INTRODUCTION

Hyperkalemia (high blood potassium concentration) is one of the most serious electrolyte abnormalities because of its association with the induction or aggravation of cardiac arrhythmias and an increase in mortality rates. 1

The increase in serum potassium concentration is multifactorial, and the main risk factors are chronic kidney disease (CKD), acute kidney disease, cardiovascular diseases, diabetes mellitus, and the use of medications such as potassium-sparing diuretics, angiotensin-converting enzyme inhibitors (iRRAS), heparins, mineralocorticoid receptor antagonists, and nonsteroidal anti-inflammatory drugs. 2, 3, 4 In such cases of drug-induced hyperkalemia, premature withdrawal5 is recommended, but this can expose patients to a higher cardiovascular risk. 4

The management of potassium homeostasis disorders has not shown any significant advances since the introduction of ion exchange resins in 1958. 6 Sodium polystyrene sulfonate (SPS) is a cation-exchanging resin that has been widely used for several decades as the first-line therapy of mild chronic hyperkalemia. 7 Concerns about the safety profile of SPS have been described, mainly due to severe disorders in the digestive system. 8 Despite this, the Institute of Healthcare Management considers that the drug should be used as a trigger tool to detect drug-induced hyperkalemia. 9

New potassium binders were developed, such as sodium zirconium cyclosilicate (ZS-9) and patiromer. Their safety and efficacy have been compared among them and/or with polysulfonate resins, but none of them were assessed with temporizing agents or other traditional therapies applied in order to decrease serum potassium levels. 10, 11, 12 While Sterns et al. described the treatment options for hyperkalemia, including both new and old approaches; they did not evaluate the quality of evidence that supports efficacy and safety of each pharmacotherapy included in the review. 6

Despite decades of knowledge regarding the potential risks of hyperkalemia, there are no guidelines to advise who should be treated. 13 Treatment approaches are based on small-scale studies, anecdotal experiences, and traditionally accepted practice standards. 14

Faced with several therapeutic options available to manage the potassium imbalances; which are applied inconsistently, monitoring safety and efficacy of treatment with SPS, as proposed by IHI, might underestimated cases of adverse drug events. 14

In this setting, our review aimed to describe the new and traditional therapies applied to manage hyperkalemia; evaluate the efficacy and safety of the treatments; and assess the quality of evidence.

METHODS

This systematic review was performed and reported in accordance with the relevant consensuses; the PROSPERO registration number is CRD4201705071018. 15, 16, 17

Eligibility and search

The assessed population included patients with hyperkalemia (without restrictions for age, sex, or current or previous past medical history) receiving hyperkalemia treatment: sodium bicarbonate, polarizing solution (insulin + glucose), fenoterol, salbutamol (albuterol), furosemide, bumetanide, calcium (CPS) or sodium polystyrene sulfonate (SPS), patiromer, ZS-9, fludrocortisone, hydrocortisone, or aminophylline compared with placebo, no treatment, or another comparator. These medications were included as search terms based on previously published reviews. 18, 19

Clinical trials, comparative cohorts, and case-control studies comparing mean serum potassium reduction, serum potassium differences at different time points, frequency of adverse events and serious adverse events, and discontinuation due to adverse events were eligible for inclusion in this review.

We excluded studies that recruited patients with normokalaemia, whose serum levels of potassium rise after treatments; and researches aimed at sustained normokalemic levels after prescriptions of treatment of hyperkalemia. Congress, abstracts, dose comparisons, and studies that did not accurately report the treatment were also excluded. There was no language restriction.

A search was conducted in MEDLINE (via PubMed) (from 1940 to present), LILACS (via BIREME) (from 1982 to present), and Cochrane Library (from 1994 to present) in October 2016. It was updated in November 2018. Manual searches in the references of review articles about hyperkalemia, clinical trials, and PROSPERO were also performed. We did not contact with study authors (Appendix A). We did not performed contact with study authors.

Study selection, data extraction, and synthesis of data

Two reviewers selected and extracted a sample of eligible studies and achieve good agreement (at least 80%, considering kappa coefficient). Then, one investigator performed the selection and data extraction, and a second investigator revised the verdicts, as recommended by AMSTAR 2 checklist. In the absence of consensus at all stages, the points of disagreement were solved via a third investigator.

Data were extracted in a worksheet of Microsoft Excel® and included: the type of study, number of participants, age group, disease, comorbidities, compared alternatives and dosages applied to manage hyperkalemia; concomitant drugs, main outcomes (mean, difference or number of serum potassium level), follow-up, adverse drug events reported.

Risk of bias in individual studies and quality of evidence

Assessment of the risk of bias was done at the outcome level (discontinuation due to adverse events, difference in mean serum potassium, baseline mean serum potassium concentration, and final time point) by two independent reviewers. The Cochrane Collaboration ROB version 2.0 tool was used to assess the risk of bias in the clinical trials. 20 The ROBINS tool evaluated the risk of bias in the cohort studies. 21

The critical evaluation of the bias risk of the included studies was conducted by two independent reviewers using GRADE Working Group guidelines. 22 In the absence of consensus, points of disagreement were resolved by the opinion of a third researcher.

RESULTS

This systematic review identified 704 studies. After considering the strategy search and duplicity elimination, 656 studies were excluded by reading titles and abstracts ( Figure 1). No additional studies were identified by manual search. After a full assessment of 48 studies, 32 were excluded (justifications are given in Appendix B).

Figure 1
Flowchart of studies selection (PRISMA).

Included studies

Sixteen studies (n=1,582 participants) were enrolled including clinical trials (n=15) and a retrospective cohort (n=1). 23- 38 The studies were published between 1989 and 2018 and described different therapies, mainly for patients diagnosed with chronic kidney disease (n=11). The commonest comorbidities reported were hypertension and diabetes (n=9)

There was no consensus about definition of hyperkalemia. Some authors considered hyperkalemia at baseline when serum potassium level was >4.5 mEq/L. Others when it was >7.0 mEq/L ( Table 1). The mean baseline serum potassium ranged from 5.0 to 7.1 mEq/L ( Table 2).

We observed follow-up times ranging from 1 to 72 hours (n=10) and reaching 7 days or 12 months for studies in patients with CKD (n=6). There were no studies included that assessed outcomes with patiromer, fenoterol, furosemide, bumetanide, hydrocortisone, or aminophylline. Most subjects were adults and elderly (n=13); 3 studies included neonatal patients ( Table 1).

Efficacy

Efficacy outcomes were reported in 14 clinical trials; the only cohort study identified did not report the effectiveness of the therapies, just the safety problems ( Table 2). We observed that all treatments assessed were able to reduce serum potassium levels, but most of them did not show any statistical difference among the therapies compared ( Table 2).

We noticed statistical significance in six comparisons: I) insulin + glucose vs. glucose alone, II) SPS vs. placebo, III) 2.5 g ZS-9 vs. placebo; IV) 5 g ZS-9 vs. placebo, V) 10 g ZS-9 vs. placebo, and VI) 3-5 g CPS three times/day vs. no treatment ( Table 2). 28, 32, 33, 38 All these treatments were prescribed for CKD patients.

Adverse events

There were 24 different adverse events reported in the studies. 23, 28, 31- 34, 36- 38 Only three showed statistical analysis regarding the occurrence of ADE among therapies compared. 31, 32, 38 A higher frequency of nausea and anorexia was observed for SPS in relation to CPS (p < 0.05). 31 No significance was observed in the occurrence of ADE between placebo and the polystyrene resins ( Table 3). 32, 38

Only three studies reported the discontinuation of treatments due to adverse drug reactions. 28, 32, 37 Lepage et al. reported one interruption (6%) in the SPS group and none in the placebo group; Chothia et al. reported one interruption (17%) in the insulin + glucose group and none in the glucose group due to serious hypoglycemia. 28, 32 Nakayama et al. reported five interruptions [edema (n=3), diarrhea (n=1) and headache (n=1)] in the CPS group and none in the SPS group. 37

Risk of bias

The predominance of efficacy outcomes suggested a high risk of bias, whereas safety outcomes were at a low risk of bias. Regarding clinical trials, the high risk of bias was mostly due to problems in the randomization process and some concerns over multiple domains. Most studies had a low risk in the outcome measurement domain. Regarding evaluation at the study level, Wang et al. 2018, Lepage et al. 2015 and Chothia et al. 2014 presented a low risk of bias independent of the outcome evaluated (Appendix C). 28, 31, 32 The only cohort study included presents a serious risk of bias regardless of the outcome evaluated, since it presented serious risk of bias for classification of interventions, deviations from intended interventions and selections of the reported result (Appendix D).

Quality of evidence

Considering recommendations of system GRADE, the assessment of quality of evidence should consider the evidence with higher quality. Therefore, we focused in clinical trials, since only one comparative cohort study was included with serious risk of bias regardless of the outcome evaluated.

There was scant evidence for each individual comparison. There was little viability for the development of direct or indirect meta-analysis. Thus, we did not consider the presence of inconsistency or potential publication bias, and there is a change in the evidence confidence upon the completion of new clinical trials. The difference was evaluated with statistical significance being equivalent to the clinical significance following the tendency proposed by the original authors, as well as with an absence of consensus for this evaluation. This evaluated the presence of precision in efficacy outcomes (serum potassium differences at the final time and differences between means).

There was moderate confidence in the evidence supporting the statistical difference of insulin + glucose vs. glucose, SPS vs. placebo, 2.5 g, 5 g, and 10 g ZS-9 versus placebo and CPS vs no treatment. The confidence in the estimate of the effect might change as new studies are reported, and these studies may even modify the effect estimation. Other comparisons showed low confidence in the evidence due to the presence of high risk of bias, as well as imprecision suggesting that future studies will likely have a significant impact on our confidence in the effect estimation (Appendix E).

DISCUSSION

Our findings showed that most studies compared at least two different interventions to manage hyperkalemia in patients diagnosed with CKD, diabetes and hypertension. Despite the potential risks, incidence and prevalence of hyperkalemia in patients with certain comorbidities and medication exposures, and the availability of effective potassium-lowering therapies, there are no guidelines to advise who should, or should not, be treated. 13

Among individuals with CKD, current guideline recommendations advocate the use of iRAAS as a first-line antihypertensive therapy, which may increase serum potassium levels. Depending on the seriousness of hyperkalemia, their discontinuation is recommended, potentially depriving patients of renoprotective effects. 39, 40

Management of hyperkalemia has traditionally involved a combination of acute treatment and avoidance of potentially contributing factors. 40 Acute therapeutic interventions included those that involve shifting potassium to the intracellular space. We observed that temporizing agents are able to reduce serum potassium levels, but there was no statistical difference between them. Except for insulin plus dextrose, which showed a significant decrease when compared with glucose (moderate confidence) in patients with CKD.

Insulin plus dextrose is a commonly applied method for the displacement of potassium into the intracellular space, which is associated with many complications. This reduces abnormal myocardial conduction from increased potassium, and is a temporary ‘fix’ at best. 41 However, there is uncertainty whether transcellular shifting causes insufficient potassium removal during hemodialysis, resulting in a subsequent need for further medical therapy or multiple sessions of hemodialysis. 42

Longer-term management of hyperkalemia has remained a challenge. Currently available therapeutic interventions to control chronic hyperkalemia include dietary potassium restriction, vigorous use of diuretic therapy, correction of acidosis, and administration of sodium polystyrene sulfonate, but these are often problematic and unsuccessful. 43

Potassium binders such as SPS used to be the only currently available exchange resin in everyday clinical practice. 8 However, its use is controversial, due to its limited profile of safety, the lack of evidence of efficacy and safety in chronic hyperkalemia and also due to the occurrence of life-threatening events, such as bowel necrosis. 7, 44, 45 In spite of this, the use of SPS (typically with sorbitol added at a concentration of 33%) for acute treatment of hyperkalemia remains common. 4 Owing to concerns related to the safety profile of polystyrene binders, new potassium-exchanging resins are being assessed.

Our data show that when potassium binders (SPS, CPS and ZS-9) were compared with the effects of a placebo they significant decrease serum potassium levels. ZS-9 had a better safety profile. Recent publications suggest that both ZS-9 and patiromer are safer than SPS, however, they are not based on direct or indirect comparison methods. 11, 46

There are several reasons why SPS is an inappropriate therapeutic option for patients with chronic hyperkalaemia or as comparators for ZS-9 in clinical trials, such as serious gastrointestinal side effects, organoleptic characteristics (making it impossible to serve as a marked treatment), and lack of efficacy for acute or chronic hyperkalaemia. 47

However, a robust and clinically meaningful indirect treatment comparison of ZS-9 to SPS/CPS is infeasible because of heterogeneity between studies, the very small sample sizes in the SPS/CPS trials, and the use of dosing regimens different from those in the product characteristics for SPS/CPS. 11

Although studies that assess the safety and efficacy of patiromer were not included in the present review, this drug shows promise as a potassium-lowering agent for patients with chronic hyperkalemia, because it may allow for dose optimization of iRAAS and improves the clinical outcomes in patients with CDK, diabetes, and heart failure. 48 However, pharmacovigilance studies are need to assess drug-drug interactions, to obtain more safety data, and to evaluate the effectiveness in long-term use, considering patients in use of mineralocorticoid receptor antagonist and iRAAS use. 11, 49, 50 In addition, it is necessary that more trials with active comparators are essential to finalize its indication and use in hyperkalemia. 12

Considering the assessment of safety profile, early detection of adverse drug events considering CPS/SPS as a trigger may have underestimated the cases, since several approaches could be prescribed to treat hyperkalemia in clinical practice, most of them as off-label use, which increase the occurrence of drug-induced harm. Therefore, we suggest serum potassium level as a trigger to detect drug-induced ADE.

Rozenfeld et al. observed that hyperkalemia is a high-performance trigger to detect ADE in neonates. 51 Serum potassium could also be used as a predictor of adverse clinical outcomes in patients with chronic ADE, and identify those likely to benefit from strategies that treat hyperkalemia, and prevent iRAAS discontinuation. 52

Finally, we can notice that there is no single definition about hyperkalemia, although it is considered as serum potassium concentrations greater than 5.0 to 5.5 mEq/L. 53 The lack of a standardized definition of hyperkalemia hinders comparisons of incidence and outcomes across epidemiological studies, since they are obscured by inconsistent serum potassium thresholds. 52 It is important establish the serum potassium levels and adverse outcomes arising from hyperkalemia, in order to drive the rational therapy to treat the imbalance.

It is recommended that researchers adopt a core outcome set for the evaluation of outcomes in future studies. Sterns et al. considered serum potassium control as a surrogate marker for clinically important outcomes such as mortality rate, reduction in CKD progression, postponement of dialysis, and improvement in outcomes of heart disease. 6 Rossignol et al. suggested as relevant outcomes the time to achieve normokalemia, the incidence of clinically significant arrhythmias, and the need for rescue therapies. 14 Since it is not established in the literature, the parameter that brings clinical benefits to the patient, in order to evaluate chronic pharmacotherapy, is more important to achieve normokalemia than the reduction of potassium. 14

Limitations of the studies included in this review include the high heterogeneity of data and high risk of bias in the randomization domain. Limitations were also observed in relation to safety outcomes — the form reporting such adverse events is not standardized, and it may come from both the patients’ spontaneous reports and an active searching by the researchers.

The limitations of this review were a lack of contact with the authors of the studies to identify omitted data—these are old publications with a low probability of success in reaching the authors. We also excluded congress and abstracts literature due to a low probability of identifying studies that presented complete and reliable information. We did not obtain four studies for the eligibility phase.

CONCLUSIONS

Our results demonstrate that the treatment of acute hyperkalemia is empirical and off-label, since ZS-9 is an unavailable option in several countries. Among the off-label therapies, insulin plus dextrose had better efficacy than glucose (moderate confidence). Other therapies had similar efficacy as active or inactive therapies for hyperkalemia (low confidence). Further studies are need to compare ZS-9 and temporizing agents used in acute hyperkalemia (insulin plus dextrose, beta-2 agonists and sodium bicarbonate), in order to assess the safety, efficacy and effectiveness of pharmacotherapies in hyperkalemic patients without kidney impairment or with chronic kidney disease.

Despite the moderate confidence of SPS vs placebo and CPS and no treatment applied to manage chronic hyperkalemia, data should be analyzed with caution, due to the limitations of the design of the studies and seriousness of adverse events in digestive tract. A new potassium binder (patiromer) has been shown to achieve better outcomes of safety and efficacy. However, there were no studies found comparing patiromer with other alternatives for patients with hyperkalemia. Detection of drug-drug interaction with the new drug binder remains under reported.

Our review demonstrated that most adverse events reported by the studies enrolled were non-specific, making it difficult to attribute the cause and classify it as a defined or probable event. Safety assessment of the available pharmacotherapies could be improved via pharmacovigilance studies, such as contemporary cohorts and case-control designs. Such studies should be delineated with a low risk of bias, large sample size, and good duration of follow-up to recognize the risks associated with treatments and to support the development of guidelines with better evidences.

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Notes

Conflict of interest declaration