 0%; low certainty evidence), and vomiting (2 studies, 122 participants: RR 1.72, 95% CI 0.35 to 8.51; I2 = 0%; low certainty evidence) in CKD. Potassium binders may lower serum potassium levels (at the end of treatment) (3 studies, 277 participants: MD -0.62 mEq/L, 95% CI -0.97, -0.27; I2 = 92%; low certainty evidence) in CKD and HD. Potassium binders had uncertain effects on constipation (4 studies, 425 participants: RR 1.58, 95% CI 0.71, 3.52; I2 = 0%; low certainty evidence) in CKD. Potassium binders may decrease systolic blood pressure (BP) (2 studies, 369 participants: MD -3.73 mmHg, 95%CI -6.64 to -0.83; I2 = 79%; low certainty evidence) and diastolic BP (one study) at the end of the treatment. No study reported outcome data for cardiac arrhythmias or major GI events. Calcium polystyrene sulfonate may make little or no difference to serum potassium levels at end of treatment, compared to sodium polystyrene sulfonate (2 studies, 117 participants: MD 0.38 mEq/L, 95% CI -0.03 to 0.79; I2 = 42%, low certainty evidence). There was no evidence of a difference in systolic BP (one study), diastolic BP (one study), or constipation (one study) between calcium polystyrene sulfonate and sodium polystyrene sulfonate. There was no difference between high-dose and low-dose patiromer for death (sudden death) (one study), stroke (one study), myocardial infarction (one study), or constipation (one study). The comparative effects whether potassium binders were administered with or without food, laxatives, or sorbitol, were very uncertain with insufficient data to perform meta-analysis.

Authors' conclusions: Evidence supporting clinical decision-making for different potassium binders to treat chronic hyperkalaemia in adults with CKD is of low certainty; no studies were identified in children. Available studies have not been designed to measure treatment effects on clinical outcomes such as cardiac arrhythmias or major GI symptoms. This review suggests the need for a large, adequately powered study of potassium binders versus placebo that assesses clinical outcomes of relevance to patients, clinicians and policy-makers. This data could be used to assess cost-effectiveness, given the lack of definitive studies and the clinical importance of potassium binders for chronic hyperkalaemia in people with CKD.

Trial registration: ClinicalTrials.gov NCT03071263 NCT01371747 NCT01493024 NCT03303521 NCT02088073 NCT02065076 NCT01810939 NCT01737697 NCT00868439 NCT02694744 NCT04217590 NCT03781089.

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Conflict of interest statement

  1. Patrizia Natale: none known

  2. Suetonia C Palmer: none known

  3. Marinella Ruospo: none known

  4. Valeria M Saglimbene: none known

  5. Giovanni FM Strippoli: none known

Figures

1
1
Study flow diagram
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
1.1
1.1. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 1: Death (any cause)
1.2
1.2. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 2: Cardiovascular death
1.3
1.3. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 3: Nausea
1.4
1.4. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 4: Diarrhoea
1.5
1.5. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 5: Vomiting
1.6
1.6. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 6: Constipation
1.7
1.7. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 7: Abdominal pain
1.8
1.8. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 8: Serum potassium
1.9
1.9. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 9: Change in serum potassium
1.10
1.10. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 10: Hypokalaemia
1.11
1.11. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 11: Hospitalisation
1.12
1.12. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 12: Angina pectoris
1.13
1.13. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 13: Infection
1.14
1.14. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 14: Systolic blood pressure
1.15
1.15. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 15: Change in systolic blood pressure
1.16
1.16. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 16: Diastolic blood pressure
1.17
1.17. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 17: Change in diastolic blood pressure
1.18
1.18. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 18: HRQoL
1.19
1.19. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 19: Change in Health‐related QoL
1.20
1.20. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 20: Shunt stenosis
1.21
1.21. Analysis
Comparison 1: Potassium binder versus placebo, Outcome 21: Kidney transplantation
2.1
2.1. Analysis
Comparison 2: Calcium polystyrene sulfonate (CPS) versus sodium polystyrene sulfonate (SPS), Outcome 1: Nausea
2.2
2.2. Analysis
Comparison 2: Calcium polystyrene sulfonate (CPS) versus sodium polystyrene sulfonate (SPS), Outcome 2: Diarrhoea
2.3
2.3. Analysis
Comparison 2: Calcium polystyrene sulfonate (CPS) versus sodium polystyrene sulfonate (SPS), Outcome 3: Vomiting
2.4
2.4. Analysis
Comparison 2: Calcium polystyrene sulfonate (CPS) versus sodium polystyrene sulfonate (SPS), Outcome 4: Constipation
2.5
2.5. Analysis
Comparison 2: Calcium polystyrene sulfonate (CPS) versus sodium polystyrene sulfonate (SPS), Outcome 5: Abdominal pain
2.6
2.6. Analysis
Comparison 2: Calcium polystyrene sulfonate (CPS) versus sodium polystyrene sulfonate (SPS), Outcome 6: Serum potassium
2.7
2.7. Analysis
Comparison 2: Calcium polystyrene sulfonate (CPS) versus sodium polystyrene sulfonate (SPS), Outcome 7: Systolic blood pressure
2.8
2.8. Analysis
Comparison 2: Calcium polystyrene sulfonate (CPS) versus sodium polystyrene sulfonate (SPS), Outcome 8: Diastolic blood pressure
3.1
3.1. Analysis
Comparison 3: High dose potassium binder versus low dose potassium binder, Outcome 1: Death (any cause)
3.2
3.2. Analysis
Comparison 3: High dose potassium binder versus low dose potassium binder, Outcome 2: Diarrhoea
3.3
3.3. Analysis
Comparison 3: High dose potassium binder versus low dose potassium binder, Outcome 3: Constipation
3.4
3.4. Analysis
Comparison 3: High dose potassium binder versus low dose potassium binder, Outcome 4: Hypokalaemia
3.5
3.5. Analysis
Comparison 3: High dose potassium binder versus low dose potassium binder, Outcome 5: Stroke
3.6
3.6. Analysis
Comparison 3: High dose potassium binder versus low dose potassium binder, Outcome 6: Myocardial infarction
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References

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References to ongoing studies

DIALIZE China 2020 {published data only}
    1. Ni Z. Reduce incidence of pre-dialysis hyperkalaemia with sodium zirconium cyclosilicate in Chinese subjects (DIALIZE China). www.clinicaltrials.gov/ct2/show/NCT04217590 (first received 3 January 2020).
DIAMOND 2019 {published data only}
    1. Goehring UM. Patiromer for the management of hyperkalemia in subjects receiving RAASi medications for the treatment of heart failure (DIAMOND). www.clinicaltrials.gov/ct2/show/NCT03888066 (first received 25 March 2019).
NCT03781089 {published data only}
    1. Middleton JP. Patiromer efficacy to reduce episodic hyperkalemia in end stage renal disease patients. www.clinicaltrials.gov/ct2/show/NCT03781089 (first received 19 December 2018).

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References to other published versions of this review

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