Potassium Binders For Chronic Hyperkalaemia in People With Chronic

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Potassium binders for chronic hyperkalaemia in people with chronic
kidney disease (Review)
Natale P, Palmer SC, Ruospo M, Saglimbene VM, Strippoli GFM
Natale P, Palmer SC, Ruospo M, Saglimbene VM, Strippoli GFM.

Potassium binders for chronic hyperkalaemia in people with chronic kidney disease.
Cochrane Database of Systematic Reviews 2020, Issue 6. Art. No.: CD013165.
DOI: 10.1002/14651858.CD013165.pub2.
www.cochranelibrary.com

Potassium binders for chronic hyperkalaemia in people with chronic kidney disease (Review)
Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.

Library Better health. Cochrane Database of Systematic Reviews
TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 4
BACKGROUND.............................................................................................................................................................................................. 9
OBJECTIVES.................................................................................................................................................................................................. 10
METHODS..................................................................................................................................................................................................... 10
RESULTS........................................................................................................................................................................................................ 13
Figure 1.................................................................................................................................................................................................. 14
Figure 2.................................................................................................................................................................................................. 15
Figure 3.................................................................................................................................................................................................. 16
DISCUSSION.................................................................................................................................................................................................. 18
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 20
ACKNOWLEDGEMENTS................................................................................................................................................................................ 20
REFERENCES................................................................................................................................................................................................ 21
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 28
DATA AND ANALYSES.................................................................................................................................................................................... 65
Analysis 1.1. Comparison 1: Potassium binder versus placebo, Outcome 1: Death (any cause)...................................................... 69
Analysis 1.2. Comparison 1: Potassium binder versus placebo, Outcome 2: Cardiovascular death................................................ 69
Analysis 1.3. Comparison 1: Potassium binder versus placebo, Outcome 3: Nausea....................................................................... 70
Analysis 1.4. Comparison 1: Potassium binder versus placebo, Outcome 4: Diarrhoea................................................................... 70
Analysis 1.5. Comparison 1: Potassium binder versus placebo, Outcome 5: Vomiting.................................................................... 71
Analysis 1.6. Comparison 1: Potassium binder versus placebo, Outcome 6: Constipation.............................................................. 71
Analysis 1.7. Comparison 1: Potassium binder versus placebo, Outcome 7: Abdominal pain......................................................... 72
Analysis 1.8. Comparison 1: Potassium binder versus placebo, Outcome 8: Serum potassium...................................................... 72
Analysis 1.9. Comparison 1: Potassium binder versus placebo, Outcome 9: Change in serum potassium...................................... 72
Analysis 1.10. Comparison 1: Potassium binder versus placebo, Outcome 10: Hypokalaemia........................................................ 73
Analysis 1.11. Comparison 1: Potassium binder versus placebo, Outcome 11: Hospitalisation...................................................... 73
Analysis 1.12. Comparison 1: Potassium binder versus placebo, Outcome 12: Angina pectoris...................................................... 74
Analysis 1.13. Comparison 1: Potassium binder versus placebo, Outcome 13: Infection................................................................. 74
Analysis 1.14. Comparison 1: Potassium binder versus placebo, Outcome 14: Systolic blood pressure......................................... 74
Analysis 1.15. Comparison 1: Potassium binder versus placebo, Outcome 15: Change in systolic blood pressure........................ 74
Analysis 1.16. Comparison 1: Potassium binder versus placebo, Outcome 16: Diastolic blood pressure........................................ 75
Analysis 1.17. Comparison 1: Potassium binder versus placebo, Outcome 17: Change in diastolic blood pressure....................... 75
Analysis 1.18. Comparison 1: Potassium binder versus placebo, Outcome 18: HRQoL.................................................................... 75
Analysis 1.19. Comparison 1: Potassium binder versus placebo, Outcome 19: Change in Health-related QoL............................... 75
Analysis 1.20. Comparison 1: Potassium binder versus placebo, Outcome 20: Shunt stenosis....................................................... 76
Analysis 1.21. Comparison 1: Potassium binder versus placebo, Outcome 21: Kidney transplantation.......................................... 76
Analysis 2.1. Comparison 2: Calcium polystyrene sulfonate (CPS) versus sodium polystyrene sulfonate (SPS), Outcome 1: 77
Nausea...................................................................................................................................................................................................
Diarrhoea...............................................................................................................................................................................................
Vomiting.................................................................................................................................................................................................
Constipation..........................................................................................................................................................................................
Abdominal pain.....................................................................................................................................................................................
Analysis 2.6. Comparison 2: Calcium polystyrene sulfonate (CPS) versus sodium polystyrene sulfonate (SPS), Outcome 6: Serum 78
potassium..............................................................................................................................................................................................
Systolic blood pressure........................................................................................................................................................................
Potassium binders for chronic hyperkalaemia in people with chronic kidney disease (Review) i
Informed decisions.

Diastolic blood pressure.......................................................................................................................................................................
Analysis 3.1. Comparison 3: High dose potassium binder versus low dose potassium binder, Outcome 1: Death (any cause)....... 79
Analysis 3.2. Comparison 3: High dose potassium binder versus low dose potassium binder, Outcome 2: Diarrhoea................... 79
Analysis 3.3. Comparison 3: High dose potassium binder versus low dose potassium binder, Outcome 3: Constipation.............. 79
Analysis 3.4. Comparison 3: High dose potassium binder versus low dose potassium binder, Outcome 4: Hypokalaemia........... 80
Analysis 3.5. Comparison 3: High dose potassium binder versus low dose potassium binder, Outcome 5: Stroke........................ 80
Analysis 3.6. Comparison 3: High dose potassium binder versus low dose potassium binder, Outcome 6: Myocardial infarction.... 80
ADDITIONAL TABLES.................................................................................................................................................................................... 80
APPENDICES................................................................................................................................................................................................. 81
HISTORY........................................................................................................................................................................................................ 85
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 85
DECLARATIONS OF INTEREST..................................................................................................................................................................... 85
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 85
Potassium binders for chronic hyperkalaemia in people with chronic kidney disease (Review) ii
Informed decisions.

[Intervention Review]
Potassium binders for chronic hyperkalaemia in people with chronic

kidney disease
Patrizia Natale1,2, Suetonia C Palmer3, Marinella Ruospo1,2, Valeria M Saglimbene1,2, Giovanni FM Strippoli1,2,4
1Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy. 2Sydney School of Public Health, The University of
Sydney, Sydney, Australia. 3Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand. 4Cochrane Kidney
and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia
Contact address: Giovanni FM Strippoli, giovanni.strippoli@uniba.it, gfmstrippoli@gmail.com.
Editorial group: Cochrane Kidney and Transplant Group.

Publication status and date: New, published in Issue 6, 2020.
Citation: Natale P, Palmer SC, Ruospo M, Saglimbene VM, Strippoli GFM. Potassium binders for chronic hyperkalaemia
in people with chronic kidney disease. Cochrane Database of Systematic Reviews 2020, Issue 6. Art. No.: CD013165. DOI:
10.1002/14651858.CD013165.pub2.
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
Potassium binders for chronic hyperkalaemia in people with chronic kidney disease (Review) 1
Informed decisions.

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.
PLAIN LANGUAGE SUMMARY
Are potassium treatments effective for reduce the excess of potassium among people with chronic kidney disease?
What is the issue?
High levels of potassium (a body salt) can build up with chronic kidney disease. This can lead to changes in muscle function including
the heart muscle, and cause problems with heart rhythms that can be dangerous. Dialysis can remove potassium from the blood, but
for some patients levels can still be high. Patients with severe kidney failure who have not yet started dialysis may have high potassium
levels. Treatments have been available for many years but can cause constipation and abdominal discomfort, which make them intolerable
for many patients. Newer treatments have been developed including patiromer and sodium zirconium cyclosilicate. These may be more
tolerable but it is uncertain whether they help to prevent heart complications.
What did we do?
We searched for all the research trials that have assessed the potassium-lowering treatments for children and adults with chronic kidney
diseases. We evaluated how certain we could be about the overall findings using a system called "GRADE".
What did we find?
Informed decisions.

There are 15 studies involving 1849 randomised adults. Patients in the studies were given a potassium binder or a dummy pill (placebo)
or standard care. The treatment they got was decided by random chance. The studies were generally short-term over days to weeks and
focused on potassium levels. Heart related complications could not be measured in this short time frame. Based on the existing research,
we can't be sure whether potassium binders improve well-being or prevent complications in people with chronic kidney disease. There
were no studies in children.
Conclusions
We can't be certain about the best treatments to reduce body potassium levels for people with chronic kidney disease. We need more
information from clinical studies that involve a larger number of patients who have the treatment over several months or years.
SUMMARY OF FINDINGS

Summary of findings 1. Potassium binder versus placebo for chronic hyperkalaemia in people with chronic kidney disease (CKD)
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Potassium binder versus placebo for chronic hyperkalaemia in people with CKD
Patient or population: people with CKD (including haemodialysis)
Settings: majority of studies involved people with CKD not requiring dialysis. Only one study involved people undergoing haemodialysis
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Trusted evidence.
Intervention: newer agents (patiromer, ZS-9, RLY5016) or older agents (SPS, CPS)
Comparison: placebo
Outcomes Illustrative comparative risks* Relative No. of Quality of Comments

(95% CI) effect partici- the evi-
(95% CI) pants dence
Assumed Corresponding (stud- (GRADE)
risk risk ies)
Placebo Potassium
binder
Death (any 6 per 1000 2 fewer per 1000 RR 0.69 688 (4) ⊕⊕⊝⊝ Potassium binder may make little or no difference to death (any cause)
cause) (5 fewer to 20 (0.11 to low 1, 2 compared to placebo in CKD
more) 4.32) (CKD, 3
Follow-up: 0.29 studies) The effect of potassium binder on death (any cause) in HD is very uncertain
to 14 weeks
(median 9 ⊕⊝⊝⊝
weeks) very low
1,2,3 (HD, 1
study)

Cardiovascular No events 1/97** RR 3.06 196 (1) ⊕⊝⊝⊝ Studies were not designed to measure effects of potassium binder on car-
death (newer (0.13 to very low 4 diovascular death in HD
agents) 74.24)
Follow-up: 10
weeks
Cardiac ar- Not report- Not reported -- -- -- No studies reported this outcome
rhythmia ed
HRQoL The mean change in HRQoL in -- 289 (1) ⊕⊝⊝⊝ Studies were not designed to measure effects of potassium binder on
the potassium binder group very low 5 HRQoL in CKD
4

Follow-up: 14 was 2 points higher (0.22 to 3.78
weeks points higher) than the placebo
group
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Serum potassi- The mean serum potassium level -- 277 (3) ⊕⊕⊝⊝ Potassium binders may lower serum potassium levels compared to placebo
um in the placebo group ranged from low 1, 6 (CKD or no treatment in CKD and HD
4.85 to 5.70 mg/dL and HD, 2
Follow-up: 1 to studies and Additional comments
10 weeks (me- The mean serum potassium lev- 1 study, re-
dian 5 weeks) el in the phosphate binder group 1) Serum potassium - newer agents (patiromer, ZS-9, RLY5016)
spectively)
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Trusted evidence.
was 0.62 mg/dL lower (0.97 to
Follow-up: 8 to 10 weeks (median 9 weeks)
0.27 mg/dL lower)
The mean serum potassium level ranged across control groups from 4.85 to
5.70 mg/dL
The mean serum potassium level with newer agents was 0.45 mg/dL lower
(0.71 to 0.19 mg/dL lower)
2) Serum potassium - older agents (SPS, CPS)
Follow-up: 1 week
The mean serum potassium level in the control arm was 5.03 mg/dL
The mean serum potassium level with the older agents was 1.04 mg/dL
lower (1.37 to 0.71 mg/dL lower)
Constipation 36 per 1000 21 more per RR 1.58 425 (4) ⊕⊕⊝⊝ Potassium binder may make little or no difference to constipation com-
1000 low 1,2 (CKD, pared to placebo in CKD
Follow-up: 0.29 (10 fewer to 90 (0.71 to 3 studies)
to 10 weeks more) 3.52) It is very uncertain the effect of potassium binder on constipation in HD
(median 4.5 ⊕⊝⊝⊝
weeks) very low
1,2,3 (HD, 1
study)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the as-
sumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; CKD: chronic kidney disease; CPS: calcium polystyrene sulphonate; HRQoL: health-related quality of life; RR: risk ratio; SPS: sodium polystyrene
sulphonate
GRADE Working Group grades of evidence
** Event rate derived from the raw data. A 'per thousand' rate is non-informative in view of the scarcity of evidence and zero events in the control group.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
5

Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
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1 Evidence certainty was downgraded by one level due to study limitations. Most studies had unclear risks for sequence generation and allocation concealment and some studies
were not blinded (participants and/or investigators)
2 Evidence certainty was downgraded by one level due to imprecision
3 Evidence certainty was downgraded by one level due to indirectness population
4 Cardiovascular death was reported by as a single study
5 HRQoL was reported by as a single study
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6 Evidence certainty was downgraded by one level due to substantial between-study heterogeneity

Summary of findings 2. Calcium polystyrene sulphonate (CPS) versus sodium polystyrene sulphonate (SPS) for chronic hyperkalaemia in people
with chronic kidney disease (CKD)
CPS versus SPS for chronic hyperkalaemia in people with CKD
Patient or population: people with CKD
Settings: all studies involved people with CKD not requiring dialysis
Intervention: CPS
Comparison: SPS
Outcomes Illustrative comparative risks* (95% CI) Relative No. of Qual- Comments
effect partici- ity of
Assumed risk Corresponding risk (95% CI) pants the evi-
(stud- dence
Sodium polystyrene Calcium polystyrene sulphonate ies) (GRADE)
sulphonate (SPS) (CPS)
Death (any cause) Not reported Not reported -- -- -- No studies reported this outcome

Cardiovascular Not reported Not reported -- -- -- No studies reported this outcome
death
Cardiac arrhythmia Not reported Not reported -- -- -- No studies reported this outcome
HRQoL Not reported Not reported -- -- -- No studies reported this outcome
Serum potassium The mean serum potassium level in the SPS group ranged from 4.12 -- 117 (2) ⊕⊕⊝⊝ CPS may make little or no difference
to 4.30 mg/dL low 1, 2 to serum potassium level compared to
SPS
6

Follow-up: 0.43 to 4 The mean serum potassium level in the CPS group was 0.38 mg/dL
weeks (median 2.2 higher (0.03 lower to 0.79 mg/dL higher)
weeks)
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Constipation 170 per 1000 51 fewer per 1000 RR 0.70 97 (1) ⊕⊕⊝⊝ Studies were not designed to measure
(0.26 to low 3 effects of CPS or SPS on constipation
Follow-up: 0.43 (126 fewer to 150 more) 1.88)
weeks
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Trusted evidence.
sumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; CKD: chronic kidney disease; CPS: calcium polystyrene sulphonate; HRQoL: health-related quality of life; RR: risk ratio; SPS: sodium polystyrene
sulphonate

1 Evidence certainty was downgraded by one level due to study limitations. All studies had unclear risks for random sequence generation and allocation concealment and were
not blinded (participants and/or investigators)
2 Evidence certainty was downgraded by one level due to moderate between-study heterogeneity
3 Constipation was reported by as a single study

Summary of findings 3. High versus with low-dose potassium binder for chronic hyperkalaemia in people with chronic kidney disease (CKD)
High versus with low-dose potassium binder for chronic hyperkalaemia in people with CKD
Patient or population: people with CKD

Settings: all studies involved people with CKD not requiring dialysis
Intervention: high-dose potassium binder
Comparison: low-dose potassium binder
Outcomes Illustrative comparative risks* (95% CI) Relative No. of Qual- Comments
effect partici- ity of
Assumed risk Corresponding risk (95% CI) pants the evi-
(stud- dence
Low-dose potassi- High-dose potassium binder ies) (GRADE)
um binder
7

Death (any cause; 10 per 1000 9 more per 1000 (8 fewer to 201 RR 1.94 203 (1) ⊕⊕⊝⊝ Studies were not designed to measure effects of
sudden death) more) (0.18 to low 1 high-dose potassium binder on death (any cause)
21.08)
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Cardiovascular Not reported Not reported -- -- -- No studies reported this outcome
death
Cardiac arrhythmia Not reported Not reported -- -- -- No studies reported this outcome
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HRQoL Not reported Not reported -- -- -- No studies reported this outcome
Serum potassium Not reported Not reported -- -- -- No studies reported this outcome
Constipation 60 per 1000 28 more per 1000 (28 fewer to RR 1.46 203 ⊕⊕⊝⊝ Studies were not designed to measure effects of
176 more) (0.54 to low 2 high dose potassium binder on constipation
Follow-up: 53 weeks 3.94) (1 study)
sumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; CKD: chronic kidney disease; HRQoL: health-related quality of life; RR: risk ratio

1 Death (any cause; sudden death) was reported by as a single study

2 Constipation was reported by a single study


8

Informed decisions.

BACKGROUND The potassium exchange resins may be administered orally or

per rectum. The first US Food and Drug Administration (FDA)-
Description of the condition approved potassium binder for the treatment of hyperkalaemia
was sodium polystyrene sulfonate, approved for use in 1958.
Hyperkalaemia, defined as a serum potassium > 5.5 mmol/L is
Sodium polystyrene sulfonate exchanges sodium for potassium,
one of the most common laboratory electrolyte abnormalities
increasing faecal potassium excretion. Despite the absence of high-
(Betts 2018). Hyperkalaemia may result from various acute and
quality randomised controlled trials (RCTs) confirming benefits
chronic conditions that affect renal potassium excretion including
on patient-level outcomes, sodium polystyrene sulfonate became
a decreased glomerular filtration rate (GFR), and impaired adaptive
widely used. Documented adverse effects of treatment included
responses to hyperkalaemia, such as decreased aldosterone
nausea, vomiting, and constipation. Co-administration of sorbitol
release or extrarenal excretion across the gut. In addition, to
to increase potassium excretion may infrequently have caused fatal
impaired potassium excretion in chronic kidney diseases (CKD),
intestinal necrosis (Cowan 2017; Davidson 2017).
hyperkalaemia can be incurred by renin-angiotensin-aldosterone
system (RAAS) inhibitors as first-line therapy to lower blood A second potassium-binding agent, calcium polystyrene sulfonate,
pressure (James 2014). Hyperkalaemia frequently results in down- exchanges calcium for potassium in the distal colon, thus
titration or discontinuation of such guideline-directed therapy potentially limiting the sodium retention associated with sodium
(Collins 2017) and may be associated with poorer clinical outcomes polystyrene sulfonate and providing calcium supplementation.
as a result, especially in patients with structural cardiac disease Calcium polystyrene sulfonate may also cause GI adverse events,
(Montford 2017). Because of the key role of the kidney in including colonic necrosis and perforation, which has led to
maintaining potassium homeostasis, CKD (GFR category 3 to 5) and warnings in the prescribing information (Das 2018; Yu 2017).
acute kidney injury are the most important risk factors associated
with hyperkalaemia, and as the estimated (e) GFR decreases, the Newer ion exchange resins have been developed for treatment
rates of major cardiovascular events and death increase (Tamargo of hyperkalaemia. These include patiromer and sodium zirconium
2018), especially in low-income countries (Chowdhury 2018). cyclosilicate (also known as ZS-9) (Cowan 2017). Patiromer is a
potassium binder consisting of a non absorbed cation exchange
Hyperkalaemia occurs at a rate of approximately 8/100 person- polymer together with a calcium-sorbitol counter-ion complex that
months for people with CKD (GFR < 60 mL/min/1.73 m2) and increases stability. Patiromer exchanges potassium ions for calcium
commonly occurs among people who have other comorbidities ions, which may limit exposure to sodium for patients who are
such as heart failure, diabetes mellitus, and hypertension (Alvarez sensitive to sodium delivery including those with severe kidney,
2017; Einhorn 2009). The prevalence of hyperkalaemia in the heart, or liver failure. ZS-9 is an insoluble, non-absorbed compound
general population has been estimated at 2% to 3% (Kumar that has a lattice structure with octahedral- and tetrahedral-
2017). When the eGFR decreases from between 60 to 90 to below coordinated zirconium and silicon atoms bridged by oxygen that
20 mL/min/1.73 m2, the prevalence of hyperkalaemia (> 5 mEq/ exchange sodium and hydrogen for potassium and ammonium
L) increases from 2% to 42% and to 56.7% in patients with as it moves through the GI tract (Kumar 2017). The zirconium
CKD GFR category 5 (Tamargo 2018). Hyperkalaemia has been octahedral units confer a negative charge to favour cation exchange
reported to develop in 44% to 73% of transplant recipients who and entrapment of potassium ions.
receive immunosuppressive therapy with cyclosporin or tacrolimus
(Palmer 2004). Patiromer and ZS-9 are available as a powder for oral suspension,
and do not expand within the GI tract, which may lead to lower
For many individuals, hyperkalaemia can be asymptomatic or GI adverse effects, such as diarrhoea, constipation, nausea, and
present with nonspecific signs and symptoms (e.g. weakness, vomiting.
fatigue, or gastrointestinal (GI) hypermotility) (Ng 2017) and
it has been suggested that the incidence and prevalence of Other adverse events are rarely reported. ZS-9 also binds and
hyperkalaemia in the general population is underestimated excretes ammonium ions which may lead to increased plasma
(Davidson 2017; Rafique 2017). In the setting of CKD or heart bicarbonate levels at higher doses. These changes might have
failure, the overall medical costs can be higher for people with potential benefit for patients with CKD, who often present with
hyperkalaemia compared with patients without hyperkalaemia metabolic acidosis (Tamargo 2018).
(Alvarez 2017).
How the intervention might work
Description of the intervention Patiromer lowers and maintains serum potassium levels among
Until recently, treatment strategies for chronic hyperkalaemia people with CKD who are prescribed RAAS inhibitors (AMETHYST-
have been limited to dietary potassium restriction, reducing DN 2015; Weir 2015). ZS-9 normalises potassium levels in patients
or eliminating exacerbating factors including RAAS inhibitor receiving RAAS inhibitors for the treatment of cardiovascular
treatment, mineralocorticoid administration or introducing loop or kidney disease (HARMONIZE 2014; Packham 2015). Newer
diuretics with or without sodium bicarbonate (Dunn 2015; Fried potassium binders may have greater selectivity for potassium than
2017; Rafique 2017). These treatment options can be unsustainable other cations such as calcium and magnesium and may therefore
due to poor tolerability or may be relatively ineffective (dietary result in lower risk of clinical electrolyte abnormalities.
restriction).
Through reductions in serum potassium, potassium exchange
Potassium binders are artificial resins that exchange cations (e.g. resins are hypothesised to improve clinically-relevant endpoints
sodium or calcium) bound to a resin for potassium ions in the gut. associated with hyperkalaemia such as death and cardiovascular
This exchange increase potassium excretion in the stool. events. However, while potassium exchange resins have been
Informed decisions.

shown to lower serum potassium levels and reduce recurrence hyperkalaemia (including people with progressive kidney decline,
of hyperkalaemia compared to placebo (AMETHYST-DN 2015; comorbidities, the use of medications that affect the RAAS, and a
HARMONIZE 2014; Packham 2015; PEARL-HF 2011; Weir 2015) in diet high potassium) (Bozkurt 2003; Einhorn 2009; Moranne 2009;
proof-of-concept, short-term studies, there is limited evidence RALES 1996; Shah 2005; Weiner 2010). We also included studies
regarding the efficacy and safety of these interventions involving participants with tubular renal disorders associated with
on clinically-relevant endpoints such as hospitalisation and hyperkalaemia, including renal tubular acidosis disorders and
cardiovascular complications (AMETHYST-DN 2015; Tamargo 2018). pseudo-hypoaldosteronism types 1 and 2. Chronic hyperkalaemia
was defined as serum potassium levels > 5.5 mmol/L (> 5.5 mEq/
The effectiveness and safety of treatments may differ in people L). CKD was defined by Kidney Disease: Improving Global Outcomes
with CKD compared with other populations, due to the increased (KDIGO) guidelines for evaluation and management of CKD (KDIGO
prevalence of metabolic derangements (e.g. hypocalcaemia, 2013) and included all stages of CKD. We included people treated
acidosis, and elevated uraemic solutes), bowel dysfunction, with dialysis (CKD stage 5D), those who had end-stage kidney
structural heart disease, and the altered metabolism of commonly- disease (ESKD) treated with conservative care, recipients of a
used medications that may lead to drug-drug interactions. kidney transplant (CKD 5T), and those with earlier stages (1 to 4) of
CKD. We included studies of potassium binders for hyperkalaemia
Why it is important to do this review in people with several medical conditions (such as heart failure)
Newer potassium exchange resins have recently been approved by if the study included people with CKD. We obtained all study
the FDA (patiromer; FDA 2015 and ZS-9; FDA 2018) and older agents characteristics and outcome data pertaining to people with CKD, if
have been widely adopted into clinical practice. In light of the these data were not available within study reports.
emergence of new pharmacological agents for hyperkalaemia and
Exclusion criteria
recent RCTs, it is necessary to review the evidence of effectiveness
and tolerability of all potassium exchange resins among people We excluded studies that evaluated acute management of
with CKD. hyperkalaemia using interventions such as salbutamol, calcium
gluconate, insulin-dextrose, or sodium bicarbonate. We excluded
As current studies of potassium exchange resins principally use studies of interventions for hyperkalaemia within the hospital
hyperkalaemia and serum potassium levels as the primary efficacy setting.
outcomes, it is important to accumulate data from all existing
studies to evaluate the evidence for patient-centred endpoints Types of interventions
including adverse events and death. A comprehensive systematic
review is required to provide guidance to practitioners and We included studies that evaluated potassium binders defined as
policy-makers interested in using potassium exchange resins for potassium exchange resins that act to bind potassium within the GI
hyperkalaemia and to enable greater use of therapies that may also tract including calcium polystyrene sulfonate, sodium polystyrene
incur hyperkalaemia, such as RAAS inhibitors. We did not examine sulfonate with or without sorbitol, patiromer sorbitex calcium,
studies evaluating treatment of acute hyperkalaemia or emergency and ZS-9. Control of serum potassium levels could be achieved
interventions for hyperkalaemia as these have been summarised in regardless of the route of administration, duration, frequency,
previous Cochrane reviews (Batterink 2015; Mahoney 2005). or dose of the potassium binders. We included interventions
administered orally or rectally.
OBJECTIVES
Comparator treatments could be any of the following.
To assess the benefits and harms of potassium binders for treating
• Placebo
chronic hyperkalaemia among adults and children with CKD.
• Usual care (best supportive care)
METHODS • Second potassium binder
• Dietary restriction
Criteria for considering studies for this review
• Withdrawal of RAAS inhibition
Types of studies • Different doses of a potassium binder
We included all RCTs of any design (e.g. parallel, cross-over, • Different routes of administration
factorial) and controlled clinical studies using a quasi-randomised • Different frequency of administration.
method of allocation (such as alternation, use of alternate medical
records, date of birth, or other predictable methods). Reports Types of outcome measures
of studies were eligible regardless of the language used or date The outcomes selected included the relevant SONG core outcome
of publication. We included studies published as full articles or sets as specified by the Standardised Outcomes in Nephrology
available as a full study report, studies in which results were initiative (SONG 2017).
published on a trial registry, or studies published as conference
proceedings. Primary outcomes
Types of participants • Death (any cause and cardiovascular death)

• Health-related quality of life (HRQoL) (using any validated
Inclusion criteria
HRQoL measure)
We included studies that enrolled adults and children with • GI symptoms (major or minor) (see Table 1 for definitions)
CKD and with chronic hyperkalaemia or at risk of chronic
Informed decisions.

Secondary outcomes Studies contained in the Register are identified through searches of
CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane
• Serum potassium level
Kidney and Transplant. Details of search strategies, as well as a
• Cardiovascular disease (including cardiac arrhythmia) list of handsearched journals, conference proceedings and current
• Hospitalisation (any cause) awareness alerts, are available on the Cochrane Kidney and
• Life participation (any validated measure) Transplant website.
• Vascular access
See Appendix 1 for search terms used in strategies for this review.
• Graft health
• Transplant graft loss, acute rejection, function Searching other resources
• Fatigue 1. Reference lists of review articles, relevant studies, and clinical
• Cancer practice guidelines.
• Infection 2. Contacting relevant individuals/organisations seeking
• Blood pressure (BP) information about unpublished or incomplete studies.
• Withdrawal of blood pressure lowering therapy 3. Grey literature sources (e.g. abstracts, dissertations, and theses),
• Adverse events in addition to those already included in the Cochrane Kidney and
Transplant Register of Studies, were searched.
We included studies that measure outcomes using standardised
questionnaires with established reliability and validity (e.g. PIPER Data collection and analysis
Fatigue Scale, Beck Depression Inventory (BDI), Short-Form 36 Selection of studies
(SF-36)). We extracted endpoints as post-intervention mean or
change scores, together with standard deviations (SD), or the The search strategy described was used to obtain titles and
number of participants experiencing one or more events. We abstracts of studies that may be relevant to the review. The titles
considered the study period and follow-up as described in the and abstracts were screened independently by two authors, who
included studies. discarded studies that were not applicable. Studies and reviews
that might include relevant data or information on studies were
We categorised treatments in newer agents (patiromer or ZS-9) retained initially. Two authors independently assessed retrieved
and older agents (calcium polystyrene sulfonate and sodium abstracts and, if necessary, the full text, of these studies to
polystyrene sulfonate). We reported outcomes as newer or older determine which studies satisfy the predetermined inclusion
agents. Outcomes were assessed at the end of the follow-up criteria. The review authors resolved discrepancies through
or as a change during follow-up. When assessing outcomes in discussion or adjudication by a third author.
relation to time points, we grouped the data as: immediate
post-intervention, short-term (post-intervention to one month), Data extraction and management
medium-term (between one and three months follow-up), and Data extraction was carried out independently by two authors
long-term (more than three months follow-up) effects. We reported using a standard data extraction form developed for this review.
all primary outcomes in a table of Summary of findings for the main The review authors resolved discrepancies through discussion or
comparisons. To maximize clinical utility, we separated studies adjudication by a third author. Studies reported in non-English
according to clinical setting (CKD/dialysis/transplant and for adults language journals were translated before assessment. Where more
and children). Where necessary, we showed the overview of our than one publication of one study existed, reports were grouped
results structure using a diagram to explain to the reader how the together and the publication with the most complete data was used
information was presented. in the analyses. Where relevant outcomes were only published in
earlier versions these data were used. Any discrepancy between
Search methods for identification of studies
published versions was highlighted.
Electronic searches
For each included study, we recorded the following:
We searched the Cochrane Kidney and Transplant Register of
Studies up to 10 March 2020 through contact with the Information • Study characteristics including type (e.g. parallel, cross-over,
Specialist using search terms relevant to this review. The Register factorial), country, source of funding, and trial registration status
contains studies identified from the following sources. (with registration number recorded if available)
• Participant characteristics including age, sex, stage of CKD,
1. Monthly searches of the Cochrane Central Register of Controlled
inclusion criteria, exclusion criteria
Trials (CENTRAL)
• Intervention characteristics for each treatment group, and use
2. Weekly searches of MEDLINE OVID SP
of co-interventions
3. Searches of kidney and transplant journals, and the proceedings
• Outcomes reports including the measurement instrument used
and abstracts from major kidney and transplant conferences
and timing of outcome assessment
4. Searching of the current year of EMBASE OVID SP
5. Weekly current awareness alerts for selected kidney and To prevent/minimise selective inclusion of data based on the
transplant journals results, we used the following a priori defined decision rules to
6. Searches of the International Clinical Trials Register (ICTRP) select data from studies.
Search Portal and ClinicalTrials.gov.
Informed decisions.

• Where trial lists report both final values and change from this and conducted sensitivity analyses to investigate the effect of
baseline for the same outcome, we extracted final values variation in the ICC.
• Where trial lists report both unadjusted and adjusted values for
the same outcome, we extracted unadjusted values Cross-over studies
• Where trial lists report both data analysed on the intention- Cross-over studies were analysed using data from the first study
to-treat principle and another sample (e.g. per protocol, as period before cross-over.
treated), we extracted intention-to-treat data
Dealing with missing data
For cross-over studies, we extracted data from the first period only.
Any further information required from the original author was
Assessment of risk of bias in included studies requested by written correspondence (e.g. emailing corresponding
author/s) and any relevant information obtained in this manner
The following items were independently assessed by two authors was included in the review. Evaluation of important numerical
using the risk of bias assessment tool (Higgins 2011) (see Appendix data such as screened, randomised patients as well as intention-
2). to-treat, as-treated and per-protocol population were carefully
performed. Attrition rates, for example drop-outs, losses to follow-
• Was there adequate sequence generation (selection bias)? up and withdrawals were investigated. Issues of missing data
• Was allocation adequately concealed (selection bias)? and imputation methods (for example, last-observation-carried-
• Was knowledge of the allocated interventions adequately forward) were critically appraised (Higgins 2011).
prevented during the study?
* Participants and personnel (performance bias) If the number of patients analysed was not presented for each time
* Outcome assessors (detection bias) point, we considered the number of randomised patients in each
group at baseline. For continuous outcomes with no SD reported,
• Were incomplete outcome data adequately addressed (attrition we calculated SDs from standard errors (SEs), 95% CIs or P-values
bias)? using the calculator tool in RevMan. If no measures of variation
• Are reports of the study free of suggestion of selective outcome were reported and SDs could not be calculated, we imputed SDs
reporting (reporting bias)? from other studies in the same meta-analysis, using the median
• Was the study apparently free of other problems that could put of the other SDs available. For continuous outcomes presented
it at a risk of bias? only graphically, we extracted the mean and 95% CIs from the
graphs using plotdigitizer (http://plotdigitizer.sourceforge.net/).
Measures of treatment effect For dichotomous outcomes, we used percentages to estimate
For dichotomous outcomes (death (any cause), myocardial the number of events or the number of people assessed for
infarction, stroke, cardiac arrhythmia, hospitalisation, dialysis an outcome. Where data were imputed or calculated (e.g. SDs
vascular access complications, kidney transplant graft outcomes, calculated from SEs, 95% CIs or P-values, or imputed from graphs
cancer, infection, withdrawal of blood pressure lowering therapy, or from SDs in other studies), we reported this in the Characteristics
adverse events), results were expressed as risk ratio (RR) with 95% of included studies.
confidence intervals (CI). Where continuous scales of measurement
Assessment of heterogeneity
were used to assess the effects of treatment (HRQoL, serum
potassium, life participation scales, depression, kidney transplant We assessed clinical heterogeneity by determining whether the
function) the mean difference (MD) was used, or the standardised characteristics of participants, interventions, outcome measures,
mean difference (SMD) if different scales have been used. and timing of outcome measurement are similar across studies. We
assessed the heterogeneity by visual inspection of the forest plot.
Meta-analysis of change scores We quantified statistical heterogeneity using the I2 statistic, which
We considered both change-from-baseline and final value scores describes the percentage of total variation across studies that is due
for continuous outcomes. We combined change-from-baseline to heterogeneity rather than sampling error (Higgins 2003).
outcomes with final measurement outcomes using the MD method.
We interpreted the I2 statistic using the following as an approximate
Time-to-event outcomes guide:
We did not perform meta-analysis of time-to-event outcomes. • 0% to 40%: may not be important heterogeneity
Unit of analysis issues • 30% to 60%: may represent moderate heterogeneity
• 50% to 90%: may represent substantial heterogeneity
Cluster-randomised studies
• 75% to 100%: considerable heterogeneity.
We anticipated that studies using clustered randomisation were
controlled for clustering effects. In case of doubt, we contacted The importance of the observed value of I2 depends on the
the authors to ask for individual participant data to calculate an magnitude and direction of treatment effects and the strength of
estimate of the intra-cluster correlation coefficient (ICC). If this was evidence for heterogeneity (e.g. P-value from the Chi2 test, or a
not possible, we obtained external estimates of the ICC from a confidence interval for I2) (Higgins 2011).
similar study or from a study of a similar population as described
in the Cochrane Handbook for Systematic Reviews of Interventions In the case of considerable heterogeneity, we explored the data
(Higgins 2011). If ICCs from other sources were used, we reported further by comparing the characteristics of individual studies and
any subgroup analyses.
Informed decisions.

Assessment of reporting biases • Repeating the analysis excluding studies using the following
filters: diagnostic criteria, language of publication, source of
To assess publication bias, we planned to generate funnel plots if
funding (industry versus other), and country
at least 10 studies examining the same treatment comparison were
included in the review, and comment on whether any asymmetry However, sensitivity analysis could not be done for heterogeneity
in the funnel plot was due to publication bias, or methodological owing to insufficient data.
or clinical heterogeneity of the studies. To assess for potential
small-study effects in meta-analysis (i.e. the intervention effect is 'Summary of findings' tables
more beneficial in smaller studies), we planned to compare effect
We presented the main results of the review in 'Summary of
estimates derived from a random-effects model and a fixed-effect
findings' tables. These tables present key information concerning
model of meta-analysis. In the presence of small-study effects, the
the quality of the evidence, the magnitude of the effects of
random-effects model could give a more beneficial estimate of the
the interventions examined, and the sum of the available data
intervention than the fixed-effect estimate.
for the main outcomes (Schunemann 2011a). The 'Summary of
To assess outcome reporting bias, we compared the outcomes findings' tables also include an overall grading of the evidence
specified in study protocols with the outcomes reported in the related to each of the main outcomes using the GRADE (Grades
corresponding study publications. of Recommendation, Assessment, Development and Evaluation)
approach (GRADE 2008; GRADE 2011). The GRADE approach defines
Data synthesis the quality of a body of evidence as the extent to which one can be
confident that an estimate of effect or association is close to the
Data were pooled using the random-effects model but the fixed-
true quantity of specific interest. The quality of a body of evidence
effect model was also used to ensure robustness of the model
involves consideration of within-trial risk of bias (methodological
chosen and susceptibility to outliers.
quality), directness of evidence, heterogeneity, precision of effect
Subgroup analysis and investigation of heterogeneity estimates and risk of publication bias (Schünemann 2011b).
We planned to perform subgroup analysis to explore possible We presented the following outcomes in the 'Summary of findings'
sources of heterogeneity (where sufficient data are available). tables.
• Stage of CKD • Death (any cause)

• Co-prescribing of RAAS inhibitors • Cardiovascular death
• Cardiac arrhythmia
However, subgroup analysis could not be done for heterogeneity
• HRQoL
owing to insufficient data.
• Serum potassium
Adverse effects were tabulated and assessed with descriptive • Major GI adverse events or minor GI adverse events
techniques, as they were likely to be different for the various agents (constipation)
used. Where possible, the risk difference (RD) with 95% CI was
calculated for each adverse effect, either compared to no treatment RESULTS
or to another agent.
Description of studies
Sensitivity analysis
Results of the search
We planned to perform sensitivity analyses in order to explore the
influence of the following factors on effect size. The electronic search strategy of the Cochrane Kidney and
Transplant Specialised Register (10 March 2020) identified 105
• Repeating the analysis excluding unpublished studies records and handsearching identified one record (Figure 1). After
• Repeating the analysis taking account of risk of bias, as specified initial title and abstract screening and examination of the full
text, none of the retrieved records were excluded. Three studies
• Repeating the analysis excluding any very long or large studies
are ongoing (DIALIZE China 2020; DIAMOND 2019; NCT03781089)
to establish how much they dominate the results
and will be assessed in a future update of this review. This
review therefore includes 15 studies (103 reports) randomising
1849 adults.

Informed decisions.

Figure 1. Study flow diagram

Included studies Japan, Russia and the UK (DIALIZE 2019), and the USA, Australia and
South Africa (HARMONIZE 2014; Packham 2015). Fourteen studies
The characteristics of the participants and the interventions in
received at least some funding from companies that manufacture
included studies are detailed in the Characteristics of included
potassium binders. Nasir 2014 provided no specific details about
studies table.
funding sources.
Study design, setting and characteristics
Study participants
Study duration varied from 12 hours to 52 weeks, with a median
Twelve studies involved participants with CKD (stages 1 to
of 4 weeks. Three studies (Gruy-Kapral 1998; Nakayama 2018;
5) not requiring dialysis. Three studies (DIALIZE 2019; Gruy-
Wang 2018a) had a cross-over study design in which participants
Kapral 1998; Wang 2018a) involved participants treated with
were administered each of the study interventions sequentially,
haemodialysis (HD). The sample size varied from six participants
with or without a washout period. Studies were conducted from
(Gruy-Kapral 1998) to 320 participants (Packham 2015) (median of
1998 to 2019 in Canada (Lepage 2015), China (Wang 2018a), Japan
39 participants). No studies evaluated treatment in children with
(Kashihara 2018; Nakayama 2018), Pakistan (Nasir 2014), Europe
CKD. The mean study age ranged from 53.1 years (Nasir 2014)
(AMETHYST-DN 2015), Europe and the USA (OPAL-HK 2015), Europe,
to 73 years (Kashihara 2018) (median 66.8 years). Four studies
the USA, Ukraine, Russia, and Georgia (PEARL-HF 2011), Europe,
(HARMONIZE 2014; Packham 2015; PEARL-HF 2011; TOURMALINE
the USA, South Africa, Ukraine and Georgia (AMBER 2018), the
2017) evaluated treatment in people with CKD and heart failure,
USA (Ash 2015; Gruy-Kapral 1998; TOURMALINE 2017), the USA,
diabetes mellitus (type 1 or 2), and/or hypertension.
Informed decisions.

Interventions of patiromer with compared to without food, and AMETHYST-DN

2015 compared high-dose to low-dose patiromer.
Eight studies compared the more recently developed potassium
binders (patiromer and ZS-9) to placebo (AMBER 2018; Ash 2015; There were no studies comparing newer (patiromer and ZS-9) to
DIALIZE 2019; HARMONIZE 2014; Kashihara 2018; OPAL-HK 2015; older (calcium polystyrene sulphonate and sodium polystyrene
Packham 2015; PEARL-HF 2011). Two studies compared an older sulphonate) potassium binders.
potassium binder (sodium polystyrene sulphonate) to placebo
(Gruy-Kapral 1998; Lepage 2015). No studies compared calcium Excluded studies
polystyrene sulphonate to placebo and in one study (Wang
No studies were excluded in this review.
2018a), calcium polystyrene sulphonate was compared to control.
Two studies (Nakayama 2018; Nasir 2014) compared calcium
Risk of bias in included studies
polystyrene sulphonate to sodium polystyrene sulphonate. Gruy-
Kapral 1998 compared sodium polystyrene sulphonate either to The risk of bias for studies overall are summarised in Figure 2 and
laxatives or placebo. TOURMALINE 2017 evaluated administration the risk of bias in each individual study is reported in Figure 3.

Figure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages
across all included studies.
Random sequence generation (selection bias)

Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias): All outcomes
Blinding of outcome assessment (detection bias): All outcomes
Incomplete outcome data (attrition bias): All outcomes
Selective reporting (reporting bias)
Other bias
0% 25% 50% 75% 100%
Low risk of bias Unclear risk of bias High risk of bias

Informed decisions.

Figure 3. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Blinding of participants and personnel (performance bias): All outcomes

Blinding of outcome assessment (detection bias): All outcomes
Incomplete outcome data (attrition bias): All outcomes
Random sequence generation (selection bias)
Allocation concealment (selection bias)
Selective reporting (reporting bias)

Other bias
AMBER 2018 ? + + + + + -
AMETHYST-DN 2015 + + - + + + -
Ash 2015 + ? + + + + -
DIALIZE 2019 ? + + + + + -
Gruy-Kapral 1998 ? ? - + ? - ?
HARMONIZE 2014 ? ? + + ? + -
Kashihara 2018 ? ? + + - - -
Lepage 2015 + ? + - + + +
Nakayama 2018 ? ? - + + + ?
Nasir 2014 ? ? - - + + ?
OPAL-HK 2015 ? ? - + - + -
Packham 2015 ? ? + + ? + -
PEARL-HF 2011 ? ? + + + + -
TOURMALINE 2017 ? ? - + ? + -
Wang 2018a + ? - + + - ?

Allocation of bias for allocation concealment was unclear in the remaining 12
studies.
Methods for generating the random sequence were deemed to be
at low risk of bias in four studies (AMETHYST-DN 2015; Ash 2015; Blinding
Lepage 2015; Wang 2018a). In the remaining 11 studies, the method
for generating the random sequence was unclear. Eight studies (AMBER 2018; Ash 2015; DIALIZE 2019; HARMONIZE
2014; Kashihara 2018; Lepage 2015; Packham 2015; PEARL-HF
Allocation concealment was judged to be at low risk of bias in three 2011) were blinded and considered to be at low risk of bias for
studies (AMBER 2018; AMETHYST-DN 2015; DIALIZE 2019). The risk performance bias. The remaining seven studies were not blinded
and were considered at high risk of performance bias.
Informed decisions.

As most studies were based on laboratory assessment or patient- (1 study, 196 participants): RR 3.06, 95% CI 0.13, 74.24). The
centred outcomes including death, 13 studies were considered at treatment effect of older potassium binders (calcium polystyrene
low risk of bias and two studies (Lepage 2015; Nasir 2014) were sulfonate or sodium polystyrene sulfonate) on death (any cause)
considered as high risk of bias for blinding of outcome assessment. and cardiovascular death was uncertain, as these outcomes were
not reported.
Incomplete outcome data
Potassium binders had uncertain effects on nausea (Analysis 1.3
Nine studies (AMBER 2018; AMETHYST-DN 2015; Ash 2015; DIALIZE
(3 studies, 229 participants): RR 2.10, 95% CI 0.65 to 6.78; I2 =
2019; Lepage 2015; Nakayama 2018; Nasir 2014; PEARL-HF 2011;
0%; low certainty evidence), diarrhoea (Analysis 1.4 (5 studies, 720
Wang 2018a) met criteria for low risk of attrition bias. Two studies
(Kashihara 2018; OPAL-HK 2015) were considered at high risk of participants): RR 0.84, 95% CI 0.47 to 1.48; I2 = 0%; low certainty
attrition bias as there was differential loss to follow-up between evidence), vomiting (Analysis 1.5 (2 studies, 122 participants): RR
treatment groups and high attrition rates was substantially higher 1.72, 95% CI 0.35 to 8.51; I2 = 0%; low certainty evidence) and
in both treatment groups. In the remaining four studies, attrition constipation (Analysis 1.6 (4 studies, 425 participants): RR 1.58, 95%
bias was considered unclear. Loss to follow-up was commonly due CI 0.71 to 3.52; I2 = 0%; low certainty evidence) in CKD. Ash 2015
to withdrawal from the study, lack of available central laboratory reported no difference between potassium binders and placebo for
results or adverse events. abdominal pain (Analysis 1.7 (1 study, 90 participants): RR 1.52, 95%
CI 0.06 to 36.34) in CKD.
Selective reporting
Potassium binders may lower serum potassium levels at the end of
Twelve studies (AMBER 2018; AMETHYST-DN 2015; Ash 2015; treatment (Analysis 1.8 (3 studies, 277 participants): MD -0.62 mEq/
DIALIZE 2019; HARMONIZE 2014; Lepage 2015; Nakayama 2018; L, 95% CI -0.97 to -0.27; I2 = 92%; low certainty evidence) in CKD
Nasir 2014; OPAL-HK 2015; Packham 2015; PEARL-HF 2011; and HD, and may favourably change serum potassium levels during
TOURMALINE 2017) reported expected and clinically-relevant treatment (Analysis 1.9 (2 studies, 105 participants): MD -0.75 mEq/
outcomes and were deemed to be at low risk of bias. The remaining
L, 95% CI -1.27 to -0.23; I2 = 90%; low certainty evidence) in CKD.
three studies did not report patient-centred outcomes of death or
There was substantial statistical heterogeneity in the treatment
adverse events.
effects between studies.
Other potential sources of bias
Potassium binders may make little or no difference to
One study (Lepage 2015) appeared to be free from other sources hypokalaemia (Analysis 1.10 (2 studies, 228 participants): RR
of bias. Ten studies (AMBER 2018; AMETHYST-DN 2015; Ash 1.71, 95% CI 0.31 to 9.47; I2 = 34%; low certainty evidence), and
2015; DIALIZE 2019; HARMONIZE 2014; Kashihara 2018; OPAL-HK hospitalisation (Analysis 1.11 (3 studies, 522 participants): RR 0.26,
2015; Packham 2015; PEARL-HF 2011; TOURMALINE 2017) were 95% CI 0.03 to 2.32; I2 = 0%; low certainty evidence) in CKD
considered at high risk of bias due to the potential role of funding and HD. DIALIZE 2019 reported no difference between potassium
and for the remaining four studies the assessment of other source binders and placebo for angina pectoris (Analysis 1.12 (1 study, 196
of bias was unclear. participants): RR 5.10, 95% CI 0.25 to 104.92) and infection (Analysis
1.13 (1 study, 196 participants): RR 1.36, 95% CI 0.60 to 3.08) in HD.
Effects of interventions
Potassium binders may decrease systolic BP (Analysis 1.14 (2
See: Summary of findings 1 Potassium binder versus placebo
studies, 369 participants): MD -3.73 mmHg, 95% CI -6.64 to
for chronic hyperkalaemia in people with chronic kidney disease
(CKD); Summary of findings 2 Calcium polystyrene sulphonate -0.83; I2 = 79%; low certainty evidence) (Analysis 1.15 (1 study,
(CPS) versus sodium polystyrene sulphonate (SPS) for chronic 74 participants): MD -5.49 mmHg, 95% CI -6.32 to -4.66), with
hyperkalaemia in people with chronic kidney disease (CKD); substantial statistical heterogeneity in the treatment effects
Summary of findings 3 High versus with low-dose potassium between studies, and diastolic BP (Analysis 1.16 (1 study. 74
binder for chronic hyperkalaemia in people with chronic kidney participants): MD -2.65 mmHg, 95% CI -3.44 to -1.86) (Analysis 1.17
disease (CKD) (1 study, 74 participants): MD -3.87 mmHg, 95% CI -4.42 to -3.32) in
CKD.
Potassium binder versus placebo
AMBER 2018 reported no difference between potassium binders
Ten studies (AMBER 2018; Ash 2015; DIALIZE 2019; Gruy-Kapral and placebo for HRQoL at end of treatment (Analysis 1.18 (1 study,
1998; HARMONIZE 2014; Kashihara 2018; Lepage 2015; OPAL-HK 189 participants): EuroQoL score MD 2.60, 95% CI 0.04, 5.16) and
2015; Packham 2015; PEARL-HF 2011) involving 1367 randomised change HRQoL (Analysis 1.19 (1 study, 189 participants): EuroQoL
participants compared a potassium binder to placebo. The median score MD 2.00, 95% CI 0.22 to 3.78) in CKD.
follow-up was 3.4 weeks. The certainty of the evidence was low for
all outcomes (Summary of findings 1) in CKD and low or very low DIALIZE 2019 reported no difference between potassium binders
in HD. and placebo for shunt stenosis (Analysis 1.20 (1 study, 196
participants): RR 0.34 (95% CI 0.04 to 3.21) and kidney
Newer potassium binders (patiromer or ZS-9) may make little or transplantation (Analysis 1.21 (1 study, 196 participants): RR 0.34,
no difference to all-cause death (any cause) in CKD (Analysis 1.1 95% CI 0.01 to 8.25) in HD.
(4 studies, 688 participants): RR 0.69, 95% CI 0.11 to 4.32; I2 =
0%; low certainty evidence), and DIALIZE 2019 (196 participants) There were no available data for the outcomes of cardiac
reported no difference between potassium binders and placebo arrhythmia or major GI events.
for cardiovascular death in people requiring HD (Analysis 1.2.1
Informed decisions.

Calcium polystyrene sulfonate versus sodium polystyrene Patiromer with food versus patiromer without food
sulfonate
TOURMALINE 2017 (85 participants) compared patiromer with food
Two studies (Nakayama 2018; Nasir 2014) involving 117 with patiromer without food for 4 weeks. No data were available for
participants compared calcium polystyrene sulfonate with sodium any of our review outcomes.
polystyrene sulfonate in CKD. Studies were not designed to
evaluate the outcomes specified in this systematic review. The High-dose versus low-dose patiromer
certainty of the evidence was low for all reported outcomes AMETHYST-DN 2015 compared high-dose with low-dose of
(Summary of findings 2). patiromer for 52 weeks (Summary of findings 3) in CKD. They
reported no difference between high- and low-dose patiromer
Nasir 2014 reported calcium polystyrene sulfonate may increase
for death (any cause; sudden death) (Analysis 3.1 (1 study, 203
nausea (Analysis 2.1 (1 study, 97 participants): RR 0.42, 95% CI
participants): RR 1.94, 95% CI 0.18 to 21.08) sudden death, while
0.21 to 0.83) compared to sodium polystyrene sulfonate, while
high-dose patiromer may increase diarrhoea (Analysis 3.2 (1 study,
reported no difference between calcium polystyrene sulfonate
203 participants): RR 0.22, 95% CI 0.05 to 0.97) compared to
and sodium polystyrene sulfonate for diarrhoea (Analysis 2.2 (1
low-dose patiromer. AMETHYST-DN 2015 reported no difference
study, 97 participants): RR 2.82, 95% CI 0.12 to 67.64), vomiting
between high-dose and low-dose patiromer for constipation
(Analysis 2.3 (1 study, 97 participants): RR 0.19, 95% CI 0.01 to
(Analysis 3.3 (1 study, 203 participants): RR 1.46, 95% CI 0.54
3.82), constipation (Analysis 2.4 (1 study, 97 participants): RR 0.70,
to 3.94), hypokalaemia (Analysis 3.4 (1 study, 203 participants):
95% CI 0.26 to 1.88), and abdominal pain (Analysis 2.5 (1 study, 97
RR 0.97, 95% CI 0.20 to 4.70), stroke (Analysis 3.5 (1 study, 203
participants): RR 0.31, 95% CI 0.03 to 2.91).
participants): RR 0.97, 95% CI 0.06 to 15.31) and myocardial
Calcium polystyrene sulfonate may make little or no difference infarction (Analysis 3.6 (1 study, 203 participants): RR 2.91, 95% CI
to serum potassium levels at the end of treatment compared 0.12 to 70.68).
to sodium polystyrene sulfonate (Analysis 2.6 (2 studies, 117
Data were not available for cardiovascular death, cardiac
participants): MD 0.38 mEq/L, 95% CI -0.03 to 0.79; I2 = 42%; low
arrhythmias, HRQoL, and serum potassium level.
certainty evidence). There was moderate statistical heterogeneity in
the treatment effects between studies. DISCUSSION
Nasir 2014 reported no difference in systolic BP (Analysis 2.7 (1 Summary of main results
study, 97 participants): MD 2.65 mmHg, 95% CI -4.79 to 10.09) and
diastolic BP (Analysis 2.8 (1 study, 97 participants): MD -4.30 mmHg, We identified 15 studies randomising 1849 adult participants
95% CI -9.32 to 0.72) at the end of treatment, between calcium with CKD evaluating potassium binders for chronic hyperkalaemia
polystyrene sulfonate and sodium polystyrene sulfonate. (defined either as > 5 or > 5.5 mmol/L). Most studies (10
studies randomising 1367 participants) compared a potassium
Data were not available for death (any cause or cardiovascular), binder with placebo for a median of 3.4 weeks. Data for clinical
cardiac arrhythmias, and HRQoL. outcomes included in this review were available in five of these
10 studies. Potassium binders for chronic hyperkalaemia reduce
Calcium polystyrene sulfonate versus control serum potassium levels compared with placebo in patients with
Wang 2018a (58 participants) evaluated calcium polystyrene CKD. In low or very low certainty evidence, it is uncertain
sulfonate versus control for three weeks. No data were available for whether potassium binders have effects on death (any cause
any of our review outcomes. or cardiovascular) and GI events. Potassium binders were also
compared to no treatment, laxatives, sorbitol, a second binder,
Sodium polystyrene sulfonate versus phenolphthalein and the administration with and without food. Meta-analysis was
docusate not possible for any of our review outcomes for these compared
treatments, since single studies available did not address outcomes
Gruy-Kapral 1998 (6 participants) evaluated sodium polystyrene
of our interest. The comparative effects of different doses of
sulfonate versus phenolphthalein docusate during a 12-hour
potassium binder is very uncertain.
experiment. No data were available for any of our review outcomes.
Sodium polystyrene sulfonate versus phenolphthalein Overall completeness and applicability of evidence
docusate versus phenolphthalein docusate + resin For this review, we identified 15 studies comparing different
Gruy-Kapral 1998 (6 participants) evaluated sodium polystyrene potassium binders approaches for patients with CKD, and the
sulfonate versus phenolphthalein docusate plus resin during a 12- information from these studies is of insufficient certainty to
hour experiment. No data were available for any of our review inform clinical care or policy. Very few studies were in dialysis
outcomes. setting or compared different treatment doses and often the
appropriateness of the dosage were not clearly reported. High-dose
Sodium polystyrene sulfonate versus sorbitol + resin patiromer was associated with more adverse events, although it
decreased the potassium concentration. Most studies compared
Gruy-Kapral 1998 (6 participants) evaluated sodium polystyrene potassium binders with placebo, and outcome data were rarely
sulfonate versus sorbitol plus resin during a 12-hour experiment. reported or missing. All studies had small sample sizes (6 to
No data were available for any of our review outcomes. 320 participants), were often short-term, had methodological
limitations, were a cross-over design, or were primarily designed
to evaluate surrogate measures of effect. No study reported
Informed decisions.

outcome data for cardiac arrhythmias and withdrawal from BP- in this review. We additionally requested data from authors. Many
lowering therapy. The short duration of the majority of included studies did not report key outcomes in a format available for meta-
studies precluded the assessment of cardiovascular outcomes, analysis.
including those potentially deriving from discontinuation or under
dosing of demonstrably beneficial RAAS inhibitors, especially in In this review the data availability in the individual studies were
proteinuric patients with CKD or concomitant heart failure. No a potential source of bias. First, there was heterogeneity between
study was designed to assess key patient outcomes, and potential treatment interventions and robust statistical estimates could
adverse events related to treatment are not well understood or not be estimated, due to the small number of included studies.
systematically reported. Standardisation of outcome reporting in Second, most studies were at high risks of bias, but poorer quality
future potassium binders studies as prioritised by the Standardised studies could not be excluded due to the small number of data
Outcomes in Nephrology (SONG 2017) by patients, caregivers and observations. The limited number of studies was a constraint on
health professionals may assist to improve the evidence base for our ability to assess for potential reporting bias and selective
potassium binder therapy studies. Consistent measures for study outcome reporting. Third, the definition of kidney disease varied
outcomes would improve our confidence in the results of available across the eligible studies, although most participants had CKD
studies. (stage 1 to 5) not requiring dialysis. Fourth, the effects of potassium
binder interventions on longer-term outcomes is uncertain and the
Quality of the evidence treatment endpoints were principally surrogate markers of health
(BP, serum potassium). Finally, adverse event reporting was rarely
We used standard risks of bias domains within the Cochrane tool provided.
together with GRADE methodology (GRADE 2008) to assess the
quality of study evidence. Since confidence in the evidence for Formal assessment for publication bias through visualisation of
death (any cause and cardiovascular), cardiac arrhythmias, and asymmetry in funnel plots was precluded for all treatments and
HRQoL were uncertain or could not be estimated, further studies outcomes because of few studies.
might provide different results. Some studies were at high or
unclear risks of bias for most of risk domains assessment, limiting Agreements and disagreements with other studies or
the certainty of the evidence. We noted that four studies were at reviews
low risk of random sequence generation and three studies were
at low risk of allocation concealment. Blinding of participants and Few studies have examined the efficacy of potassium binders for
investigators and outcome assessment were at low risk of bias people with CKD and the number of meta-analysis published in
in eight and 13 studies, respectively. Nine studies were at low this field is limited. The current Cochrane review is consistent with
risk methods for attrition, 12 studies were at low risk of selective the findings of systematic review and meta-analysis of published
reporting, and one study was at low risk of other potential sources RCTs evaluating the efficacy and safety of patiromer for treating
of bias. The overall certainty of the evidence was assessed as low or hyperkalaemia in patients with CKD or heart failure (Das 2018).
very low certainty for all outcomes for which there were extractable In that review that included three studies, the authors found
data. that there was a reduction of serum potassium with patiromer
compared to placebo. Patiromer compared with placebo did
In this review, clinical outcomes were rarely available for many not show a significant reduction in death risk (any cause) and
of the treatments. The variabilities of reporting methods in serious cardiovascular events. In a second meta-analysis of both
the individual studies hamper the data summary. Moderate or RCTs and observational studies, dietary education significantly
substantial heterogeneity in definitions and methods of reporting reduced the prevalence of hyperkalaemia and serum potassium,
serum potassium levels and systolic BP were particularly relevant. compared with control (Palaka 2018). In that analysis, the
The limited number of studies prevented exploration of other population of interest was not restricted to chronic hyperkalaemia
potential sources of heterogeneity in the analyses. Subgroup and in CKD, the interventions were both pharmacological and non-
sensitivity analysis could not be done for heterogeneity owing pharmacological, observational studies were included, and GRADE
to insufficient data. Due to the limited number of studies and was not used to evaluate evidence certainty.
participants, it was not clear if there was a difference between
the evidence from older to newer potassium binders. Since data A single large RCT, evaluating the effect of ZS-9 in 320
were sparse, the assessment of adverse events in both treatments patients with hyperkalaemia, reported a significant reduction in
categories was not possible. All studies reported SD or SE as potassium levels compared with placebo (Packham 2015). In a
estimate of variance and some of them provided data in descriptive previous Cochrane review of pharmacological interventions for
or figure format only. the acute management of hyperkalaemia in adults (7 studies,
241 participants), salbutamol and other medications were safe
Potential biases in the review process and well-tolerated, and may decrease serum potassium levels.
There was very low certainty about whether medications made
This review was carried out using standard Cochrane methods. any difference to reduce death and cardiac arrhythmias compared
Each step was completed independently by at least two authors to placebo (Batterink 2015). Potassium binders decreased serum
including selection of studies, data management, and risk of bias potassium but did not improve death, cardiovascular events, or
assessment, thus reducing the risks of errors in identification of HRQoL.
eligible studies and adjudication of evidence certainty. A highly
sensitive search of the Cochrane Kidney Transplant specialised
register was last undertaken without language restriction in
March 2020. The registry contains hand-searched literature and
conference proceedings, maximising the inclusion of grey literature
Informed decisions.

AUTHORS' CONCLUSIONS of treatments for chronic hyperkalaemia. Future potassium binder

studies compared with placebo will increase our certainty of the
Implications for practice evidence based on limitations in existing studies and a paucity of
evidence in the CKD setting.
Potassium binders reduce serum potassium level compared
to placebo among people with CKD, although there is low Evaluation of cost-effectiveness for potassium binders approaches
certainty evidence on all-cause and cardiovascular death, cardiac in CKD setting would assist decision-making by policy-makers and
arrhythmias and HRQoL. No data for treatment effects in children health care providers.
were identified. There is scant evidence to inform decision-making
about newer potassium binders or the comparative effectiveness ACKNOWLEDGEMENTS
and safety between older and newer treatments. Evidence is largely
lacking in the setting of peritoneal dialysis, HD, home-based HD, We would like to thank the editorial team of Cochrane Kidney
or transplantation. The potential adverse effects of treatment are Transplant for guidance and support throughout this protocol
largely unknown - in particular, major GI events. process. We would like to thank the editor and reviewers of this
protocol and review.
Implications for research
The authors are grateful to the following peer reviewers for their
Future adequately powered, rigorous RCTs are needed to assess time and comments: Kwek Jia Liang (Consultant, Department of
the benefits and potential harms of potassium binders, including Renal Medicine, Singapore General Hospital, Singapore), George
determining if their use will lead to maximizing the concomitant L Bakris MD (Professor of Medicine, Director, Am. Heart Assoc.
administration of RAAS inhibitors to improve clinical outcomes in Comprehensive Hypertension Center, Department of Medicine,
people with CKD treated for chronic hyperkalaemia. More recent University of Chicago Medicine, Chicago, IL, USA), Stephen Walsh
studies seem to be more promising and could show sufficient (Associate Professor in Experimental Medicine and Honorary
statistical power to detect treatment effects on important patient Consultant Nephrologist, UCL Department of Renal Medicine,
outcomes (including death, cardiovascular, and major GI adverse University College London, London, UK), Michael Emmett MD
events). Further research is likely to change the estimated effects (Department of Internal Medicine, Baylor University Medical Center,
Dallas, Texas, USA).
Informed decisions.

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Handbook for Systematic Reviews of Interventions Version Yu MY, Yeo JH, Park JS, Lee CH, Kim GH. Long-term efficacy of
5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. oral calcium polystyrene sulfonate for hyperkalemia in CKD
Available from www.cochrane-handbook.org. patients. PLoS ONE [Electronic Resource] 2017;12(3):e0173542.
[MEDLINE: 28328954]
Schünemann 2011b
Schunemann HJ, Oxman AD, Higgins JP, Deeks JJ, Glasziou P,
Guyatt GH. Chapter 12: Interpreting results and drawing References to other published versions of this review
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5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Natale P, Palmer SC, Ruospo M, Saglimbene VM, Strippoli GF.
Available from www.cochrane-handbook.org. Potassium binders for chronic hyperkalaemia in people with
chronic kidney disease. Cochrane Database of Systematic
Shah 2005 Reviews 2018, Issue 11. [DOI: 10.1002/14651858.CD013165]
Shah KB, Rao K, Sawyer R, Gottlieb SS. The adequacy of
laboratory monitoring in patients treated with spironolactone * Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

AMBER 2018
Study characteristics
Methods • Study design: phase 2, double-blind, placebo-controlled RCT

• Study duration: February 2017 to August 2018
• Duration of follow-up: 14 weeks (12 weeks of treatment + 2 weeks for safety follow-up)
Participants • Country: 10 countries (USA, Bulgaria, South Africa, UK, France, Germany, Croatia, Hungary, Georgia,
Ukraine)
• Setting: 62 sites
Informed decisions.

AMBER 2018 (Continued)
• Inclusion criteria: ≥ 18 years with uncontrolled resistant hypertension and CKD; eGFR 25 to 45 mL/
min/1.73 m2; serum potassium 4.3 to 5.1 mEq/L; taking ≥ 3 antihypertensive medications at stable
doses for ≥ 28 days; one agent must be a diuretic, and the regimen should also include an ACEi or ARB
unless previously not tolerated or contraindicated; SBP 135 to 160 mm Hg at the 1st screening visit
SBP may be < 135 mm Hg either at the 2nd or 3rd screening visit (but not both); women of childbearing
potential must have a negative serum pregnancy test and agree to use medically acceptable contra-
ception from 28 days before screening until 28 days after study completion
• Number (randomised/analysed): treatment group (147/147); control group (148/148)
• Mean age ± SD (years): treatment group (67.8 ± 12.2); control group (68.5 ± 11.1)
• Sex (men): treatment group (76, 52%); control group (77, 52%)
• eGFR (mL/min/1.73 m2): treatment group (35.4 ± 7.3); control group (36.1 ± 7.6)
• Cause of CKD: not reported
• Duration on HD: not applicable
• Baseline serum potassium (mmol/L): treatment group (4.74 ± 0.36); control group (4.69 ± 0.37)
• Baseline beta blockers: treatment group (87, 59%); control group (86, 58%)
• Baseline calcium channel blockers: treatment group (107, 73%); control group (106, 72%)
• Baseline non-RAASi (diuretics): treatment group (146, 99%); control group (145, 98%)
• Baseline RAASi: treatment group (147, 100%); control group (147, 99%)
• Baseline other antihypertensive medications: treatment group (40, 27%); control group (31, 21%)
• Exclusion criteria: history of untreated secondary causes of hypertension other than CKD; BP > 160
mm Hg; cardiovascular event within the past 3 months; clinically significant ventricular arrhythmia;
atrial fibrillation > 100 BPM; current use of spironolactone or other mineralocorticoid antagonists
(e.g. eplerenone); change in kidney function requiring hospitalisation or dialysis within 3 months be-
fore screening; kidney transplant (or anticipated need for kidney transplant during the study); his-
tory of bowel obstruction, swallowing disorders, clinically significant gastroparesis, severe GI disor-
ders or major GI surgery (e.g., large bowel resection); previous use of patiromer in a clinical study;
bronchodilators, theophylline, heparin, canagliflozin if doses not stable for at least 28 days prior to
screening; use of any investigational product within 30 days or 5 half-lives, whichever is longer, pri-
or to screening; calcium acetate or calcium carbonate supplements (unless for occasional antacid
use, at the discretion of the Investigator), digoxin, direct renin inhibitors (e.g. aliskiren), lanthanum
carbonate, lithium, sevelamer, quinidine, sodium polystyrene sulfonate or calcium polystyrene sul-
fonate, colesevelam, colestipol, cholestyramine, drospirenone, potassium supplements, bicarbonate
or baking soda (unless for occasional antacid use, at the discretion of the Investigator), triamterene,
amiloride, trimethoprim, tacrolimus, cyclosporine, systemic glucocorticoids, NSAIDs or COX-2 in-
hibitors (with the exception of low dose aspirin), sympathomimetics within 7 days prior to screening;
inability to measure BP; clinical history of noncompliance with antihypertensive medications; history
of malignancy within the past 12 months except for cured non-melanoma skin cancer; alcohol or drug
abuse within the past year
Interventions Treatment group
• Patiromer (oral): packets as a powder for oral suspension 4.2 g, initiate study medication with 2 pack-
ets daily (overall 8.4 g)
• Spironolactone: 25 mg
Control group
• Placebo: microcrystalline cellulose

• Spironolactone: 25 mg
Co-interventions
• Dietary counselling was also provided at each visit in accordance with the standard practices of the
investigator. Spironolactone started at 25 mg once daily and increased to 50 mg once/day at week 3 in
patients with SBP ≥ 120 mm Hg and K+ ≤ 5.1 mmol/L. If spironolactone was discontinued, double-blind
study drug (patiromer or placebo) was discontinued at the same time. All randomised patients were
instructed to take spironolactone, assigned study drug and their antihypertensive medications
Informed decisions.

Outcomes • Between-group difference in the proportion of patients remaining on spironolactone
• Difference in SBP
• Within-group changes in SBP
• Changes in potassium levels over time measured by a central laboratory and by local laboratories
• Urine chemistry and haematology
• Changes in kidney function (e.g. creatinine, eGFR)
• N-terminal pro B-type natriuretic peptide levels
• Proportion of patients with serum K+ ≥ 5.5 mEq/L, average daily dose and cumulative dose of spirono-
lactone
• Time to discontinuation of spironolactone
• Changes in albuminuria (urine ACR)
• Incremental changes in health (EuroQoL Group 5-domain 5-level (EQ-5D-5L) questionnaire)
* Mobility
* Self-care
* Usual activities
* Pain/discomfort
* Anxiety/depression
• Adverse events: hypotension; hypertensive crisis; renal colic; subacute renal insufficiency; hypomag-
nesaemia; hypercalcaemia
• Severe adverse events
• Biomarkers of cardiac stress
• Changes in magnesium and calcium levels
Notes • Funding: Relypsa Inc., a Vifor Pharma Group Company acknowledges the support of the National In-
stitute for Health Research Clinical Research Network (NIHR CRN). The steering committee designed
the study in collaboration with the sponsor. Worldwide Clinical Trials (Morrisville, NC, USA) was re-
sponsible for site management and monitoring and data collection. The authors had full access to the
data, which were analysed by the sponsor. Susan Arthur (Relypsa; Santa Clara, CA, USA) contributed
to critical data analyses and data interpretation. RA, DG, MRM, AR, WBW, PR, and BW designed the
study. SW collected the data. JM analysed the data. RA wrote the first draft of the manuscript. All au-
thors were involved in data interpretation, review, and writing of the manuscript. RA reports person-
al fees from Relypsa, during the conduct of the study, personal fees from AbbVie, Akebia, Amgen, As-
traZeneca, Bayer, Birdrock Bio, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Gilead, Glax-
oSmithKline, Ironwood Pharmaceuticals, Johnson & Johnson, Merck, Novartis, Opko, Otsuka, Reata,
Relypsa, Sandoz, Sanofi, Takeda, and ZS Pharma, outside the submitted work, has served as associate
editor of the American Journal of Nephrology, Nephrology Dialysis and Transplantation and as an
author on UpToDate, and has received research grants from the US Veterans Administration and the
National Institutes of Health. PR reports personal fees from Relypsa, during the conduct of the study,
consulting for Idorsia and G3P, outside the submitted work, honoraria from AstraZeneca, Bayer, CVRx,
Fresenius, Grunenthal, Novartis, NovoNordisk, Servier, Stealth Peptides, Ablative Solutions, Corvidia,
and Vifor Fresenius Medical Care Renal Pharma, outside the submitted work, and travel grants from
AstraZeneca, Bayer, CVRx, Novartis, and Vifor Fresenius Medical Care Renal Pharma outside the sub-
mitted work. PR is the cofounder of CardioRenal. DG, SW, JM, and AR report employment by Relyp-
sa, a Vifor Pharma Group Company, and stock in Vifor Pharma, during the conduct of the study. MRM
reports current consulting for and previous employment by Relypsa, a Vifor Pharma Group Compa-
ny. WBW reports serving as a consultant to Relypsa, a Vifor Pharma Group Company (AMBER Steering
Committee), during the conduct of the study. BW reports consulting for Relypsa, a Vifor Pharma Group
Company, during the conduct of the study, and honoraria for lectures on hypertension from Daichii
Sankyo, Pfizer, Novartis, Servier, and Boehringer Ingelheim, and consulting for Vascular Dynamics and
Novartis, outside the submitted work
• Trials registration: NCT03071263
• Email: Rajiv Agarwal; ragarwal@iu.edu
Risk of bias
Informed decisions.

Bias Authors' judgement Support for judgement
Random sequence genera- Unclear risk Quote: "Participants were randomly assigned (1:1)."
tion (selection bias)
Comment: Methods for generation of the random sequence were not reported
in sufficient detail to assess risk
Allocation concealment Low risk Quote: "Participants were randomly assigned (1:1) with an interactive web re-
(selection bias) sponse system to receive either placebo or patiromer (8.4 g once daily), in ad-
dition to open-label spironolactone (starting at 25 mg once daily) and their
baseline blood pressure medications."
Comment: An interactive web response system is considered as a low risk of

bias
Blinding of participants Low risk Quote: "This phase 2, multicentre, randomised, double-blind, placebo-con-
and personnel (perfor- trolled, parallel-group study of patiromer to enable spironolactone use for
mance bias) blood pressure control in patients with resistant hypertension and chronic kid-
All outcomes ney disease. [...] Participants, the study team that administered treatments
and measured blood pressure, and the investigators were masked to assigned
treatment groups."
Comment: A double-blind study is considered as a low risk of bias
Blinding of outcome as- Low risk Quote: "At weeks 1, 4, 8, and 12, medication adherence was evaluated via the
sessment (detection bias) measurement of spironolactone in plasma (validated liquid chromatogra-
All outcomes phy–tandem mass spectrometry; minimum level of detection 1 ng/mL) and
qualitative assessment of associated chromatograms for peaks corresponding
to spironolactone metabolites 7α-thiomethylspironolactone and canrenone. A
single 24-h urine collection was done, beginning at least 24 h before the base-
line visit, which was used to determine urine sodium, K+, and the albumin to
creatinine ratio. [...] Blood pressure was measured using an oscillometric mon-
itoring device. [...] The study was overseen by an independent Data Safety and
Monitoring Committee, which was responsible for reviewing and evaluating all
relevant information that may have had an impact on the safety of the study
participants, assessing risks and benefits to study participants, providing rec-
ommendations to the study sponsor concerning continuation, termination or
amendments to the study and reviewing safety, dosing and pharmacodynamic
data of both spironolactone and patiromer throughout the study."
Comment: An independent Data Safety and Monitoring Committee assessed

the outcomes. Outcomes were at low risk of detection bias due to the nature
of other outcome measures
Incomplete outcome data Low risk Quote: "Overall, 141 (95%) of 148 patients in the placebo group and 144 (98%)
(attrition bias) of 147 patients in the patiromer group completed the study. The most com-
All outcomes mon reasons for premature study discontinuation were adverse events (three
patients in the placebo group and one patient in the patiromer group) and
consent withdrawal (three patients in the placebo group and one patient in
the patiromer group). [...] Efficacy endpoints and safety were assessed in all
randomised patients (intention to treat)."
Comment: As reported in figure 1, all participants were analysed
Selective reporting (re- Low risk Clinically-relevant outcomes that would be expected for this type of interven-
porting bias) tion were reported
Other bias High risk Similar participants baseline characteristics and co-interventions. Funder was
likely to influence data analysis and study reporting or interpretation
Informed decisions.


AMETHYST-DN 2015
Methods • Study design: phase 2 multicentre, open-label, dose-ranging, parallel-group RCT

• Study duration: June 2011 to June 2013 (from first enrolment to final patient completion)
• Duration of follow-up: 52 weeks
Participants • Country: multinational, 5 European countries

• Inclusion criteria: patients aged 30 to 80 years with type 2 diabetes and CKD with or without hyperten-
sion; eGFR 15 to < 60 mL/min/1.73 m2 and serum potassium level > 5.0 mEq/L (stage CKD: 1-5); receiv-
ing therapy ACEi, ARB or both, with or without spironolactone for at least 28 days prior to screening
• Exclusion criteria: not reported
• Stratum 1: mild hyperkalaemia with serum potassium > 5.0 to 5.5 mEq/L
* Number (randomised/analysed): treatment group 1 (74/56); treatment group 2 (74/51); treatment
group 3 (74/50)
* Mean age ± SD (years): treatment group 1 (66.7 ± 7.55); treatment group 2 (65.9 ± 9.67); treatment
group 3 (66.9 ± 9.01)
* Sex (men): treatment group 1 (45, 60.8%); treatment group 2 (47, 64.4%); treatment group 3 (47,
64.4%)
* Stage of CKD: 1-5
* eGFR (mL/min/1.73 m2): treatment group 1 (41.1 ± 14.6); treatment group 2 (42.5 ± 15.3); treatment
group 3 (43.3 ± 15.4)
* Cause of CKD: not reported
* Duration on HD: not applicable
* Baseline serum potassium (mEq/L): treatment group 1 (5.1 ± 0.3); treatment group 2 (5.2 ± 0.2);
treatment group 3 (5.1 ± 0.2)
* Baseline ACEi: treatment group 1 (32, 43.2%); treatment group 2 (37, 50.7%); treatment group 3
(34, 46.6%)
* Baseline ARB: treatment group 1 (21, 28.4%); treatment group 2 (15, 20.5%); treatment group 3 (14,
19.2%)
* Baseline aldosterone antagonist: treatment group 1 (1, 1.4%); treatment group 2 (0); treatment
group 3 (0)
* Baseline non-RAASi (diuretic): treatment group 1 (35, 47%); treatment group 2 (24, 33%); treatment
group 3 (36, 49%)
Informed decisions.

AMETHYST-DN 2015 (Continued)
• Stratum 2: moderate hyperkalaemia with serum potassium > 5.5 to < 6.0 mEq/L
* Number (randomised/analysed): treatment group 1 (26/26); treatment group 2 (28/27); treatment
group 3 (30/30)
* Mean age ± SD (years): treatment group 1 (66.2 ± 5.58); treatment group 2 (66.3 ± 9.61); treatment
group 3 (65.0 ± 8.98)
* Sex (men): treatment group 1 (18, 69.2%); treatment group 2 (15, 53.6%); treatment group 3 (20,
66.7%)
* eGFR (mL/min/1.73 m2): treatment group 1 (37.0 ± 18.0); treatment group 2 (37.4 ± 13.8); treatment
group 3 (34.1 ± 17.5)
* Cause of CKD: not reported
* Duration on HD: not applicable
* Baseline serum potassium (mEq/L): treatment group 1 (5.7 ± 0.4); treatment group 2 (5.7 ± 0.3);
treatment group 3 (5.6 ± 0.4)
* Baseline ACEi: treatment group 1 (17, 65.4%); treatment group 2 (17, 60.7%); treatment group 3
(13, 43.3%)
* Baseline ACEi: treatment group 1 (7, 26.9%); treatment group 2 (5, 17.9%); treatment group 3 (12,
40.0%)
* Baseline aldosterone antagonist: treatment group 1 (0); treatment group 2 (0); treatment group 3
(0)
* Baseline non-RAASi (diuretic): treatment group 1 (13, 50%); treatment group 2 (8, 29%); treatment
group 3 (14, 47%)
Interventions Stratum 1
• Treatment group 1
* Patiromer: starting dose 4.2 g twice daily (8.4 g in total)
* Patiromer:starting dose 8.4 g twice daily (16.8 g in total)
Stratum 2
Co-interventions
• Patients were counselled at each visit to restrict their intake of high-potassium foods (> 250 mg/100 g)
and to maintain a low-potassium diet (potassium intake of ≤ 3 g/d). Patiromer was titrated to achieve
and maintain serum potassium level 5.0 mEq/L or lower
Outcomes • Death (any cause)

• Cardiovascular death
• Sudden cardiac death
• Major adverse cardiovascular events: acute left ventricular failure; acute MI; angina; atrial fibrillation;
atrioventricular block complete; cardiac failure; cardiac failure, chronic; MI; cerebrovascular accident;
Ischaemic stroke; transient Ischaemic attack
• Adverse GI events: constipation; diarrhoea; gastric ulcer; gastric ulcer haemorrhage; mesenteric artery
thrombosis
• Serum potassium level (mean reduction from baseline to week 4 or first patiromer titration (primary
study outcome); baseline to week 8 or first patiromer titration; maintenance in range of 4.0 to 5.0 mEq/
L; maintenance in range of 3.5 to 5.5 mEq/L)
• Biochemistry: serum calcium; serum sodium; serum phosphate; serum magnesium; urine ACR
Informed decisions.

• Electrocardiography
• BP
Notes • Funding: Mayo. This study was sponsored and funded by Relypsa. Relypsa and the steering commit-
tee designed the study. Relypsa conducted the study, data collection, and management analysis. Re-
lypsa, with the steering committee, was responsible for the interpretation of the data; preparation,
review, or approval of the manuscript; and decision to submit the manuscript for publication. Statis-
tical analyses were performed by Mayo, Zawadzki
• Email: George L. Bakris; gbakris@gmail.com
Risk of bias
Random sequence genera- Low risk Quote: "A validated interactive web response system was used to assign pa-
tion (selection bias) tients to cohorts and starting doses using computer-generated randomisation
lists stratified by cohort, with a block size of 3."
Comment: A computer generation model is considered as a low risk of bias
Allocation concealment Low risk Quote: "A validated interactive web response system was used to assign pa-
(selection bias) tients to cohorts."
Comment: A validated interactive web response system is consider as a low

risk of bias
Blinding of participants High risk Quote: "The AMETHYST-DN phase 2 multicenter, open-label, dose-ranging ran-
and personnel (perfor- domised clinical trial was conducted to inform dose selection."
mance bias)
All outcomes Comment: An open-label study is considered as a high risk of bias
Blinding of outcome as- Low risk Quote: "Central laboratory measurements were used for assessments of base-
sessment (detection bias) line values and efficacy and safety analyses. [...] Prior to database lock and af-
All outcomes ter the last patient’s follow-up visits were completed, a safety review board
was convened to independently review all deaths occurring within the study.
Adjudication was performed for cause of death and whether the death was re-
lated to hypokalaemia or hyperkalaemia."
Comment: Outcomes were at low risk of detection bias due to independent

outcome adjudication and the nature of other outcome measures. It was not
stated whether GI adverse events were assessed without knowledge of treat-
ment allocation, and knowledge of treatment assignment may have influ-
enced reporting
Incomplete outcome data Low risk Quote: "A total of 324 patients were enrolled; 222 patients entered stratum 1
(attrition bias) (mild hyperkalaemia) and 84 entered stratum 2 (moderate hyperkalaemia),
All outcomes for a total of 306 randomised patients (Figure 1). Two patients with mild hy-
perkalaemia did not receive patiromer and therefore were not included in the
efficacy or safety analyses. Of the 304 patients evaluated at week 4 or time of
first dose titration, 300 were analysed for the primary efficacy endpoint. One
patient each with mild hyperkalaemia in the patiromer 8.4 g/d and 25.2 g/d
groups and 1 patient with moderate hyperkalaemia in the patiromer 25.2 g/d
group were excluded from the analysis because of missing baseline values. A
patient with mild hyperkalaemia in the patiromer 33.6 g/d group was excluded
because of a lack of available central laboratory results. Disposition for the en-
tire study is presented in Figure 1."
Comment: As reported in figure 1, 300/306 participants were analysed
Informed decisions.


Ash 2015
Methods • Study design: prospective, double-blind, placebo-controlled, phase 2, multi-dose parallel RCT
• Study duration: November 2011 to May 2012
• Duration of follow-up: 2 days
Participants • Country: USA

• Setting: multicentre (9 sites)
• Inclusion criteria: ≥ 18 years; stable stage 3 CKD; eGFR 30 to 60 mL/min/1.73 m2 and mild-to-moderate
hyperkalaemia (serum potassium 5.0 to 6.0 mEq/L); diabetes, heart failure, and hypertension were
allowed
• Exclusion criteria: pseudohyperkalaemia; treatment with oral Kayexalate or phosphate binders ≤
7 days before enrolment; severe acidosis; AKI and/or hyperkalaemia-related electrocardiogram
changes
• Number (randomised/analysed): treatment group 1 (12/12); treatment group 2 (24/24); treatment
group 3 (24/24); control group (30/30)
• Mean age ± SD (years): treatment group 1 (70.3 ± 6.9); treatment group 2 (72.0 ± 6.3); treatment group
3 (72.3 ± 11.7); control group (69.7 ± 11.0)
• Sex (men): treatment group 1 (6, 50%); treatment group 2 (14, 58%); treatment group 3 (9, 38%); con-
trol group (23, 77%)
• eGFR (mL/min/1.73 m2): treatment group 1 (56.5 ± 24.0); treatment group 2 (57.1 ± 22.1); treatment
group 3 (51.6 ± 22.3); control group (58.1 ± 26.5)
• Baseline serum potassium (mEq/L): treatment group 1 (5.2 ± 0.3); treatment group 2 (5.0 ± 0.3); treat-
ment group 3 (5.1 ± 0.4); control group (5.1 ± 0.4)
• Baseline ACEi: treatment group 1 (6, 50%); treatment group 2 (12, 50%), treatment group 3 (13, 54%);
control group (11, 37%)
• Baseline ARB: treatment group 1 (3, 33%); treatment group 2 (1, 13%); treatment group 3 (3, 29%);
• Baseline spironolactone: treatment group 1 (0); treatment group 2 (3, 17%); treatment group 3 (0);
• Baseline dual therapy: treatment group 1 (1, 8%); treatment group 2 (2, 8%); treatment group 3 (4,
17%); control group (3, 10%)
• Baseline diuretics: treatment group 1 (2, 16.7%); treatment group 2 (11, 45.8%); treatment group 3 (9,
37.5%); control group (8, 26.7%)
Interventions Treatment group 1
• ZS-9 (oral): 0.3 g
Treatment group 2
• ZS-9 (oral): 3 g
Treatment group 3
Informed decisions.

Ash 2015 (Continued)
• ZS-9 (oral) 10 g
Control group
• Placebo (oral): microcrystalline cellulose
Co-interventions
• Not reported

• Adverse GI events: constipation; diarrhoea; dyspepsia; nausea; vomiting; abdominal tenderness; ab-
dominal pain
• Serum potassium: rate of decline in first 48 hours (primary study outcome), change in serum potassi-
um from baseline to various time-points
• Urinary potassium excretion
• Biochemistry: serum bicarbonate; serum calcium; serum creatinine; serum glucose; 24-hour urea ni-
trogen excretion; urine creatinine excretion
• Urinary sediment
• SBP and DBP
• Vital signs
• Heart rate
Notes • Funding: ZS Pharma. Medical writing assistance was provided by Xelay Acumen, and was funded by ZS
Pharma. SRA owns a minority interest in HemoCleanse, which owns a minority interest in ZS Pharma.
BS was an employee of Apex Research of Riverside at the time of the study, has served as a consultant
for Amgen and Keryx, and is on the speakers’ bureau for Questcor. PTL is an employee of Boston Bio-
statistics Research Foundation, which conducted the statistical analyses for the study. BS, HSR, and
FS are employees of, and hold stock options in, ZS Pharma
• Email: Stephen R. Ash; sash@hemocleanse.com
Risk of bias
Random sequence genera- Low risk Quote; "A centralized computer-generated, block randomisation scheme was
tion (selection bias) used (random block size, three or six per site for each cohort)."
Comment: A computer generation model is considered as a low risk of bias
Allocation concealment Unclear risk Methods to conceal allocation were not reported in sufficient detail to perform
(selection bias) adjudication
Blinding of participants Low risk Quote: "Here we conducted a phase 2 randomised, double-blind, placebo-con-
and personnel (perfor- trolled dose-escalation study to assess safety and efficacy of sodium zirconium
mance bias) cyclosilicate (ZS-9)."
All outcomes
Blinding of outcome as- Low risk Quote: "Serum samples were analysed locally and by the central laboratory;
sessment (detection bias) study eligibility used local laboratory values."
All outcomes
Comment: Outcomes were principally laboratory measures and were at low
risk of detection bias regardless of whether blinding of investigators or out-
come assessors occurred. It was not stated whether GI adverse events were as-
sessed without knowledge of treatment allocation, and knowledge of treat-
ment assignment may have influenced reporting
Informed decisions.

Ash 2015 (Continued)
Incomplete outcome data Low risk Quote: "None withdrew and sodium zirconium cyclosilicate (ZS-9) dose depen-
(attrition bias) dently reduced serum potassium."
All outcomes
Comment: As reported in figure 1, all participants completed the study

DIALIZE 2019
Methods • Study design: double-blind, placebo-controlled, phase 3b RCT

• Study duration: December 2017 to November 2018
• Duration of follow-up: 63 days (8-week treatment period and a 2-week follow-up)
Participants • Country: multinational (Japan, Russia, USA, UK)

• Inclusion criteria: HD 3 times weekly for treatment of ESKD for at least 3 months before randomisation;
provision of informed consent prior to any study specific procedures; aged ≥ 18 years at screening;
HD access consisting of an AV fistula, AV graft, or tunnelled (permanent) catheter, which was expected
to remain in place for the entire duration of the study; predialysis serum K+ > 5.4 mmol/L after the
long interdialytic interval and > 5.0 mmol/L after one short interdialytic interval during screening; pre-
scribed dialysate K+ ≤ 3 mmol/L during screening; sustained blood flow ≥ 200 mL/min and single-pool
Kt/V ≥ 1.2 (or URR ≥ 63) on stable HD/HDF prescription during screening with prescription (time, dial-
yser, sustained blood flow, dialysate flow rate, and bicarbonate concentration) expected to remain
unchanged during study; heparin dose (if used) was stable during screening and expected to be stable
during the study; receiving dietary counselling appropriate for patients with ESKD treated with HD/
HDF as per local guidelines, which included dietary potassium restriction
• Exclusion criteria: involvement in the planning and/or conduct of the study; Hb < 9 g/dL at screening;
lack of compliance with HD prescription (both number and duration of treatments) during the 2-week
period preceding screening (100% compliance required); treated with sodium polystyrene sulfonate,
calcium polystyrene sulfonate, or patiromer within 7 days before screening or anticipated in requir-
ing any of these agents during the study; MI, acute coronary syndrome, stroke, seizure, or a thrombot-
ic/thromboembolic event (e.g., deep vein thrombosis or pulmonary embolism, but excluding vascu-
lar access thrombosis) within 12 weeks prior to randomisation; laboratory diagnosis of hypokalaemia
(serum K+ < 3.5 mmol/L), hypocalcaemia (calcium < 8.2 mg/dL; for Japan, hypocalcaemia defined as
albumin-corrected calcium < 8.0 mg/dL), hypomagnesaemia (magnesium < 1.7 mg/dL), or severe aci-
dosis (serum bicarbonate ≤ 16 mEq/L) in the 4 weeks preceding randomisation; pseudohyperkalaemia
secondary to haemolyzed blood specimen (this situation was not considered screening failure; sam-
pling or full screening could be postponed to a later time as applicable); severe leucocytosis (> 20 x
109/L) or thrombocytosis (≥ 450 x 109/L) during screening; polycythaemia (Hb > 14 g/dL); diagnosis
of rhabdomyolysis during the 4 weeks preceding randomisation; treated with lactulose, rifaximin, or
other non-absorbed antibiotics for hyperammonaemia within 7 days prior to the first dose of study
drug; unable to take oral ZS-9 drug mix; scheduled date for living donor kidney transplant; life ex-
pectancy < 6 months; pregnant or breastfeeding; females of childbearing potential, unless using con-
traception or sexual abstinence; known hypersensitivity or previous anaphylaxis to ZS-9 or to compo-
nents thereof; participation in another clinical study with an investigational product during 1 month
before screening; any medical condition (including active clinically significant infection) that in the
opinion of the investigator or sponsor may have posed a safety risk to a patient in this study, which
may have confounded safety or efficacy assessment and jeopardized the quality of the data, or inter-
fered with study participation; presence of cardiac arrhythmias or conduction defects that required
Informed decisions.

DIALIZE 2019 (Continued)
immediate treatment; history of alcohol or drug abuse within 2 years prior to randomisation; previous
randomisation in the present study
• Mean age ± SD (years): treatment group (55.7 ± 13.8), control group (60.4 ± 13.2)
• Sex (men): treatment group (57, 58.8%); treatment group (58, 58.6%)
• eGFR: not reported
• Duration on HD (years): treatment group (8.0 ± 6.1), control group (7.8 ± 7.6)
• Baseline serum potassium (mmol/L): treatment group (5.8 ± 0.6, data referred to 81 participants); con-
trol group (5.9 ± 0.6, data referred to 86 participants)
• Antihypertensive medications: not reported
• ZS-9: 5 g (powder for oral suspension in a sachet) once daily on non-dialysis days, and titrated towards
maintaining normokalaemia over 4 weeks, in 5 g increments to a maximum of 15 g
Control group
• Placebo: microcrystalline cellulose
Co-interventions
• Not reported
Outcomes • Proportion of patients who maintained predialysis serum potassium of 4.0 to 5.0 mmol/L and did not
require urgent rescue therapy to reduce serum potassium
• Proportion of patients requiring any urgent rescue intervention to reduce serum K+ in the setting of
severe hyperkalaemia (> 6.0 mmol/L)
• Adverse events: hypokalaemia; infections; GI disorders; constipation; diarrhoea; headache; na-
sopharyngitis; hyperkalaemia; hordeolum; muscle spasm; dizziness; dyspnoea; pruritus; shunt steno-
sis
• Serious adverse events: angina pectoris; hyperkalaemia requiring rescue therapy; fluid overload; pe-
ripheral arterial occlusive; gangrene of the leg and feet starting
• Interdialytic weight gain
• Intradialytic potassium shift
• Dialysis potassium gradient
• Haematology: Hb; leukocytes; platelets
• Biochemistry: SCr; bilirubin; alkaline phosphatase; aspartate transaminase; alanine transaminase;
gamma-glutamyl transferase; albumin; potassium; calcium; sodium; chloride; creatine kinase; bicar-
bonate; phosphorus, glucose; BUN; magnesium; lactate dehydrogenase; total protein
• Pregnancy test (serum human chorionic gonadotropin)
• Vital signs
• Heart rate
• BP
• 12-lead ECG
• Death (any cause and cardiovascular)
• Hospitalisation
Notes • Funding: AstraZeneca. Medical writing support, including assisting authors with the development of
the outline and initial draft and incorporation of comments, was provided by Shaun W. Foley, BSc
(Hons) CMPP and editorial support, including figure preparation, formatting, proofreading, and sub-
mission, was provided by Bethany King, BSc (Hons) both of Core Medica (London, United Kingdom)
supported by AstraZeneca according to Good Publication Practice guidelines. Data underlying the
findings described in this manuscript may be obtained in accordance with AstraZeneca’s data sharing
policy. The sponsor was involved in the study design, collection, analysis, and interpretation of data
Informed decisions.

DIALIZE 2019 (Continued)
as well as data checking of information provided in the manuscript. However, ultimate responsibility
for opinions, conclusions, and data interpretation lies with the authors
• Email: Steven Fishbane; sfishbane@northwell.edu
Risk of bias
Random sequence genera- Unclear risk Quote: "In the treatment period, patients were randomised 1:1 to receive oral-
tion (selection bias) ly a starting dose of sodium zirconium cyclosilicate 5 g or placebo once daily
on non dialysis days. [...] Randomization codes were generated in blocks of 4
(2 + 2 for each treatment arm) to ensure balance (1:1) between the two treat-
ment arms. Randomization was stratified by country."
Allocation concealment Low risk Quote: "Randomization was performed using randomisation codes and an in-
(selection bias) teractive voice/interactive web response system."
Comment: An interactive voice/interactive web response system is considered

as low risk of bias
Blinding of participants Low risk Quote: "Study site staff and patients were blinded to treatment assignment. To
and personnel (perfor- ensure blinding, sachets were enclosed in a carton with a tamper evident seal
mance bias) intended to be broken exclusively by patients immediately before taking the
All outcomes study drug."
Blinding of outcome as- Low risk Quote: "All adverse events were classified using the Medical Dictionary for Reg-
sessment (detection bias) ulatory Activities. [...] Serum K+ concentrations were measured using central
All outcomes laboratory assessment and a point-of-care i-STAT device."

come assessors occurred. It was not stated whether adverse events were as-
Incomplete outcome data Low risk Quote: "All randomised patients except for one patient in the sodium zirco-
(attrition bias) nium cyclosilicate group received treatment (99.5% [n=195 of 196]). In total,
All outcomes 95.9% of patients (n=188 of 196) completed the study. Rates of study comple-
tion were balanced between treatment groups (sodium zirconium cyclosilicate
group, 94.8% [n=92 of 97]; placebo group, 97.0% [n=96 of 99])."
Comment: As reported in figure 1, all participants were analysed

Informed decisions.

Gruy-Kapral 1998
Methods • Study design: cross-over RCT

• Study duration: not reported
• Duration of follow-up: 12 hours experiment (overall 5 different test days)

• Setting: single centre
• Inclusion criteria: maintained on HD volunteered for the study
• Number randomised/analysed: 6/not reported for the first period
• Mean age ± SD (years): not reported
• Sex (men): not reported
• Duration on HD: not reported
• Baseline serum potassium: not reported
• Sodium polystyrene sulfonate (Kayexalate); 30 g of resin with 500 mL of water
Treatment group 2
• Phenolphthalein-docusate (Correctol): 8 tablets with 500 mL of water
Treatment group 3
• Phenolphthalein-docusate (Correctol) plus resin; 8 tablets + 30 g of resin with 500 mL of water
Treatment group 4
• Sorbitol plus resin: 60 g of sorbitol plus 30 g of resin with 500 mL of water
Control group
• Placebo: 8 gelatin capsules with 500 mL of water
Co-interventions
• Dietary intake was controlled
Outcomes • Serum potassium concentration (primary study outcome)

• Faecal excretion of water (bowel movement, stool weight, stool water, stool solid, soluble potassium
concentration, potassium output total, potassium output soluble, potassium output insoluble, sol-
uble sodium concentration, sodium output soluble, sodium output insoluble, soluble chloride con-
centration, chloride output soluble, soluble HCO3 concentration, HCO3 output soluble, resin output,
serum potassium)
• Changes in body weight
• Biochemistry: serum sodium; serum chloride; serum bicarbonate; serum glucose
Notes • Funding: U.S. Public Health Service Grant 5-R01-DK37172-05 from the National Institute of Diabetes,
Digestive and Kidney Disease and by the Southwest Digestive Disease Foundation
• Trials registration: Not applicable as published before end of 2005
• Email: not reported
Risk of bias
Informed decisions.

Gruy-Kapral 1998 (Continued)
Random sequence genera- Unclear risk Methods for generation of the random sequence were not reported in suffi-
tion (selection bias) cient detail to assess risk
Blinding of participants High risk Not reported. Participants and investigators were unlikely to be blinded to
and personnel (perfor- treatment allocation due to physical differences in the interventions
mance bias)
All outcomes
Blinding of outcome as- Low risk Quote: "Total stool output of cations was calculated as the product of stool
sessment (detection bias) weight and cation concentration of an acid-digested stool sample. Insoluble
All outcomes cation concentration is the difference between total and soluble cation out-
put. Plasma concentration of chloride, bicarbonate, and glucose were mea-
sured by automated analysis. Stool resin concentration was estimated by
measuring stool cation binding capacity."

come assessors occurred
Incomplete outcome data Unclear risk Not reported in sufficient detail to perform adjudication
(attrition bias)
All outcomes
Selective reporting (re- High risk Major clinical and adverse event outcomes were not systematically reported.
porting bias) Data were not reported appropriately for a cross-over trial design in a format
that was extractable for meta-analysis
Other bias Unclear risk Co-interventions, adherence, similarity of treatment groups at baseline, inten-
tion-to-treat analysis and timing of outcome assessments were not reported
sufficiently to adjudicate risk. Funder was unlikely to influence data analysis
and study reporting or interpretation

HARMONIZE 2014
Methods • Study design: phase 3, double-blind, placebo-controlled, parallel RCT

• Study duration: March 2014 to August 2014 (final data collection date for primary outcome measure)
Participants • Country: multinational (USA, Australia, South Africa)

• Inclusion criteria: ≥ 18 years; potassium level ≥ 5.1 mEq/L; CKD < 30 mL/min/1.73 m2 (stages 4-5); ability
to have repeated blood draws or effective venous catheterization; women of childbearing potential
must be using two forms of medically acceptable contraception (at least one barrier method) and have
a negative pregnancy test at Study Day 1; women who are surgically sterile or those who are post-
menopausal for at least 2 years are not considered to be of childbearing potential; controlled diabetic
subjects can be enrolled
• Exclusion criteria: pseudohyperkalaemia signs and symptoms, such as excessive fist clenching
haemolyzed blood specimen, history of severe leukocytosis or thrombocytosis; treated with lactulose,
Xifaxan or other non-absorbed antibiotics for hyperammonaemia within 7 days prior to the first dose
Informed decisions.

HARMONIZE 2014 (Continued)
of study drug; treated with resins (such as sevelamer acetate or sodium polystyrene sulfonate (SPS;
e.g. Kayexalate)), calcium acetate, calcium carbonate, or lanthanum carbonate, within 7 days prior to
the first dose of study drug; life expectancy < 3 months; severely physically or mentally incapacitated
and who in the opinion of investigator are unable to perform the subjects’ tasks associated with the
protocol; women who are pregnant, lactating, or planning to become pregnant; diabetic ketoacidosis;
presence of any condition which, in the opinion of the investigator, places the subject at undue risk
or potentially jeopardizes the quality of the data to be generated; known hypersensitivity or previous
anaphylaxis to ZS-9 (ZS-9) or to components; randomisation into the previous ZS-002 or ZS-003 stud-
ies; treatment with a drug or device within the last 30 days that has not received regulatory approval
at the time of study entry; cardiac arrhythmias requiring immediate treatment; dialysis requirement
• Number: treatment group (29); treatment group 2 (36); treatment group 3 (37); control group (50)
• Duration on HD (years): not applicable
• ZS-9 (oral): 5 g
Treatment group 2
• ZS-9 (oral): 10 g
Treatment group 3
• ZS-9 (oral): 15 g
Control group
• Placebo (oral)
Co-interventions
• No protocol-directed advice on dietary potassium was provided to participants

• Cardiovascular disease (MI)
• Adverse GI events: constipation
• Serum potassium levels between placebo and each treatment group (highest to lowest) during days
8 through 29 of the randomised phase. Serum potassium was measured at 1, 2, and 4 hours after first
dose on day 1, as well as just prior to and 1 hour after first dose on day 2 of the open-label phase
(primary study outcome)
• Biochemistry: serum calcium; serum magnesium; serum phosphate; SCr; BUN; serum bicarbonate;
serum aldosterone; plasma renin activity
• Urine analysis (including urinary sodium excretion) and urine culture
• Proportion of patients who were normokalaemic at end of study
• Cumulative days patients remained normokalaemic
• Time to first recurrence of hyperkalaemia (potassium ≥ 5.1 mEq/L)
• Vital signs
• Body weight
• Heart rate
Informed decisions.

HARMONIZE 2014 (Continued)
Notes • Funding: The study was sponsored and funded by ZS Pharma. ZS Pharma had a role in the design and
conduct of the study; collection, management, analysis, and interpretation of the data; preparation,
review, or approval of the manuscript; and decision to submit the manuscript for publication
• Email: Mikhail Kosiborod; mkosiborod@saint-lukes.org. Authors were contacted.
Risk of bias
Blinding of participants Low risk Quote: "HARMONIZE was a phase 3, multicenter, randomised, double-blind,
and personnel (perfor- placebo-controlled trial evaluating zirconium cyclosilicate in outpatients with
mance bias) hyperkalaemia (serum potassium >= 5.1 mEq/L)."
All outcomes
Blinding of outcome as- Low risk Quote: "All potassium levels were measured (after an 8-hour fast) in whole
sessment (detection bias) blood with a point-of-care device. All samples were then centrifuged on site
All outcomes and serum sent to a central laboratory."

Incomplete outcome data Unclear risk Not reported in sufficient detail to perform an adjudication for people with
(attrition bias) CKD
All outcomes
Other bias High risk Baseline characteristics were not reported for patients with CKD. Funder was

Kashihara 2018
Methods • Study design: double-blind, placebo-controlled phase 2/3 RCT

• Duration of follow-up: 48 hours
Participants • Country: Japan

• Setting: multicentre
• Inclusion criteria: aged ≥18 years with serum potassium ≥ 5.1 to ≤ 6.5 mEq/L
Informed decisions.

Kashihara 2018 (Continued)
• Number (randomised/analysed): treatment group 1 (34/34); treatment group 2 (36/36); control group
(33/31)
• Mean age ± SD (years): overall (73, SD not reported)
• Sex (men): overall (77, 75%)
• eGFR (mL/min/1.73 m2): overall (26.1, SD not reported) (29%, 40%, 28%, and 3% had eGFR < 15, 15 to
< 30, 30 to < 60, and ≥ 60, respectively)
• Duration on HD: not reported
• Baseline serum potassium (mEq/L): overall (5.6, SD not reported)
• ZS-9: 5 g powder in water 3 times/day for 48 hours
Treatment group 2
• ZS-9: 10 g powder in water 3 times/day for 48 hours
Control group
• Placebo
Co-interventions
• Not reported
Outcomes • Change in serum potassium

• Normokalaemia
• Adverse events
Notes • Funding: AstraZeneca

• Trials registration: not reported
• Email: not reported
• Abstract-only publication
Risk of bias
Blinding of participants Low risk Quote: "We evaluated sodium zirconium cyclosilicate doses for correcting
and personnel (perfor- serum potassium in Japanese patients with hyperkalaemia in a multicenter,
mance bias) double-blind,
All outcomes placebo-controlled phase 2/3 trial."
Blinding of outcome as- Low risk Outcomes were principally laboratory measures and were at low risk of de-
sessment (detection bias) tection bias regardless of whether blinding of investigators or outcome asses-
All outcomes sors occurred. It was not stated whether adverse events were assessed with-
out knowledge of treatment allocation, and knowledge of treatment assign-
ment may have influenced reporting
Informed decisions.

Kashihara 2018 (Continued)
Incomplete outcome data High risk Quote: "All patients (34 on sodium zirconium cyclosilicate 5 g; 36 on sodium
(attrition bias) zirconium cyclosilicate 10 g; 33 on placebo) completed the study except 2
All outcomes placebo patients discontinued due to hyperkalaemia."
Comment: 101/103 participants completed the study. However, all patients

who discontinued the treatment were assigned in the placebo group, meaning
that there were differences between groups
Selective reporting (re- High risk Major clinical and adverse event outcomes were not systematically reported
porting bias)
Other bias High risk Co-interventions, adherence, similarity of treatment groups at baseline, inten-
tion-to-treat analysis were not reported sufficiently to adjudicate risk. Funder
was likely to influence data analysis and study reporting or interpretation

Lepage 2015
Methods • Study design: parallel RCT

• Study duration: February to September 2014, which was the predetermined end date
Participants • Country: Canada

• Setting: Single centre; nephrology clinics of Maisonneuve-Rosemont Hospital, Montreal, Quebec
• Inclusion criteria: pre-dialysis (stages 3-5) outpatients ages ≥ 18 years with eGFR < 40 mL/min/1.73
m2 and mild hyperkalaemia (5.0 to 5.9 mEq/L); patients who had taken sodium polystyrene sulfonate
in the 7 days before their initial visit were eligible if their serum potassium level measured for their
regular follow-up was from 4.5 to 5.5 mEq/L inclusively and from 5.0 to 5.9 mEq/L inclusively after a
7-day washout period (day of randomisation)
• Exclusion criteria: on dialysis; change in medication affecting potassium levels within 30 days before
enrolment. Exception was made for insulin, for which dose modifications occurring > 7 days before
randomisation were accepted or if more recent modifications were not > 10% of the total daily dose up
to a maximum variation of five units. Patients with changes in dosage of ACEI, ARBs, or aliskiren with-
in 60 days before randomisation; pregnant or breastfeeding; contraindication to sodium polystyrene
sulfonate; lactose intolerance; episode of decompensated heart failure in the 30 days before enrol-
ment; symptomatic hyperkalaemia; enrolled in another study
• Sex (men): treatment group (10, 62.5%); control group (13, 76.5%)
• Cause of CKD
* Treatment group: vascular (includes diabetic nephropathy) (14, 87.5%); glomerulonephritis (0);
polycystic (1, 6.3%); other (1, 6.3%)
* Control group: vascular (includes diabetic nephropathy) (12, 70.6%); glomerulonephritis (2,
11.8%); polycystic (0); other (3, 17.3%)
• Baseline serum potassium (mEq/L): treatment group (5.26 ± 0.22); control group (5.23 ± 0.22)
• Baseline beta-blockers: treatment group (12, 75.0%); control group (9, 52.9%)
• Baseline loop diuretics: treatment group (10, 62.5%); control group (8, 47.1%)
• Baseline ACEi or ARB: treatment group (13, 81.3%); control group (10, 58.8%)
• Baseline thiazide diuretics: treatment group (2, 12.5%); control group (2, 11.8%)
• Baseline potassium-sparing diuretics: treatment group (0); control group (2, 11.8%)
Informed decisions.

Lepage 2015 (Continued)
• Sodium polystyrene sulfonate (Kayexalate powders): 30 g orally without sorbitol
Control group
• Placebo: carob gum and lactose without sorbitol
Co-interventions
• Although no formal diet education was part of this trial, all patients with CKD and hyperkalaemia fol-
lowed in nephrology and predialysis outpatient clinics routinely receive information on a low–potas-
sium intake diet by a nutritionist, and patients were instructed not to modify their diet
Outcomes • Change of serum potassium levels between the day after the last dose of treatment (day 7) and base-
line (day 0) (primary study outcome)
• Adverse GI events: nausea; diarrhoea; constipation
• Normokalaemia
• Hospitalisation
Notes • Funding: The Nephrology Research Axis of Maisonneuve-Rosemont Hospital, the Dean’s Circle of
the Faculty of Pharmacy of the University of Montreal, and the Department of Pharmacy of Maison-
neuve-Rosemont Hospital. One author had a research chair from Sanofi Canada on drug use but has
not received any funding for this specific project
• Email: Jean-Philippe Lafrance; jean-philippe.lafrance@umontreal.ca
Risk of bias
Random sequence genera- Low risk Quote: "Eligible patients were randomised in a 1:1 ratio in blocks of four to re-
tion (selection bias) ceive a fixed dose of 30 g sodium polystyrene sulfonate (SPS) or placebo orally
one time per day for 7 days. The random treatment arm sequence was gener-
ated by the web site www.randomization.com and managed by independent
pharmacists of the research sector of the pharmacy department."
Comment: This sequence generation (using the web site www.randomiza-

tion.com) is considered as low risk of bias
Blinding of participants Low risk Quote: "33 outpatients with CKD and mild hyperkalaemia (5.0–5.9 mEq/L) in a
and personnel (perfor- single teaching hospital were included in this double–blind randomised clin-
mance bias) ical trial. [...] Patients, investigators, care providers, and statisticians were
All outcomes blinded for the duration of the trial and until all statistical analyses were com-
pleted."
Blinding of outcome as- High risk Quote: "Seven days after randomisation, patients returned for blood tests and
sessment (detection bias) completed the same side effects questionnaire as on day 3."
All outcomes
come assessors occurred. However, subjective measures were included in out-
comes, and were possibly influenced by knowledge of treatment assignment
Informed decisions.

Lepage 2015 (Continued)
Incomplete outcome data Low risk Quote: "Two patients had no measure of serum potassium levels at the end
(attrition bias) of the study period (day 7) and therefore, could not be included in the analy-
All outcomes sis. One patient allocated to the sodium polystyrene sulfonate (SPS) group left
the study on day 3 for important gastrointestinal side effects and refused to
come to the follow-up visit on day 7. One patient receiving placebo had un-
planned blood work done through a different laboratory, which revealed an el-
evated serum potassium level of 6.2 mEq/L. On the basis of the commendation
of the patient’s regular physician, the patient left the study to receive unblind-
ed treatment."
Comment: 31/33 participants completed the study, without differences be-

tween groups
Other bias Low risk Similar participants baseline characteristics and co-interventions. Funder was
unlikely to influence data analysis and study reporting or interpretation. No
other apparent sources of bias

Nakayama 2018
Methods • Study design: open-labelled, prospective, cross-over RCT

• Study duration: October 2013 to November 2014
Participants • Country: Japan

• Setting: multicentre (3 sites)
• Inclusion criteria: pre-dialysis CKD 4–5 outpatients with hyperkalaemia (> 5 mmol/L) not treated with
polystyrene sulfonate
• Exclusion criteria: already given polystyrene sulfonate; AKI
• Cause of CKD: diabetic nephropathy (6); glomerulonephritis (5); nephrosclerosis (3); lupus nephritis
(2); membranous nephropathy (1); IgA nephropathy (1); unknown (2)
• Baseline RAS inhibitors: treatment group (8, 80%); control group (3, 30%)
• Baseline calcium blockers: treatment group (7, 70%); control group (6, 60%)
• Baseline alfa and beta-blockers: treatment group (5, 50%); control group (1, 10%)
• Calcium polystyrene sulfonate (Argamate): oral
Control group
• Sodium polystyrene sulfonate (Kayexalate dry syrup): oral
Co-interventions
Informed decisions.

Nakayama 2018 (Continued)
• Not reported
Outcomes • Change in serum potassium from the baseline between the two groups (primary study outcome)
• Adverse GI events: diarrhoea (reported during the second period)
• Urinary potassium excretion levels
• Urinary sodium excretion levels
• Biochemistry: serum calcium, serum magnesium, iPTH, atrial natriuretic peptide, serum ammonia,
urea nitrogen, SCr, serum albumin, BUN, serum phosphorous
Notes • Funding: Grants-in-Aid for Welfare and Scientific Research (C) (no. 16k09637) (K.F) from the Ministry
of Education, Culture, Sports, Science and Technology of Japan
• Trials registration: UMIN 000021955
• Email: Kei Fukami; fukami@med.kurume-u.ac.jp
Risk of bias
Allocation concealment Unclear risk Quote: "Twenty hyperkalaemic patients were randomly assigned to calcium
(selection bias) polystyrene sulfonate (CPS) group (n = 10) or sodium polystyrene sulfonate
(SPS) group (n = 10) by an envelope method."
Comment: Methods to conceal allocation were not reported in sufficient detail

to perform adjudication
Blinding of participants High risk Quote: "This study was designed as a prospective, open-labelled, randomised,
and personnel (perfor- and cross-over study."
mance bias)
All outcomes Comment: An open-label study is considered as a high risk of bias
Blinding of outcome as- Low risk Quote: "Blood and urine chemistries were measured at a commercially avail-
sessment (detection bias) able laboratory. [...] We calculated corrected calcium levels using the calcium
All outcomes correction formula. Venous blood gas was taken to analyse the plasma bicar-
bonate (HCO3-) levels."

Incomplete outcome data Low risk All participants completed the study
(attrition bias)
All outcomes
Other bias Unclear risk There was no similarity between treatment groups at baseline. Funder was un-
likely to influence data analysis and study reporting or interpretation. No other
apparent sources of bias

Informed decisions.

Nasir 2014
Methods • Study design: parallel RCT

• Study duration: January 2010 to December 2010
Participants • Country: Pakistan

• Setting: single site
• Inclusion criteria: various stages of CKD, stages 1-4 with hyperkalaemia; > 18 years, either gender;
serum potassium level of > 5.2 mg/dL
• Exclusion criteria: on medication like ACEi, ARB, beta blockers, digitalis, potassium sparing diuretics,
NSAIDs, cyclosporin, tacrolimus; haemodynamic compromise; arrhythmias or heart block; on main-
tenance HD and those with kidney transplants
• Mean age ± SD: 53.08 ± 12.86 years
• Sex (men): 36 (37.1%)
• Baseline serum potassium (mEq/L): treatment group (5.8 ± 0.26), control group (5.8 ± 0.6)
• Antihypertensive medications: all patients were on antihypertensive medications and majority were
taking diuretics either loop diuretic or thiazide diuretic
• Calcium polystyrene sulphonate: dosing not reported
Control group
• Sodium polystyrene sulphonate: dosing not reported
Co-interventions
• Not reported
Outcomes • Serum potassium level between baseline and the end of treatment (primary study outcome)
• Adverse GI events: nausea; abdominal distension; abdominal pain; constipation; vomiting; diarrhoea
• Weight gain
• Blood pressure (SBP and DBP)
• Biochemistry: serum calcium, serum phosphorous, serum sodium, SCr, serum albumin
Notes • Funding: not reported

• Trials registration: not reported
• Email: Kiran Nasir; neph.kiran@yahoo.com
Risk of bias
Informed decisions.

Nasir 2014 (Continued)
Blinding of participants High risk Quote: "This single-blind randomised control trial was done from 15th January
and personnel (perfor- 2010 till 31st December 2010."
mance bias)
All outcomes Comment: A single-blind study is considered as a high risk of bias
Blinding of outcome as- High risk Quote: "Adverse events were recorded in an event reporting form."
sessment (detection bias)
All outcomes Comment: Outcomes were principally laboratory measures and were at low
come assessors occurred. However, subjective measures were included in out-
comes, and were possibly influenced by knowledge of treatment assignment
Incomplete outcome data Low risk As reported in figure 1, all participants completed the study
(attrition bias)
All outcomes
Other bias Unclear risk There were similarities between treatment groups at baseline. Supporting
source and timing of outcome assessments were not reported sufficiently to
adjudicate risk

OPAL-HK 2015
Methods • Study design: 2 phases (a 4-week single group, single-blind initial treatment phase and an 8-week
placebo-controlled, single-blind, randomised withdrawal phase), parallel RCT
• Study duration: Not reported
• Duration of follow-up: 8 weeks (overall there were 4 weeks initial phase + 8 weeks of randomisation
phase)
Participants • Country: multinational

• Setting: multicentre; Eastern Europe (24 sites), European Union (21), USA (14)
• Inclusion criteria: CKD (stage 3 or 4), eGFR 15 to < 60 mL/min/1.73 m2; receiving RAASi for at least
28 days and who had serum potassium levels of 5.1 to < 6.5 mmol/L; anti-hypertensive medications,
receiving a stable dose for the 28 days prior at screening; aged 18 to 80 years; females of child-bear-
ing potential were required to have been non-lactating, to have had a negative serum pregnancy test
at screening, and to have used a highly effective form of contraception for at least 3 months before
patiromer administration; female subjects had to continue to use contraception throughout the study
and for 1 month after study completion
• Exclusion criteria: Potassium-related electrocardiographic changes; severe GI disorders; uncontrolled
or unstable arrhythmias or clinically significant ventricular arrhythmias; recent cardiac surgery; kid-
ney or heart transplantation; acute coronary syndrome, transient Ischaemic attack or stroke within
the previous 2 months; confirmed SBP ≥ 180 mm Hg or < 110 mm Hg or DBP ≥ 110 mm Hg or < 60 mm
Hg; type 1 diabetes, or a HbA1c measurement of > 10.0% within the previous 6 months in subjects with
type 2 diabetes; emergency treatment for type 2 diabetes or for exacerbation of acute heart failure
within the previous 3 months; New York Heart Association class IV heart failure; subjects with auto-im-
mune related CKD such as lupus nephritis, renal scleroderma/scleroderma renal crisis, or mixed con-
nective tissue disease with renal involvement; hospitalisation (either in-patient or emergency room
treatment) for hyper- or hypoglycaemia in subjects with type 2 diabetes or for acute exacerbations of
heart failure within the last 3 months; history of, or currently diagnosed diabetic gastroparesis or his-
tory of bariatric surgery; symptoms associated with postural hypotension; anuria or history of acute
renal insufficiency in the past 3 months; confirmed diagnosis or history of renal artery stenosis (unilat-
eral or bilateral); BMI ≥ 40 kg/m2; serum magnesium < 1.4 mg/dL (< 0.58 mmol/L) at screening, based
Informed decisions.

OPAL-HK 2015 (Continued)
on the local laboratory results; liver enzymes (ALT, AST) >3 times upper limit of normal at screening,
based on the local laboratory results; active cancer, currently on cancer treatment or history of cancer
in the past 2 years except for non-melanocytic skin cancer that was considered cured; history of alco-
holism or drug/chemical abuse within 1 year of screening; use of potassium supplements, bicarbon-
ate or baking soda in the last 7 days prior to screening; any of the following potassium-altering chronic
medications if doses had not been stable for at least 28 days prior to screening or if doses were an-
ticipated to change during study participation: loop and thiazide diuretics, non-selective beta block-
ers, amiloride, triamterene, drospirenone, NSAIDs, COX-2 inhibitors, digoxin, bronchodilators, theo-
phylline, heparin, synthetic thyroid hormone; current use of the following drugs: calcium acetate or
calcium carbonate, lanthanum carbonate, sevelamer, sodium polystyrene sulfonate or calcium poly-
styrene sulfonate, colesevelam, colestipol, cholestyramine, potassium supplements, lithium, bicar-
bonate or baking soda, trimethoprim, tacrolimus, cyclosporine; use of any investigational product
within 30 days or 5 half-lives, whichever is longer, prior to screening; prior participation (excluding
screen or enrolment failures) in any study assessing the efficacy and safety of patiromer; inability to
consume the investigational product or, in the opinion of the Investigator, inability to comply with the
protocol; history of bowel obstruction, swallowing disorders, severe GI disorders or major GI surgery
(e.g., large bowel resection); in the opinion of the Investigator, any medical condition, uncontrolled
systemic disease, or serious intercurrent illness that would significantly decrease study compliance
or jeopardize the safety of the subject or affect the validity of the trial results
• Baseline ACEi: treatment group (37, 67%); control group (38, 73%)
• Baseline ARB: treatment group (24, 44%); control group (16,31%)
• Baseline aldosterone antagonist: treatment group (4, 7%); control group (4, 8%)
• Baseline renin inhibitor: treatment group (0); control group (0)
• Baseline dual RAAS blockade: treatment group (10, 18%); control group (6, 12%)
• Baseline non-RAASi (diuretic): treatment group (28, 51%); control group (27, 52%)
• Patiromer: twice a day as a powder mixed with water
Control group
• Placebo: twice a day as a powder mixed with water
Co-interventions
• Diet was not controlled; however, patients were counselled at each visit to restrict their intake of high-
potassium foods (> 250 mg/100 g) and to maintain a low-potassium diet (potassium intake of ≤ 3 g/
day)

• Adverse GI events: thrombosis mesenteric vessel; constipation
• Cardiovascular adverse events: atrial fibrillation
• Between-group difference in the median change in the serum potassium level at baseline of the initial
treatment phase (primary study outcome)
• Proportion of patients with a recurrence of hyperkalaemia
• Decal potassium excretion
• SBP and DBP
• Biochemistry: ACR; plasma renin activity; aldosterone levels; serum magnesium; SCr
Informed decisions.

OPAL-HK 2015 (Continued)
• eGFR
• Hospitalisation
• Cost-effectiveness
Notes • Funding: Relypsa. The study was designed by the authors in collaboration with the sponsor. The first
author wrote the introduction and discussion of the manuscript and oversaw all revisions; an employ-
ee of the sponsor wrote the preliminary draft of the Methods and Results sections under the direc-
tion of the first author. MRW reports consulting fees from Akebia Therapeutics, Amgen, AstraZeneca,
Boston Scientific, Janssen Pharmaceutica, Lexicon, Merck Sharp & Dohme, Relypsa, Inc, Sanofi, and
Sandoz. GLB reports consulting fees from AbbVie Inc., AstraZeneca, Bayer, CVRx, Janssen Pharma-
ceutica, Medtronic, Relypsa, Inc., and Takeda Pharmaceutical Company. GHW reports consulting fees
from Daiichi Sankyo, Mitsubishi Tanabe Pharma, Pfizer Japan Inc, and Relypsa, Inc. CG, MRM, DG, JY,
and LB are employees of Relypsa, Inc. YS was an employee of Relypsa, Inc. when the study was con-
ducted and a paid consultant of Relypsa Inc. when this manuscript was submitted
• Email: Matthew R. weir; mweir@medicine.umaryland.edu
Risk of bias
Blinding of participants High risk Quote: "The study had two phases (a 4-week single group, single-blind initial
and personnel (perfor- treatment phase and an 8-week) placebo-controlled, single-blind, randomised
mance bias) withdrawal phase."
All outcomes
Comment: A single-blind study is considered as a high risk of bias
Blinding of outcome as- Low risk Quote: "All electrocardiograms were read at a core electrocardiographic labo-
sessment (detection bias) ratory."
All outcomes
Incomplete outcome data High risk Quote: "Ten patients (18%) in the patiromer group and 22 (42%) in the place-
(attrition bias) bo group discontinued the randomised withdrawal phase prematurely; the
All outcomes most common reasons for discontinuation were elevated potassium levels
that met the prespecified withdrawal criteria (2 patients (4%) in the patiromer
group and 16 (31%) in the placebo group) and potassium levels of less than 3.8
mmol per litre (3 patients (5%) in the patiromer group and 1 (2%) in the place-
bo group)."
Comment: 75/107 participants completed the study, with differences between

groups
Other bias High risk There were similarities between treatment groups at baseline. Funder was
Informed decisions.


Packham 2015
Methods • Study design: phase 3, two-stage, double-blind, placebo-controlled, dose-ranging, parallel RCT
• Study duration: November 2012 to November 2013
• Duration of follow-up: 2 days (initial phase) + 12 days (maintenance phase) + 7 days (follow-up)
Participants • Country: multinational, US, Australia, South Africa

• Inclusion criteria: CKD, stage 3; aged ≥ 18 years; serum potassium level 5.0 to 6.5 mmol/L; able to un-
dergo repeated blood draws; women of childbearing potential must be practicing a highly effective
method of birth control
• Exclusion criteria: receiving dialysis; potassium level > 6.5 mmol/L; cardiac arrhythmia that required
immediate treatment; pseudohyperkalaemia signs and symptoms, such as excessive fist clinching
haemolysed blood specimen, severe leukocytosis or thrombocytosis; treated with lactulose, xifaxan
or other non-absorbed antibiotics for hyperammonaemia within the last 7 days; treated with resins
(such as sevelamer acetate or sodium polystyrene sulfonate, calcium acetate, calcium carbonate, or
lanthanum carbonate, within the last 7 days; life expectancy < 3 months; HIV positive; severely physi-
cally or mentally incapacitated and who in the opinion of investigator are unable to perform the sub-
jects’ tasks associated with the protocol; pregnant, lactating, or planning to become pregnant; ke-
toacidosis/acidaemia; presence of any condition which, in the opinion of the investigator, places the
subject at undue risk or potentially jeopardizes the quality of the data to be generated; known hyper-
sensitivity or previous anaphylaxis to ZS-9 or to components; previous treatment with ZS-9; treatment
with a drug or device within the last 30 days that has not received regulatory approval at the time of
study entry; cardiac arrhythmias that require immediate treatment; insulin-dependent diabetes mel-
litus
• Number: treatment group 1 (52); treatment group 2 (57); treatment group 3 (59); treatment group 4
(79); control group (73)
• ZS-9: 1.25 g, 3 times/day for 48 hours
Treatment group 2
• ZS-9: 2.5 g, 3 times/day for 48 hours
Treatment group 3
• ZS-9: 5 g, 3 times/day for 48 hours
Treatment group 4
• ZS-9: 10 g, 3 times/day for 48 hours
Control group
• Placebo: 3 times/day for 48 hours
Co-interventions
Informed decisions.

Packham 2015 (Continued)
• No dietary restrictions were imposed; patients were instructed to continue their usual diet without
any specified alterations
Outcomes • Change in the mean serum potassium within the first 48 hours of treatment (primary study outcome)
• Death (any cause)
• Cardiac adverse events: diastolic dysfunction; arrhythmia; atrial fibrillation
• Adverse GI events: gastroenteritis; constipation; diarrhoea; dyspepsia; nausea; vomiting
• Hospitalisation
• Vital signs
• Biochemistry: serum magnesium
• Blood pressure
• Body weight
Notes • Funding: ZS Pharma. The first draft of the article was written by the first author and the last two au-
thors, with editorial assistance paid for by ZS Pharma
• Email: David K. Packham; dmpackham@netspace.net.au. Authors were contacted.
Risk of bias
Blinding of participants Low risk Quote: "In this multicenter, two-stage, double-blind, phase 3 trial, we random-
and personnel (perfor- ly assigned 753 patients with hyperkalaemia to receive either sodium zirconi-
mance bias) um cyclosilicate (at a dose of 1.25 g, 2.5 g, 5 g, or 10 g) or placebo three times
All outcomes daily for 48 hours."
Blinding of outcome as- Low risk Quote: "All samples were centrifuged on site, and serum samples were sent to
sessment (detection bias) a central laboratory for analysis and verification."
All outcomes
Incomplete outcome data Unclear risk Not reported in sufficient detail to perform an adjudication for people with
(attrition bias) CKD
All outcomes
Other bias High risk Baseline characteristics were not reported for patients with CKD. Funder was

Informed decisions.

PEARL-HF 2011
Methods • Study design: double-blind, placebo-control, parallel RCT

• Study duration: June 2009 to November 2009
Participants • Country: multinational (USA, Germany, the Czech Republic, Poland, Ukraine, Russia, Georgia)
• Inclusion criteria: CKD, ≥18 years (5D and 5T patients were excluded); history of chronic heart fail-
ure, an indication to initiate spironolactone therapy, per the investigator’s clinical judgment; serum
potassium concentration of 4.3 to 5.1 mEq/L at screening; either CKD with eGFR < 60 mL/min and were
receiving one or more heart failure therapies (ACEi, ARB, beta-blocker) or a documented history of
hyperkalaemia that led to discontinuation of therapy with an aldosterone antagonists, ACEi, ARB, or
beta-blocker within 6 months prior to the baseline visit
• Exclusion criteria: severe GI disorders, major GI surgery, bowel obstruction, swallowing disorders; sig-
nificant primary valvular disease; known obstructive or restrictive cardiomyopathy, uncontrolled or
unstable arrhythmia, episode of unstable angina within 3 months prior to baseline, acute coronary
syndrome, transient Ischaemic attack, a QTc value of > 500 ms (using Bazett’s correction formula);
recent or anticipated cardiac surgery or intervention; kidney transplantation or need for transplanta-
tion; receiving dialysis or anticipated need for dialysis during the study; sustained SBP > 170 or < 90
mm Hg; elevated liver enzymes (more than 3 times the upper limit of normal); any condition that had
the potential to interfere with study compliance or jeopardize the safety of the patient
• Number randomised/analysed: 66/not reported (numbers per group not reported)
• eGFR (< 60 mL/min): treatment group (27, 50%); control group (30, 63%)
• RLY5016 (patiromer): 30 g/day, oral
Control group
• Placebo, oral
Co-interventions
• Patients were also instructed to start spironolactone at a dose of 25 mg/day
Outcomes • Change in serum potassium from baseline

• Death (any cause)
• Sudden cardiac death
• Cardiovascular adverse events: coronary artery disease; acute MI; atrial fibrillation
• Adverse GI events: constipation; diarrhoea; flatulence
• Proportion of patients with hyperkalaemia (potassium > 5.5 mEq/L)
• Proportion titrated to spironolactone 50 mg/day
• Biochemistry: serum calcium, serum iron, serum magnesium, serum phosphorous, serum sodium, SCr
• Vital signs
• Urinalysis
Informed decisions.

PEARL-HF 2011 (Continued)
Notes • Funding: Relypsa, Inc. Funding to pay the Open Access publication charge for this article was provided
by Relypsa Inc
• Email: Bertram Pitt; bpitt@med.umich.edu. Authors were contacted.
Risk of bias
Blinding of participants Low risk Quote: "This 4-week, double-blind, randomised, placebo-controlled, paral-
and personnel (perfor- lel-group study was conducted at 38 centres. [...] Following baseline assess-
mance bias) ments, patients who continued to meet eligibility criteria were randomised 1:1
All outcomes to RLY5016 or placebo treatment in a blinded fashion."
Blinding of outcome as- Low risk Not reported. Key outcomes were laboratory measures and were unlikely to be
sessment (detection bias) influenced by knowledge of treatment assignment. It was not stated whether
All outcomes GI adverse events were assessed without knowledge of treatment allocation,
and knowledge of treatment assignment may have influenced reporting
Incomplete outcome data Low risk Quote: "Efficacy and safety analyses were performed on the modified in-
(attrition bias) tent-to-treat population, defined as all randomised patients who received
All outcomes study medication and had available efficacy data. All modified intent-to-treat
patients were included in the primary and secondary efficacy analyses."
Comment: All participants were included into the analysis

TOURMALINE 2017
Methods • Study design: open-label, parallel RCT


• Setting: Multicentre (29 sites)
• Inclusion criteria: aged ≥18 years with hyperkalaemia with 2 potassium values > 5.0 mEq/L at the
screening visit, each obtained from separate venipunctures, in different arms when possible; receiv-
ing RAASi, beta blockers, or diuretics were required to be on stable doses for at least 14 days prior to
screening; CKD, stages 1-5 (pre-dialysis), and could have heart failure, diabetes mellitus (type 1 or 2),
and/or hypertension
Informed decisions.

TOURMALINE 2017 (Continued)
• Exclusion criteria: major organ transplantation; dialysis or expected need for dialysis; cardiovascu-
lar event or intervention within 3 months before screening; haemodynamically unstable arrhythmia;
hospitalisation for heart failure within the previous 3 months; poorly controlled diabetes mellitus or
blood pressure; received treatment with calcium or potassium supplementation or sodium or calcium
polystyrene sulfonate within 7 days before screening
• Number: treatment group (41); control group (44)
• eGFR: 41 ± 2 6 mL/min/1.73 m2
• Patiromer: 8.4 g with titrations with food
Control group
• Patiromer: 8.4 g with titrations without food
Co-interventions
• Patients were allowed to continue their usual diets without study-prescribed dietary counselling

• Proportion of patients with serum potassium in the target range (3.8 to 5.0 mEq/L)
• Serum potassium change from baseline to week 4 (primary study outcome)
• Cardiovascular adverse events: angina pectoris; cardio-respiratory arrest
• Adverse GI events: diarrhoea; constipation
• Hypokalaemia
• Biochemistry: serum potassium, serum calcium, serum phosphate, serum magnesium, SCr
• PTH and markers of mineral metabolism including 25-dihydroxyvitamin D (25-D), 1, 25-dihydroxyvit-
amin D (1,25-D) , and fibroblast growth factor 23 (FGF-23)
• BP
• Early withdrawal data
Notes • Funding: This study was sponsored and funded by Relypsa, Inc., a Vifor Pharma Group Company. Writ-
ing and editorial support services were provided by Impact Communication Partners, Inc. PEP reports
receiving honoraria from Akebia, Astra-Zeneca, Keryx, Reata, and ExThera; and reports serving as a
consult or participating in advisory boards for Akebia, Vifor, and Keryx. As the principal investigator
for many pharmaceutical companies, his institution has received research support. DMS, SW, and JY
report employment by Relypsa, Inc., a Vifor Pharma Group Company. M.R.W. reports personal fees for
scientific advisory boards from Relypsa and Vifor Pharma Management Ltd., both Vifor Pharma Group
Companies; and from Akebia, Janssen, AstraZeneca, Sanofi, MSD, AbbVie, and Boston Scientific out-
side the submitted work
• Email: Pablo E. Pergola; ppergola@raparesearch.com. Authors were contacted.
Risk of bias
Random sequence genera- Unclear risk Quote: "Adults with hyperkalaemia (potassium ≥ 5.0 mEq/L) were randomised
tion (selection bias) (1:1) to receive patiromer once daily without food or with food for 4 weeks."
Informed decisions.

TOURMALINE 2017 (Continued)
Blinding of participants High risk Quote: "TOURMALINE was an open-label study of patients with hyperkalaemia.
and personnel (perfor- Patients and site study staff were not blinded to treatment assignment (i.e.,
mance bias) with or without food groups); sponsor, contractors, and personnel support-
All outcomes ing the study who did not require access to patient source documents or to the
electronic data capture system were blinded to treatment assignment."
Comment: An open-label study is considered as a high risk of bias
Blinding of outcome as- Low risk Outcomes were principally laboratory measures and were at low risk of detec-
sessment (detection bias) tion bias regardless of whether blinding of investigators or outcome assessors
All outcomes occurred. It was not stated whether GI adverse events were assessed without
knowledge of treatment allocation, and knowledge of treatment assignment
may have influenced reporting
Incomplete outcome data Unclear risk Quote: "Overall, 114 patients were randomised to patiromer without food (n=
(attrition bias) 57) or with food (n= 57). Of these, 103 patients (90%) completed the study (fig-
All outcomes ure 2); reasons for early study termination included adverse events (n= 3), in-
vestigator’s decision (n= 3), withdrawal by patient (n= 3), lost to follow-up (n=
1), and other reason (n= 1; patient did not disclose taking prohibited medica-
tions). One patient in the with-food group did not receive any patiromer dose
and was excluded from the efficacy and safety analyses. A second patient in
the with-food group had an important protocol deviation, had no post-base-
line serum potassium, and was excluded from the efficacy analyses."
Comment: Not reported in sufficient detail to perform an adjudication for peo-

ple with CKD
Other bias High risk Treatment groups were quite similar at baseline. Funder was likely to influ-
ence data analysis and study reporting or interpretation

Wang 2018a
Methods • Study design: prospective, cross-over RCT

• Study duration: February 2014 to July 2014
Participants • Country: China

• Setting: single centre
• Inclusion criteria: hyperkalaemic patients undergoing HD; Aged 18 and 80 years; repeated predialysis
hyperkalaemia; good coordination; no pregnancy or lactation; no other comorbidities such as intesti-
nal stenosis or peptic ulcers
• Exclusion criteria: transferred to another hospital and/or underwent peritoneal dialysis or kidney
transplantation during the study period; used ACEi or ARB for more than 4 weeks
Informed decisions.

Wang 2018a (Continued)
• Sex (men): treatment group (16, 55.2%); control group (16, 55.2%)
• Duration on HD (years): overall (7.14 ± 4.38)
• Baseline ACEi: treatment group (10, 34.5%); control group (9, 31.0%)
• Baseline ARB: treatment group (29, 100%); control group (29, 100%)
• Calcium polystyrene sulfonate: powder 5 g, 3 times/day
Control group
• Blank control
Co-interventions
• All patients had adequate dialysis (Kt/V 1.37 ± 0.23) and intensive education on dietary intake of potas-
sium
Outcomes • Change in serum potassium after treatment (primary study outcome)

• Adverse GI events: constipation
• Safety (volume overload and electrolyte imbalance)
• Biochemistry/haematology: serum phosphorus, serum calcium, serum sodium, BUN, SCr, uric acid,
ALT and AST, serum albumin, Hb
• Carbon dioxide-combing power
• BP
• Interdialytic weight gain
Notes • Funding: Grants from the Liaoning Province Translational Medicine Center funded projects (No.
2104225018)
• Trials registration: ChiCTR-TTRCC-14004155
• Email: Hong-Li Lin; linhldlmedu@126.com. Authors were contacted
Risk of bias
Random sequence genera- Low risk Quote: "Patients were randomly assigned in a 1:1 ratio into two groups, the
tion (selection bias) calcium–polystyrene sulfonate group and the blank control group, using com-
puter-generated randomised sequences."
Comment: Computer generation is considered as a low risk of bias
Blinding of participants High risk Not reported. Participants and investigators were unlikely to be blinded to
and personnel (perfor- treatment allocation due to physical differences in the interventions
mance bias)
All outcomes
Blinding of outcome as- Low risk Quote: "Before and after treatments, patients underwent conventional 12-lead
sessment (detection bias) electrocardiography after a 5-minute resting period. Under the guidance of
All outcomes standardised operation procedures, two specialists who were blinded to the
Informed decisions.

Wang 2018a (Continued)
serum potassium concentration independently evaluated the electrocardiog-
raphy changes."

come assessors occurred. The specialists who assessed electrocardiography
changes were blind to the treatment assigned. It was not stated whether GI ad-
verse events were assessed without knowledge of treatment allocation, and
knowledge of treatment assignment may have influenced reporting
Incomplete outcome data Low risk As reported in figure 1, all participant completed the study
(attrition bias)
All outcomes
Selective reporting (re- High risk Major clinical and adverse event outcomes were not systematically reported.
porting bias) Data were not reported appropriately for a cross-over trial design in a format
that was extractable for meta-analysis
Other bias Unclear risk There was no similarity between treatment groups at baseline. Funder was un-
likely to influence data analysis and study reporting or interpretation. No other
apparent sources of bias
ACEi - angiotensin-converting enzyme inhibitor; ACR - albumin:creatinine ratio; ARB - angiotensin receptor blocker; AKI - acute kidney
injury; AV - arteriovenous; BMI - body mass index; BP - blood pressure; BPM - beats per minute; CKD - chronic kidney disease; DBP - diastolic
blood pressure; (e)GFR - (estimated) glomerular filtration rate; ESKD - end-stage kidney disease; GI - gastrointestinal; Hb - haemoglobin;
HD - haemodialysis; HDF - haemodiafiltration; HIV - human immunodeficiency virus; Kt/V - dialysis adequacy; MI - myocardial infarction;
NSAID - nonsteroidal anti-inflammatory drug; (i)PTH - (intact) parathyroid hormone; RCT - randomised controlled trial; RAAS(i) - renin-
angiotensin-aldosterone system (inhibitor); SBP - systolic blood pressure; SCr - serum creatinine; SD - standard deviation; URR - urea
reduction ratio; ZS-9 - sodium zirconium cyclosilicate

Characteristics of ongoing studies [ordered by study ID]

DIALIZE China 2020
Study name A phase 3b, multicentre, prospective, randomised, double-blind, placebo-controlled study to re-
duce incidence of pre-dialysis hyperkalaemia with sodium zirconium cyclosilicate in Chinese sub-
jects
Methods Randomised, double-blind, placebo-controlled study to determine the safety and efficacy of ZS-9
in ESKD subjects with hyperkalaemia and on stable HD. This study consists of a screening period,
an 8-week randomised treatment period, and a follow-up period. Approximately 134 stable HD
subjects with persistent pre-dialysis hyperkalaemia will be enrolled in the study across research
sites in China
Participants Country: China
Setting: multicentre
Inclusion criteria
1. Provision of signed and dated, written informed consent form prior to any mandatory study spe-
cific procedures, sampling, and analyses
2. Subject must be ≥ 18 years of age inclusive, at the time of signing the informed consent form.
3. Subjects must have HD access consisting of an arteriovenous fistula, AV graft, or tunnelled (per-
manent) catheter which is expected to remain in place for the entire duration of the study
4. Receiving HD (or HDF) 3 times a week for treatment of ESKD for at least 3 months before randomi-
sation
5. Pre-dialysis serum K+ > 5.4 mmol/L after long inter-dialytic interval and > 5.0 mmol/L after at least
one short inter-dialytic interval during screening (as assessed by central lab)
Informed decisions.

DIALIZE China 2020 (Continued)

6. Prescribed dialysate K+ concentration ≤ 3 mmol/L during screening
7. Sustained Qb ≥ 200 ml/min and Kt/V ≥ 1.2 (or URR ≥ 63) on stable HD/HDF prescription during
screening with prescription (time, dialyser, blood flow (Qb), dialysate flow rate (Qd) and bicarbon-
ate concentration) expected to remain unchanged during study
8. Subjects must be receiving dietary counselling appropriate for ESKD subjects treated with HD/
HDF as per local guidelines, which includes dietary potassium restriction.
Exclusion criteria
1. MI, acute coronary syndrome, stroke, seizure or a thrombotic/thromboembolic event (e.g., deep
vein thrombosis or pulmonary embolism, but excluding vascular access thrombosis) within 12
weeks prior to randomisation
2. Pseudohyperkalaemia secondary to haemolysed blood specimen (this situation is not considered
screening failure, sampling or full screening can be postponed to a later time as applicable).
3. Diagnosis of rhabdomyolysis during the 4 weeks preceding randomisation
4. Presence of cardiac arrhythmias or conduction defects that require immediate treatment
5. Any medical condition, including active, clinically significant infection or liver disease, that in the
opinion of the investigator or Sponsor may pose a safety risk to a subject in this study, which may
confound safety or efficacy assessment and jeopardize the quality of the data, or may interfere
with study participation
6. History of QT prolongation associated with other medications that required discontinuation of
that medication; congenital long QT syndrome or QTc(f) > 550 msec; uncontrolled atrial fibrilla-
tion despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial
fibrillation controlled by medication or with transient atrial fibrillation associated with dialysis or
pre-dialytic period are permitted
7. Subjects treated with sodium polystyrene sulfonate (e.g. Kayexalate, Resonium), calcium poly-
styrene sulfonate (Resonium calcium) or patiromer (Veltassa) within 7 days before screening or
anticipated in requiring any of these agents during the study.
8. Participation in another clinical study with an investigational product administered in the last 1
mouth before screening
9. Hb < 9 g/dL on screening (as assessed on Visit 1)
10.Laboratory diagnosis of hypokalaemia (K+ < 3.5 mmol/L), hypocalcaemia (Ca < 8.2 mg/d or albu-
min-corrected Ca < 8.0 mg/dL if the latter is used in local practice), hypomagnesaemia (Mg < 1.7
mg/dL) or severe acidosis (serum bicarbonate ≤ 16 mEq/L) in the 4 weeks preceding randomisa-
tion.
11.Severe leukocytosis (> 20 × 109/L) or thrombocytosis (≥ 450 × 109/L) during screening
12.Polycythaemia (Hb > 14 g/dL) during screening
13.Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/
or staff at the study site)
14.Judgment by the investigator that the subject should not participate in the study if the subject is
unlikely to comply with study procedures, restrictions and requirements
15.Previous randomisation in the present study
16.For women only - currently pregnant (confirmed with positive pregnancy test or uterine ultra-
sound if pregnancy test is questionable) or breast-feeding
17.Females of childbearing potential, unless using contraception as detailed in the protocol or sexual
abstinence
18.Lack of compliance with HD prescription (both number and duration of treatments) during the
two-week period preceding screening (100% compliance required)
19.Subjects unable to take investigational product drug mix
20.Scheduled date for living donor kidney transplant
21.Subjects with a life expectancy of less than 6 months
22.Known hypersensitivity or previous anaphylaxis to ZS-9 or to components thereof
23.History of alcohol or drug abuse within 2 years prior to randomisation
Informed decisions.

DIALIZE China 2020 (Continued)

• ZS-9: suspension administered orally for a treatment period of eight weeks (4 weeks of dose ad-
justment, 4 weeks in stable dose). Single dose contains from 1 to 3 sachets of ZS-9 5g depending
on dose level assigned to a patient per non-dialysis days
Control group
• Placebo: suspension administered orally for a treatment period of eight weeks (4 weeks of dose
adjustment, 4 weeks in stable dose) Single dose contains from 1 to 3 sachets of placebo depending
on dose level assigned to a patient per non-dialysis days
Outcomes Primary outcome measures
• Proportion of subjects in the following categories during the evaluation period: maintain a pre-
dialysis serum K+ between 4.0 to 5.0 mmol/L on 3 out of 4 dialysis treatments following the long
interdialytic interval do not receive rescue therapy
• To evaluate the efficacy of ZS-9 as compared to placebo in keeping the serum K+ concentration
between 4.0 and 5.0 mmol/L in subjects on HD
Secondary outcome measures
• To evaluate the efficacy of ZS-9 as compared to placebo in maintaining the pre-dialysis serum K+
concentration below 5.5 mmol/L
• To evaluate the efficacy of ZS-9 as compared to placebo in maintaining the pre-dialysis LIDI serum
K+ concentration between 5.5 and 3.5 mmol/L
• To evaluate the efficacy of ZS-9 as compared to placebo with respect to number of predialysis LIDI
visits with serum K+ concentration between 4.0 and 5.0 mmol/L
• To evaluate the efficacy of ZS-9 as compared to placebo in reducing the potassium gradient to
below 3.0 mmol/L
Starting date 5 June 2020
Contact information AstraZeneca
Email: information.center@astrazeneca.com
Notes Study stage: not yet recruiting

DIAMOND 2019
Study name Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the
Treatment of Heart Failure (DIAMOND) - the official title should be: "A Multicenter, Double-blind,
Placebo-controlled, randomised Withdrawal, Parallel Group Study of Patiromer for the Manage-
ment of Hyperkalemia in Subjects Receiving Renin Angiotensin Aldosterone System Inhibitor
(RAASi) Medications for the Treatment of Heart Failure (DIAMOND)"
Methods Study design: phase 3b multinational, multicentre, double-blind, placebo-controlled, randomised

withdrawal, parallel group study
Study duration: not reported
Duration of follow-up: approximately 2.5 years
Participants Country: multinational
Setting: multicentre
Inclusion criteria
• Age at least 18 years or greater

Informed decisions.

DIAMOND 2019 (Continued)
• History of symptomatic low ejection fraction heart failure (weak heart muscle)
• Receiving any dose of a beta blocker for the treatment of heart failure (unless not able to tolerate)
• Kidney function not more than mild or moderately impaired
• High blood potassium (> 5.0 mEq/L) currently while receiving medications for heart failure or nor-
mal blood potassium currently but previously had high potassium in the past 12 months which
caused reduction or discontinuation of heart failure medications
• Hospitalisation for heart failure or treatment in an outpatient setting with intravenous medica-
tions within last 12 months
Exclusion criteria
• Current acute decompensated heart failure

• Subjects with a discharge from a hospitalisation for acute decompensation of heart failure at least
4 weeks before screening may be included
• Significant primary aortic or mitral valvular heart disease (except mitral regurgitation due to left
ventricular dilatation)
• Heart transplantation or planned heart transplantation (i.e., currently on a heart transplant list)
during the study period
Number estimated randomised: 2388
• Patiromer 1 packet/day and may be taken either with food or without food (patiromer may be
increased by 1 packet per day in intervals of at least 1 week (± 3 days). For subjects who become
hypokalaemic, patiromer may be decreased to a minimum of 0 packets/day. Doses of patiromer
will be 0 packets/day, 1 packet/day, 2 packets/day, and 3 packets/day (maximum dose))
Control group
• Placebo 1 packet/day and may be taken either with food or without food
C0-interventions
• Not reported
Outcomes • Cardiovascular death

• Cardiovascular hospitalisation
• Proportion of subjects on ≥ 50% of guideline-recommended target dose of RAASi medications
• Total heart failure hospitalisations
• Kansas City Cardiomyopathy Questionnaire (KCCQ)
Starting date April 2019
Contact information Study director: Goehring UM
Phone number: 650-421-9500
Email: Diamond_Study@viforpharma.com
Notes Funding: Relypsa, Inc. and Vifor Pharma
Trials registration: NCT03888066

Informed decisions.

NCT03781089
Study name Patiromer Efficacy to Reduce Episodic Hyperkalemia in End Stage Renal Disease Patients Treated
With Hemodialysis (PEARL-HD)
Methods A prospective, randomised, open-label trial. Eligible ESRD patients who are on thrice weekly HD
schedule will be screened from retrospective review of clinical and laboratory parameters from
our clinical practice group. A total of 40 patients (randomised 1:1 study drug: usual care) will be en-
rolled. Duration of study medication exposure will be 4 weeks. The total duration of study, from en-
rolment until the end of the washout period will be 7 weeks
Participants Inclusion criteria
• Males and females, age at least 18 years

• ESKD treated with thrice-weekly HD for ≥ 6 months.
• At least two measured pre-dialysis serum K+ ≥ 5.5 mEq/L or one K+ ≥ 6.0 mEq/L noted over the
past three months
• Current use of dialysate with potassium concentration ≤ 2 mEq/L
• Typical consumption of at least two meals/day
• Have received customary dietary instruction over prior month
• Considered by the treating physician(s) to be in otherwise stable clinical condition
• If patient is of childbearing potential, he/she will be willing to avoid pregnancy during the study
using an acceptable birth control method
Exclusion criteria
• Not considered by the treating physician(s) to be adherent with recommended dialysis schedule
and prescribed medications
• Life expectancy < 3 months
• Dialysis-dependent for less than 6 months
• Non-elective hospitalisation in prior 3 months
• Currently prescription of oral potassium supplements
• In the prior 3 months, therapy with oral potassium-lowering medication
• Underlying severe GI disorders, including history of Ischaemic bowel
• Corrected serum calcium concentration > 10.5 mg/dL in prior three months
• Anticipated kidney transplant within the next 3 months
• Prisoners or others who are involuntarily incarcerated or detained
• Pregnant, breastfeeding, or considering pregnancy
• Participation in a clinical trial of an experimental treatment within the past 30 days
• Patiromer Oral Powder Product: Patients randomised to the patiromer arm will initiate on 8.4 g/
day (one pack) given once a day with breakfast or lunch (in place of the full dose of phosphate
binder), to start at the end of Week 0. The patiromer dose will be titrated based on serum potas-
sium concentrations drawn on HD1 of Weeks 1, 2, and 3. Patiromer will be increased by 8.4 g/day
if K+ ≥ 5.1 mEq/L, decreased by 8.4 g/day if K+ < 4.0 mEq/L, and patiromer will be discontinued
if K+ < 3.5 mEq/L
Control group
• Patients randomised to the usual care arm will undergo monitoring with laboratory measure-
ments as outlined in the study protocol
Outcomes Primary outcome measures
• Number of episodes of serum K+ ≥ 5.5 mEq/L
Secondary outcome measures
Informed decisions.

NCT03781089 (Continued)
• Percent of patients with serum K+ > 5.5 mEq/L
• Average dose of patiromer that was given in treatment arm
• Number of additional HD treatments due to hyperkalaemia
• Number of significant arrhythmia events as detected with cardiac monitors in Week 4
• Difference percentage in serum albumin concentrations
• Difference percentage in PTH concentrations
• Number of patients who completed all study visits
• Change percentage in serum potassium concentration two weeks after study drug is discontinued
• Change percentage in serum phosphorus concentration two weeks after study drug has been dis-
continued
• Number of > 1000 PVC/24 hours
• Number of significant arrhythmias
Starting date 20 June 2019
Contact information Robin Gilliam, MSW
Email: robin.gilliam@duke.edu
Notes
AV - arteriovenous; ESKD - end-stage kidney disease; Hb - haemoglobin; HD - haemodialysis; HDF - haemodiafiltration; MI - myocardial
infarction; PTH - parathyroid hormone; Qb - blood flow; RAAS(i) - renin-angiotensin-aldosterone system (inhibitor); URR - urea reduction
ratio; ZS-9 - sodium zirconium cyclosilicate

DATA AND ANALYSES

Comparison 1. Potassium binder versus placebo
Outcome or subgroup title No. of No. of Statistical method Effect size

studies partici-
pants
1.1 Death (any cause) 4 688 Risk Ratio (M-H, Random, 95% 0.69 [0.11, 4.32]
CI)
1.1.1 Newer agents (patiromer, ZS-9, 4 688 Risk Ratio (M-H, Random, 95% 0.69 [0.11, 4.32]
RLY5016) CI)
1.1.2 Older agents (SPS, CPS) 0 0 Risk Ratio (M-H, Random, 95% Not estimable
CI)
1.2 Cardiovascular death 1 Risk Ratio (M-H, Random, 95% Totals not selected
CI)
1.2.1 Newer agents (patiromer, ZS-9, 1 Risk Ratio (M-H, Random, 95% Totals not selected
RLY5016) CI)
1.2.2 Older agents (SPS, CPS) 0 Risk Ratio (M-H, Random, 95% Totals not selected
CI)
1.3 Nausea 3 229 Risk Ratio (M-H, Random, 95% 2.10 [0.65, 6.78]
CI)
Informed decisions.


studies partici-
pants
RLY5016) CI)
1.3.2 Older agents (SPS, CPS) 1 32 Risk Ratio (M-H, Random, 95% 2.00 [0.42, 9.42]
CI)
1.4 Diarrhoea 5 720 Risk Ratio (M-H, Random, 95% 0.84 [0.47, 1.48]
CI)
RLY5016) CI)
CI)
1.5 Vomiting 2 122 Risk Ratio (M-H, Random, 95% 1.72 [0.35, 8.51]
CI)
RLY5016) CI)
CI)
1.6 Constipation 4 425 Risk Ratio (M-H, Random, 95% 1.58 [0.71, 3.52]
CI)
RLY5016) CI)
CI)
1.7 Abdominal pain 1 Risk Ratio (M-H, Random, 95% Totals not selected
CI)
RLY5016) CI)
CI)
1.8 Serum potassium 3 277 Mean Difference (IV, Random, -0.62 [-0.97, -0.27]
95% CI)
1.8.1 Newer agents (patiromer, ZS-9, 2 246 Mean Difference (IV, Random, -0.45 [-0.71, -0.19]
RLY5016) 95% CI)
1.8.2 Older agents (SPS, CPS) 1 31 Mean Difference (IV, Random, -1.04 [-1.37, -0.71]
95% CI)
1.9 Change in serum potassium 2 105 Mean Difference (IV, Random, -0.75 [-1.27, -0.23]
95% CI)
Informed decisions.


studies partici-
pants
RLY5016) 95% CI)
1.9.2 Older agents (SPS, CPS) 1 31 Mean Difference (IV, Random, -1.04 [-1.36, -0.72]
95% CI)
1.10 Hypokalaemia 2 228 Risk Ratio (M-H, Random, 95% 1.71 [0.31, 9.47]
CI)
RLY5016) CI)
CI)
1.11 Hospitalisation 3 522 Risk Ratio (M-H, Random, 95% 0.26 [0.03, 2.32]
CI)
RLY5016) CI)
1.11.2 Older agents (SPS, CPS) 1 31 Risk Ratio (M-H, Random, 95% Not estimable
CI)
1.12 Angina pectoris 1 Risk Ratio (M-H, Random, 95% Totals not selected
CI)
RLY5016) CI)
CI)
1.13 Infection 1 Risk Ratio (M-H, Random, 95% Totals not selected
CI)
RLY5016) CI)
CI)
1.14 Systolic blood pressure 2 369 Mean Difference (IV, Random, -3.73 [-6.64, -0.83]
95% CI)
RLY5016) 95% CI)
1.14.2 Older agents (SPS, CPS) 0 0 Mean Difference (IV, Random, Not estimable
95% CI)
1.15 Change in systolic blood pressure 1 Mean Difference (IV, Random, Totals not selected
95% CI)
Informed decisions.


studies partici-
pants
1.15.1 Newer agents (patiromer, ZS-9, 1 Mean Difference (IV, Random, Totals not selected
RLY5016) 95% CI)
1.15.2 Older agents (SPS, CPS) 0 Mean Difference (IV, Random, Totals not selected
95% CI)
1.16 Diastolic blood pressure 1 Mean Difference (IV, Random, Totals not selected
95% CI)
RLY5016) 95% CI)
95% CI)
1.17 Change in diastolic blood pressure 1 Mean Difference (IV, Random, Totals not selected
95% CI)
RLY5016) 95% CI)
95% CI)
1.18 HRQoL 1 Mean Difference (IV, Random, Totals not selected

95% CI)
RLY5016) 95% CI)
95% CI)
1.19 Change in Health-related QoL 1 Mean Difference (IV, Random, Totals not selected
95% CI)
RLY5016) 95% CI)
95% CI)
1.20 Shunt stenosis 1 Risk Ratio (M-H, Random, 95% Totals not selected
CI)
RLY5016) CI)
CI)
1.21 Kidney transplantation 1 Risk Ratio (M-H, Random, 95% Totals not selected
CI)
Informed decisions.


studies partici-
pants
RLY5016) CI)
CI)

Analysis 1.1. Comparison 1: Potassium binder versus placebo, Outcome 1: Death (any cause)
Potassium binder Placebo Risk Ratio Risk Ratio

Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI
1.1.1 Newer agents (patiromer, ZS-9, RLY5016)

Ash 2015 0 60 0 30 Not estimable
AMBER 2018 0 147 1 148 33.2% 0.34 [0.01 , 8.17]
DIALIZE 2019 1 97 0 99 33.3% 3.06 [0.13 , 74.24]
OPAL-HK 2015 0 55 1 52 33.5% 0.32 [0.01 , 7.57]
Subtotal (95% CI) 359 329 100.0% 0.69 [0.11 , 4.32]
Total events: 1 2
Heterogeneity: Tau² = 0.00; Chi² = 1.27, df = 2 (P = 0.53); I² = 0%
Test for overall effect: Z = 0.40 (P = 0.69)
1.1.2 Older agents (SPS, CPS)

Subtotal (95% CI) 0 0 Not estimable
Total events: 0 0
Heterogeneity: Not applicable
Test for overall effect: Not applicable
Total (95% CI) 359 329 100.0% 0.69 [0.11 , 4.32]

Total events: 1 2
Heterogeneity: Tau² = 0.00; Chi² = 1.27, df = 2 (P = 0.53); I² = 0% 0.01 0.1 1 10 100
Test for overall effect: Z = 0.40 (P = 0.69) Less with potassium binder Less with placebo
Test for subgroup differences: Not applicable

Analysis 1.2. Comparison 1: Potassium binder versus placebo, Outcome 2: Cardiovascular death

Study or Subgroup Events Total Events Total M-H, Random, 95% CI M-H, Random, 95% CI

DIALIZE 2019 1 97 0 99 3.06 [0.13 , 74.24]
0.01 0.1 1 10 100

Less with potassium binder Less with placebo

Informed decisions.

Analysis 1.3. Comparison 1: Potassium binder versus placebo, Outcome 3: Nausea


OPAL-HK 2015 2 55 0 52 15.1% 4.73 [0.23 , 96.30]
Ash 2015 3 60 1 30 27.8% 1.50 [0.16 , 13.82]
Subtotal (95% CI) 115 82 42.9% 2.25 [0.38 , 13.43]
Total events: 5 1

Lepage 2015 4 16 2 16 57.1% 2.00 [0.42 , 9.42]
Subtotal (95% CI) 16 16 57.1% 2.00 [0.42 , 9.42]
Total events: 4 2
Total (95% CI) 131 98 100.0% 2.10 [0.65 , 6.78]

Total events: 9 3
Test for subgroup differences: Chi² = 0.01, df = 1 (P = 0.92), I² = 0%

Analysis 1.4. Comparison 1: Potassium binder versus placebo, Outcome 4: Diarrhoea


OPAL-HK 2015 2 55 0 52 3.6% 4.73 [0.23 , 96.30]
Ash 2015 2 60 0 30 3.6% 2.54 [0.13 , 51.31]
DIALIZE 2019 4 97 6 99 21.3% 0.68 [0.20 , 2.34]
AMBER 2018 9 147 8 148 37.9% 1.13 [0.45 , 2.86]
Subtotal (95% CI) 359 329 66.3% 1.09 [0.54 , 2.18]
Total events: 17 14

Lepage 2015 4 16 8 16 33.7% 0.50 [0.19 , 1.33]
Subtotal (95% CI) 16 16 33.7% 0.50 [0.19 , 1.33]
Total events: 4 8
Total (95% CI) 375 345 100.0% 0.84 [0.47 , 1.48]

Total events: 21 22
Test for subgroup differences: Chi² = 1.59, df = 1 (P = 0.21), I² = 37.2%

Informed decisions.

Analysis 1.5. Comparison 1: Potassium binder versus placebo, Outcome 5: Vomiting


Ash 2015 3 60 1 30 51.7% 1.50 [0.16 , 13.82]
Subtotal (95% CI) 60 30 51.7% 1.50 [0.16 , 13.82]
Total events: 3 1

Lepage 2015 2 16 1 16 48.3% 2.00 [0.20 , 19.91]
Subtotal (95% CI) 16 16 48.3% 2.00 [0.20 , 19.91]
Total events: 2 1
Total (95% CI) 76 46 100.0% 1.72 [0.35 , 8.51]

Total events: 5 2

Analysis 1.6. Comparison 1: Potassium binder versus placebo, Outcome 6: Constipation


Ash 2015 1 60 0 30 6.4% 1.52 [0.06 , 36.34]
OPAL-HK 2015 2 55 0 52 7.0% 4.73 [0.23 , 96.30]
DIALIZE 2019 4 97 3 99 29.6% 1.36 [0.31 , 5.92]
Subtotal (95% CI) 212 181 43.0% 1.70 [0.50 , 5.75]
Total events: 7 3

Lepage 2015 6 16 4 16 57.0% 1.50 [0.52 , 4.32]
Subtotal (95% CI) 16 16 57.0% 1.50 [0.52 , 4.32]
Total events: 6 4
Total (95% CI) 228 197 100.0% 1.58 [0.71 , 3.52]

Total events: 13 7

Informed decisions.

Analysis 1.7. Comparison 1: Potassium binder versus placebo, Outcome 7: Abdominal pain


Ash 2015 1 60 0 30 1.52 [0.06 , 36.34]
0.01 0.1 1 10 100


Analysis 1.8. Comparison 1: Potassium binder versus placebo, Outcome 8: Serum potassium
Potassium binder Placebo Mean Difference Mean Difference
Study or Subgroup Mean [mEq/L] SD [mEq/L] Total Mean [mEq/L] SD [mEq/L] Total Weight IV, Random, 95% CI [mEq/L] IV, Random, 95% CI [mEq/L]

DIALIZE 2019 5.1 0.6 82 5.7 0.7 90 33.9% -0.60 [-0.79 , -0.41]
OPAL-HK 2015 4.52 0.06 45 4.85 0.08 29 37.7% -0.33 [-0.36 , -0.30]
Subtotal (95% CI) 127 119 71.6% -0.45 [-0.71 , -0.19]

Lepage 2015 3.99 0.56 15 5.03 0.34 16 28.4% -1.04 [-1.37 , -0.71]
Subtotal (95% CI) 15 16 28.4% -1.04 [-1.37 , -0.71]
Test for overall effect: Z = 6.20 (P < 0.00001)
Total (95% CI) 142 135 100.0% -0.62 [-0.97 , -0.27]

Heterogeneity: Tau² = 0.08; Chi² = 24.53, df = 2 (P < 0.00001); I² = 92%
Test for overall effect: Z = 3.48 (P = 0.0005) -2 -1 0 1 2
Test for subgroup differences: Chi² = 7.63, df = 1 (P = 0.006), I² = 86.9% Lower with potassium binder Lower with placebo

Analysis 1.9. Comparison 1: Potassium binder versus placebo, Outcome 9: Change in serum potassium

OPAL-HK 2015 0.04 0.07 45 0.55 0.08 29 54.7% -0.51 [-0.55 , -0.47]
Subtotal (95% CI) 45 29 54.7% -0.51 [-0.55 , -0.47]

Lepage 2015 -1.25 0.57 15 -0.21 0.29 16 45.3% -1.04 [-1.36 , -0.72]
Subtotal (95% CI) 15 16 45.3% -1.04 [-1.36 , -0.72]
Total (95% CI) 60 45 100.0% -0.75 [-1.27 , -0.23]

Test for subgroup differences: Chi² = 10.31, df = 1 (P = 0.001), I² = 90.3% Less with potassium binder Less with placebo

Informed decisions.

Analysis 1.10. Comparison 1: Potassium binder versus placebo, Outcome 10: Hypokalaemia


DIALIZE 2019 5 97 5 99 73.1% 1.02 [0.31 , 3.41]
Subtotal (95% CI) 97 99 73.1% 1.02 [0.31 , 3.41]
Total events: 5 5

Lepage 2015 3 16 0 16 26.9% 7.00 [0.39 , 125.44]
Subtotal (95% CI) 16 16 26.9% 7.00 [0.39 , 125.44]
Total events: 3 0
Total (95% CI) 113 115 100.0% 1.71 [0.31 , 9.47]

Total events: 8 5
Test for subgroup differences: Chi² = 1.46, df = 1 (P = 0.23), I² = 31.3%

Analysis 1.11. Comparison 1: Potassium binder versus placebo, Outcome 11: Hospitalisation


DIALIZE 2019 0 97 1 99 47.4% 0.34 [0.01 , 8.25]
AMBER 2018 0 147 2 148 52.6% 0.20 [0.01 , 4.16]
Subtotal (95% CI) 244 247 100.0% 0.26 [0.03 , 2.32]
Total events: 0 3

Lepage 2015 0 15 0 16 Not estimable
Total events: 0 0
Total (95% CI) 259 263 100.0% 0.26 [0.03 , 2.32]

Total events: 0 3
Test for subgroup differences: Not applicable

Informed decisions.

Analysis 1.12. Comparison 1: Potassium binder versus placebo, Outcome 12: Angina pectoris


DIALIZE 2019 2 97 0 99 5.10 [0.25 , 104.92]
0.005 0.1 1 10 200


Analysis 1.13. Comparison 1: Potassium binder versus placebo, Outcome 13: Infection


DIALIZE 2019 12 97 9 99 1.36 [0.60 , 3.08]
0.1 0.2 0.5 1 2 5 10


Analysis 1.14. Comparison 1: Potassium binder versus placebo, Outcome 14: Systolic blood pressure
Study or Subgroup Mean [mmHg] SD [mmHg] Total Mean [mmHg] SD [mmHg] Total Weight IV, Random, 95% CI [mmHg] IV, Random, 95% CI [mmHg]

AMBER 2018 131.9 10 147 133.9 12 148 42.2% -2.00 [-4.52 , 0.52]
OPAL-HK 2015 128.5 1.88 45 133.5 2.23 29 57.8% -5.00 [-5.98 , -4.02]
Subtotal (95% CI) 192 177 100.0% -3.73 [-6.64 , -0.83]

Total (95% CI) 192 177 100.0% -3.73 [-6.64 , -0.83]

Test for subgroup differences: Not applicable Lower with potassium binder Lower with placebo

Analysis 1.15. Comparison 1: Potassium binder versus placebo, Outcome 15: Change in systolic blood pressure
Study or Subgroup Mean [mmHg] SD [mmHg] Total Mean [mmHg] SD [mmHg] Total IV, Random, 95% CI [mmHg] IV, Random, 95% CI [mmHg]

OPAL-HK 2015 -6.7 1.59 45 -1.21 1.89 29 -5.49 [-6.32 , -4.66]
-10 -5 0 5 10
Favours potassium binder Favours placebo

Informed decisions.


Analysis 1.16. Comparison 1: Potassium binder versus placebo, Outcome 16: Diastolic blood pressure

OPAL-HK 2015 74.98 1.13 45 77.63 1.98 29 -2.65 [-3.44 , -1.86]
-10 -5 0 5 10
Lower with potassium binder Lower with placebo

Analysis 1.17. Comparison 1: Potassium binder versus placebo, Outcome 17: Change in diastolic blood pressure

OPAL-HK 2015 -2.15 1.06 45 1.72 1.26 29 -3.87 [-4.42 , -3.32]
-10 -5 0 5 10
Favours potassium binder Favours placebo

Analysis 1.18. Comparison 1: Potassium binder versus placebo, Outcome 18: HRQoL
Study or Subgroup Mean SD Total Mean SD Total IV, Random, 95% CI IV, Random, 95% CI

AMBER 2018 71.7 11.1 145 69.1 11.1 144 2.60 [0.04 , 5.16]
-10 -5 0 5 10
Improves with placebo Improves with potassium binder

Analysis 1.19. Comparison 1: Potassium binder versus placebo, Outcome 19: Change in Health-related QoL
Study or Subgroup Mean SD Total Mean SD Total IV, Random, 95% CI IV, Random, 95% CI

AMBER 2018 4.8 6.8 145 2.8 8.5 144 2.00 [0.22 , 3.78]
-10 -5 0 5 10
Improves with placebo Improves with potassium binder

Informed decisions.

Analysis 1.20. Comparison 1: Potassium binder versus placebo, Outcome 20: Shunt stenosis


DIALIZE 2019 1 97 3 99 0.34 [0.04 , 3.21]
0.01 0.1 1 10 100


Analysis 1.21. Comparison 1: Potassium binder versus placebo, Outcome 21: Kidney transplantation


DIALIZE 2019 0 97 1 99 0.34 [0.01 , 8.25]
0.01 0.1 1 10 100


Comparison 2. Calcium polystyrene sulfonate (CPS) versus sodium polystyrene sulfonate (SPS)

studies partici-
pants
2.1 Nausea 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
2.2 Diarrhoea 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
2.3 Vomiting 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
2.4 Constipation 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
2.5 Abdominal pain 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
2.6 Serum potassium 2 117 Mean Difference (IV, Random, 95% CI) 0.38 [-0.03, 0.79]
2.7 Systolic blood pressure 1 Mean Difference (IV, Random, 95% CI) Totals not selected
2.8 Diastolic blood pressure 1 Mean Difference (IV, Random, 95% CI) Totals not selected

Informed decisions.

Analysis 2.1. Comparison 2: Calcium polystyrene sulfonate (CPS)

versus sodium polystyrene sulfonate (SPS), Outcome 1: Nausea
CPS SPS Risk Ratio Risk Ratio

Nasir 2014 9 50 20 47 0.42 [0.21 , 0.83]
0.1 0.2 0.5 1 2 5 10

Less with CPS Less with SPS

versus sodium polystyrene sulfonate (SPS), Outcome 2: Diarrhoea

Nasir 2014 1 50 0 47 2.82 [0.12 , 67.64]
0.01 0.1 1 10 100


versus sodium polystyrene sulfonate (SPS), Outcome 3: Vomiting

Nasir 2014 0 50 2 47 0.19 [0.01 , 3.82]
0.005 0.1 1 10 200


versus sodium polystyrene sulfonate (SPS), Outcome 4: Constipation

Nasir 2014 6 50 8 47 0.70 [0.26 , 1.88]
0.01 0.1 1 10 100


Informed decisions.


versus sodium polystyrene sulfonate (SPS), Outcome 5: Abdominal pain

Nasir 2014 1 50 3 47 0.31 [0.03 , 2.91]
0.01 0.1 1 10 100


Analysis 2.6. Comparison 2: Calcium polystyrene sulfonate (CPS) versus
sodium polystyrene sulfonate (SPS), Outcome 6: Serum potassium
CPS SPS Mean Difference Mean Difference
Nakayama 2018 4.14 0.91 10 4.12 0.64 10 25.5% 0.02 [-0.67 , 0.71]
Nasir 2014 4.8 0.5 50 4.3 0.53 47 74.5% 0.50 [0.29 , 0.71]
Total (95% CI) 60 57 100.0% 0.38 [-0.03 , 0.79]

Test for subgroup differences: Not applicable Lower with CPS Lower with SPS

sodium polystyrene sulfonate (SPS), Outcome 7: Systolic blood pressure
Study or Subgroup Mean [mm Hg] SD [mm Hg] Total Mean [mm Hg] SD [mm Hg] Total IV, Random, 95% CI [mm Hg] IV, Random, 95% CI [mm Hg]
Nasir 2014 139.25 18 50 136.6 19.3 47 2.65 [-4.79 , 10.09]
-20 -10 0 10 20
Lower with CPS Lower with SPS

sodium polystyrene sulfonate (SPS), Outcome 8: Diastolic blood pressure
Study or Subgroup Mean [mm Hg] SD [mm Hg] Total Mean [mm Hg] SD [mm Hg] Total IV, Random, 95% CI [mm Hg] IV, Random, 95% CI [mm Hg]
Nasir 2014 77.9 13.5 50 82.2 11.7 47 -4.30 [-9.32 , 0.72]
-20 -10 0 10 20
Lower with CPS Lower with SPS

Comparison 3. High dose potassium binder versus low dose potassium binder

studies partici-
pants
3.1 Death (any cause) 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
3.1.1 Sudden death 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
Informed decisions.


studies partici-
pants
3.2 Diarrhoea 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
3.3 Constipation 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
3.4 Hypokalaemia 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
3.5 Stroke 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected
3.6 Myocardial infarction 1 Risk Ratio (M-H, Random, 95% CI) Totals not selected

Analysis 3.1. Comparison 3: High dose potassium binder versus
low dose potassium binder, Outcome 1: Death (any cause)
High-dose Low-dose Risk Ratio Risk Ratio

3.1.1 Sudden death

AMETHYST-DN 2015 2 103 1 100 1.94 [0.18 , 21.08]
0.01 0.1 1 10 100

Less with high-dose Less with low-dose

Analysis 3.2. Comparison 3: High dose potassium binder versus low dose potassium binder, Outcome 2: Diarrhoea

AMETHYST-DN 2015 2 103 9 100 0.22 [0.05 , 0.97]
0.01 0.1 1 10 100


Analysis 3.3. Comparison 3: High dose potassium binder
versus low dose potassium binder, Outcome 3: Constipation

AMETHYST-DN 2015 9 103 6 100 1.46 [0.54 , 3.94]
0.01 0.1 1 10 100


Informed decisions.

Analysis 3.4. Comparison 3: High dose potassium binder

versus low dose potassium binder, Outcome 4: Hypokalaemia

AMETHYST-DN 2015 3 103 3 100 0.97 [0.20 , 4.70]
0.01 0.1 1 10 100


Analysis 3.5. Comparison 3: High dose potassium binder versus low dose potassium binder, Outcome 5: Stroke

AMETHYST-DN 2015 1 103 1 100 0.97 [0.06 , 15.31]
0.01 0.1 1 10 100


Analysis 3.6. Comparison 3: High dose potassium binder versus
low dose potassium binder, Outcome 6: Myocardial infarction

AMETHYST-DN 2015 1 103 0 100 2.91 [0.12 , 70.68]
0.01 0.1 1 10 100


ADDITIONAL TABLES

Table 1. List of the most important gastrointestinal side effects
Gastrointestinal side effects
Major Minor
Haematemesis Nausea
GI bleeding Vomiting
GI haemorrhage Gastroenteritis
Gastric ulceration Abdominal pain
Gastric cancer Indigestion
Pyloric stenosis Diarrhoea
Informed decisions.

Table 1. List of the most important gastrointestinal side effects (Continued)

Melena Constipation
Peptic ulcer Flatulence
Bowel perforation Heart-burn
Bowel ischemias/necrosis Dyspepsia
Irritable bowel syndrome -
Gastroesophageal reflux disease -
Crohn's disease -
Ulcerative colitis -
Haemorrhoids -
Diverticulitis -
Appendicitis -
Colitis -
Blood in stool (visible/occult) -
Vomiting blood -
GI event leading to abdominal surgery, including for bowel resection -
Gallstones -
Pancreatitis -
GI - gastrointestinal

APPENDICES
Appendix 1. Electronic search strategies

Database Search terms
CENTRAL 1. MeSH descriptor: [Kidney Diseases] explode all trees

2. MeSH descriptor: [Renal Replacement Therapy] explode all trees
3. MeSH descriptor: [Renal Insufficiency] explode all trees
4. MeSH descriptor: [Renal Insufficiency, Chronic] explode all trees
5. dialysis:ti,ab,kw (Word variations have been searched)
6. haemodialysis or haemodialysis:ti,ab,kw (Word variations have been searched)
7. hemofiltration or haemofiltration:ti,ab,kw (Word variations have been searched)
8. hemodiafiltration or haemodiafiltration:ti,ab,kw (Word variations have been searched)
9. kidney disease* or renal disease* or kidney failure or renal failure:ti,ab,kw (Word variations have
been searched)
Informed decisions.

(Continued)
10.ESRF or ESKF or ESRD or ESKD:ti,ab,kw (Word variations have been searched)
11.CKF or CKD or CRF or CRD:ti,ab,kw (Word variations have been searched)
12.CAPD or CCPD or APD:ti,ab,kw (Word variations have been searched)
13.predialysis or pre-dialysis:ti,ab,kw (Word variations have been searched)
14.{or 1-13}
15.MeSH descriptor: [Hyperkalemia] this term only
16.hyperkalemia or hyperkalaemia
17.{or #15-#16}
18.sodium zirconium cyclosilicate*:ti,ab,kw (Word variations have been searched)
19.sodium polystyrene sulfonate* or sodium polystyrene sulphonate*:ti,ab,kw (Word variations have
been searched)
20.calcium polystyrene sulfonate* or calcium polystyrene sulphonate*:ti,ab,kw (Word variations
have been searched)
21.patiromer:ti,ab,kw (Word variations have been searched)
22.potassium binder*:ti,ab,kw (Word variations have been searched)
23.{or 18-22}
24.{and 14, 17, 23}
MEDLINE 1. Kidney Diseases/

2. exp Renal Replacement Therapy/
3. Renal Insufficiency/
4. exp Renal Insufficiency, Chronic/
5. Diabetic Nephropathies/
6. exp Hypertension, Renal/
7. dialysis.tw.
8. (haemodialysis or haemodialysis).tw.
9. (hemofiltration or haemofiltration).tw.
10.(hemodiafiltration or haemodiafiltration).tw.
11.(kidney disease* or renal disease* or kidney failure or renal failure).tw.
12.(ESRF or ESKF or ESRD or ESKD).tw.
13.(CKF or CKD or CRF or CRD).tw.
14.(CAPD or CCPD or APD).tw.
15.(predialysis or pre-dialysis).tw.
16.or/1-15
17.Hyperkalemia/
18.(hyperkalemia or hyperkalaemia).tw.
19.or/17-18
20.exp Silicates/
21.Polystyrenes/
22.Potassium/
23.sodium zirconium cyclosilicate$.tw.
24.zs-9.tw.
25.patiromer.tw.
26.(sodium polystyrene sulfonate$ or sodium polystyrene sulphonate$).tw.
27.(calcium polystyrene sulfonate$ or calcium polystyrene sulphonate$).tw.
28.potassium binder$.tw.
29.or/20-28
30.and/16,19,29
EMBASE 1. exp renal replacement therapy/

2. kidney disease/
3. chronic kidney disease/
Informed decisions.

(Continued)
4. kidney failure/
5. chronic kidney failure/
6. mild renal impairment/
7. stage 1 kidney disease/
8. moderate renal impairment/
9. severe renal impairment/
10.end stage renal disease/
11.renal replacement therapy-dependent renal disease/
12.diabetic nephropathy/
13.kidney transplantation/
14.renovascular hypertension/
15.(haemodialysis or haemodialysis).tw.
16.(hemofiltration or haemofiltration).tw.
17.(hemodiafiltration or haemodiafiltration).tw.
18.dialysis.tw.
19.(CAPD or CCPD or APD).tw.
20.(kidney disease* or renal disease* or kidney failure or renal failure).tw.
21.(CKF or CKD or CRF or CRD).tw.
22.(ESRF or ESKF or ESRD or ESKD).tw.
23.(predialysis or pre-dialysis).tw.
24.((kidney or renal) adj (transplant* or graft* or allograft*)).tw.
25.or/1-24
26.hyperkalemia/
27.(hyperkalemia or hyperkalaemia).tw.
28.or/26-27
29.sodium zirconium cyclosilicate/
30.polystyrenesulfonate calcium/
31.polystyrenesulfonate sodium/
32.patiromer/
33.sodium zirconium cyclosilicate$.tw.
34.(calcium polystyrene sulfonate$ or calcium polystyrene sulphonate$).tw.
35.(sodium polystyrene sulfonate$ or sodium polystyrene sulphonate$).tw.
36.patiromer.tw.
37.potassium binder$.tw.
38.or/29-37
39.and/25,28,38

Appendix 2. Risk of bias assessment tool

Potential source of bias Assessment criteria
Random sequence genera- Low risk of bias: Random number table; computer random number generator; coin tossing; shuf-
tion fling cards or envelopes; throwing dice; drawing of lots; minimisation (minimisation may be imple-
mented without a random element, and this is considered to be equivalent to being random).
Selection bias (biased alloca-
tion to interventions) due to High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; se-
inadequate generation of a quence generated by hospital or clinic record number; allocation by judgement of the clinician; by
randomised sequence preference of the participant; based on the results of a laboratory test or a series of tests; by avail-
ability of the intervention.
Informed decisions.

(Continued)
Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Low risk of bias: Randomisation method described that would not allow investigator/participant to
know or influence intervention group before eligible participant entered in the study (e.g. central
Selection bias (biased alloca- allocation, including telephone, web-based, and pharmacy-controlled, randomisation; sequential-
tion to interventions) due to ly numbered drug containers of identical appearance; sequentially numbered, opaque, sealed en-
inadequate concealment of al- velopes).
locations prior to assignment
High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); as-
signment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or
non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record num-
ber; any other explicitly unconcealed procedure.
Unclear: Randomisation stated but no information on method used is available.
Blinding of participants and Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome
personnel is not likely to be influenced by lack of blinding; blinding of participants and key study personnel
ensured, and unlikely that the blinding could have been broken.
Performance bias due to
knowledge of the allocated High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by
interventions by participants lack of blinding; blinding of key study participants and personnel attempted, but likely that the
and personnel during the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
study
Unclear: Insufficient information to permit judgement
Blinding of outcome assess- Low risk of bias: No blinding of outcome assessment, but the review authors judge that the out-
ment come measurement is not likely to be influenced by lack of blinding; blinding of outcome assess-
ment ensured, and unlikely that the blinding could have been broken.
Detection bias due to knowl-
edge of the allocated interven- High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be
tions by outcome assessors. influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could
have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
Incomplete outcome data Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be relat-
ed to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome
Attrition bias due to amount, data balanced in numbers across intervention groups, with similar reasons for missing data across
nature or handling of incom- groups; for dichotomous outcome data, the proportion of missing outcomes compared with ob-
plete outcome data. served event risk not enough to have a clinically relevant impact on the intervention effect esti-
mate; for continuous outcome data, plausible effect size (difference in means or standardised dif-
ference in means) among missing outcomes not enough to have a clinically relevant impact on ob-
served effect size; missing data have been imputed using appropriate methods.
High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either
imbalance in numbers or reasons for missing data across intervention groups; for dichotomous
outcome data, the proportion of missing outcomes compared with observed event risk enough to
induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausi-
ble effect size (difference in means or standardized difference in means) among missing outcomes
enough to induce clinically relevant bias in observed effect size; ‘as-treated’ analysis done with
substantial departure of the intervention received from that assigned at randomisation; potentially
inappropriate application of simple imputation.
Selective reporting Low risk of bias: The study protocol is available and all of the study’s pre-specified (primary and
secondary) outcomes that are of interest in the review have been reported in the pre-specified way;
Reporting bias due to selective
outcome reporting
Informed decisions.

(Continued)
the study protocol is not available but it is clear that the published reports include all expected out-
comes, including those that were pre-specified (convincing text of this nature may be uncommon).
High risk of bias: Not all of the study’s pre-specified primary outcomes have been reported; one or
more primary outcomes is reported using measurements, analysis methods or subsets of the data
(e.g. sub-scales) that were not pre-specified; one or more reported primary outcomes were not pre-
specified (unless clear justification for their reporting is provided, such as an unexpected adverse
effect); one or more outcomes of interest in the review are reported incompletely so that they can-
not be entered in a meta-analysis; the study report fails to include results for a key outcome that
would be expected to have been reported for such a study.
Other bias Low risk of bias: The study appears to be free of other sources of bias.
Bias due to problems not cov- High risk of bias: Had a potential source of bias related to the specific study design used; stopped
ered elsewhere in the table early due to some data-dependent process (including a formal-stopping rule); had extreme base-
line imbalance; has been claimed to have been fraudulent; had some other problem.
Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient ra-
tionale or evidence that an identified problem will introduce bias.

HISTORY
Protocol first published: Issue 11, 2018
Review first published: Issue 6, 2020
CONTRIBUTIONS OF AUTHORS
1. Draft the protocol: PN, SP
2. Study selection: PN, MR
3. Extract data from studies: PN, MR
4. Enter data into RevMan: PN, MR
5. Carry out the analysis: PN, SP
6. Interpret the analysis: PN, SP, MR, VS, GFMS
7. Draft the final review: PN, SP
8. Disagreement resolution: SP
9. Update the review: SP, GFMS
DECLARATIONS OF INTEREST
• Patrizia Natale: none known
• Suetonia C Palmer: none known
• Marinella Ruospo: none known
• Valeria M Saglimbene: none known
• Giovanni FM Strippoli: none known
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
Since major GI adverse events were not reported, we included minor GI events (constipation) in Summary of findings tables. We categorised
treatments in newer agents (patiromer or ZS-9) and older agents (calcium polystyrene sulfonate and sodium polystyrene sulfonate). We
reported outcomes as newer or older agents.

Potassium Binders For Chronic Hyperkalaemia in People With Chronic

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Potassium Binders For Chronic Hyperkalaemia in People With Chronic

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Natale P, Palmer SC, Ruospo M, Saglimbene VM, Strippoli GFM

Natale P, Palmer SC, Ruospo M, Saglimbene VM, Strippoli GFM.

Potassium binders for chronic hyperkalaemia in people with chronic

Contact address: Giovanni FM Strippoli, giovanni.strippoli@uniba.it, gfmstrippoli@gmail.com.

Editorial group: Cochrane Kidney and Transplant Group.

Data collection and analysis

What is the issue?

What did we do?

What did we find?

Patient or population: people with CKD (including haemodialysis)

Outcomes Illustrative comparative risks* Relative No. of Quality of Comments

Cochrane Database of Systematic Reviews

2) Serum potassium - older agents (SPS, CPS)

Cochrane Database of Systematic Reviews

GRADE Working Group grades of evidence

CPS versus SPS for chronic hyperkalaemia in people with CKD

Patient or population: people with CKD

Cochrane Database of Systematic Reviews

HRQoL Not reported Not reported -- -- -- No studies reported this outcome

GRADE Working Group grades of evidence

Patient or population: people with CKD

Cochrane Database of Systematic Reviews

Intervention: high-dose potassium binder

Comparison: low-dose potassium binder

GRADE Working Group grades of evidence

1 Death (any cause; sudden death) was reported by as a single study

Cochrane Database of Systematic Reviews

BACKGROUND The potassium exchange resins may be administered orally or

Types of participants • Death (any cause and cardiovascular death)

• Stage of CKD • Death (any cause)

Figure 1. Study flow diagram

Interventions of patiromer with compared to without food, and AMETHYST-DN

Random sequence generation (selection bias)

0% 25% 50% 75% 100%

Low risk of bias Unclear risk of bias High risk of bias

Blinding of participants and personnel (performance bias): All outcomes

Selective reporting (reporting bias)

AUTHORS' CONCLUSIONS of treatments for chronic hyperkalaemia. Future potassium binder

zirconium cyclosilicate (ZS-9) [abstract no: 307]. American

Bushinsky DA, Spiegel DM, Yuan J, Warren S, Fogli J, Pergola PE. Alvarez 2017

Cowan 2017 Higgins 2003

Dunn 2015 KDIGO 2013

Fried 2017 Moranne 2009

GRADE 2011 Palaka 2018

Characteristics of included studies [ordered by study ID]

Methods • Study design: phase 2, double-blind, placebo-controlled RCT

Interventions Treatment group

• Placebo: microcrystalline cellulose

Comment: An interactive web response system is considered as a low risk of

Comment: A double-blind study is considered as a low risk of bias

Comment: An independent Data Safety and Monitoring Committee assessed

Comment: As reported in figure 1, all participants were analysed

Methods • Study design: phase 2 multicentre, open-label, dose-ranging, parallel-group RCT

Participants • Country: multinational, 5 European countries

Outcomes • Death (any cause)

Bias Authors' judgement Support for judgement

Comment: A computer generation model is considered as a low risk of bias

Comment: A validated interactive web response system is consider as a low

Comment: Outcomes were at low risk of detection bias due to independent

Comment: As reported in figure 1, 300/306 participants were analysed

Participants • Country: USA

Interventions Treatment group 1

• ZS-9 (oral): 0.3 g