FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1892570064> ?p ?o ?g. }

• W1892570064 endingPage "738" @default.
• W1892570064 startingPage "731" @default.
• W1892570064 abstract "HomeHypertensionVol. 66, No. 4New Potassium Binders for the Treatment of Hyperkalemia Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessReview ArticlePDF/EPUBNew Potassium Binders for the Treatment of HyperkalemiaCurrent Data and Opportunities for the Future Bertram Pitt and George L. Bakris Bertram PittBertram Pitt From the Department of Medicine, University of Michigan School of Medicine, Ann Arbor (B.P.); and ASH Comprehensive Hypertension Center, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Chicago Medicine, IL (G.L.B.) Search for more papers by this author and George L. BakrisGeorge L. Bakris From the Department of Medicine, University of Michigan School of Medicine, Ann Arbor (B.P.); and ASH Comprehensive Hypertension Center, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Chicago Medicine, IL (G.L.B.) Search for more papers by this author Originally published24 Aug 2015https://doi.org/10.1161/HYPERTENSIONAHA.115.04889Hypertension. 2015;66:731–738Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2015: Previous Version 1 Hyperkalemia is a clinical problem with potential mechanisms ranging from increased cellular potassium release (eg, pseudohyperkalemia, metabolic acidosis) to reduced potassium excretion (eg, reduced responsiveness to aldosterone, reduced aldosterone secretion, reduced distal sodium, and water delivery).1,2 Patients with chronic kidney disease (CKD), defined as an estimated glomerular filtration rate (eGFR) <45 mL/min per 1.73 m2, are at increased risk of hyperkalemia, resulting from ≥1 of these mechanisms.3 Renin–angiotensin–aldosterone system inhibitors (RAASis) are recommended by guidelines for lowering blood pressure, slowing CKD progression in patients with CKD,4,5 and reducing cardiovascular mortality and heart failure hospitalizations in patients with heart failure and a reduced ejection fraction,6,7 but these drugs compound the hyperkalemia risk.1,8–10 The risk is magnified when the drugs are used in combination (eg, aliskiren in combination with ACE inhibitors or angiotensin receptor blockers;8,11 mineralocorticoid receptor antagonists in combination with ACE inhibitors or angiotensin receptor blockers). Moreover, the risk for hyperkalemia is magnified in diseases, such as diabetes mellitus and heart failure.4,5,12,13 The occurrence or fear of inducing hyperkalemia has led to premature discontinuation, suboptimal dosing, and often failure to use an RAASi, thereby exposing patients to increased cardiovascular risk.Current treatment approaches for chronic hyperkalemia are limited. Options for the management of hyperkalemia include discontinuation or reduced doses of RAASi, administration of loop diuretics, dietary potassium restriction, or sodium polystyrene sulfonate.14 None of these approaches are optimal because they require withholding life-saving or kidney preserving therapy (ie, RAASi), have a low rate of patient adherence (eg, dietary restriction), or have an unfavorable adverse effect profile and low tolerability (ie, sodium polystyrene sulfonate).15New agents to treat hyperkalemia are in the late stages of development. Clinical trial data suggest that these new agents effectively lower serum potassium and are well tolerated.16–20 Therefore, these agents offer promising advantages over existing management options. It is possible that these agents might also facilitate maintenance of RAASi across the broad spectrum of patients with RAASi intolerance because of hyperkalemia (eg, CKD and heart failure),18 and testing this hypothesis in larger clinical trials is warranted. This article reviews the clinical problem of hyperkalemia and identifies predictors of hyperkalemia in patients with hypertension, CKD, diabetes mellitus, and heart failure. It also presents recent clinical trial evidence of the efficacy and safety of new treatments for hyperkalemia, and it discusses how these agents may be used clinically, if approved.Overview of HyperkalemiaThe rate of hyperkalemia is low in uncomplicated hypertension patients treated with RAASi,21 but it rises in the setting of other comorbidities (eg, eGFR <60 and especially <45 mL/min per 1.73 m2, and heart failure) or dual RAAS inhibition.22 Hyperkalemia rates reported in observational studies vary by patient population (Table S1 in the online-only Data Supplement). Estimates of hyperkalemia rates are likely to be biased by underreporting, and actual rates may be higher, especially for patients with multiple risk factors (eg, CKD, diabetes mellitus, heart failure, and dual RAASi) or who are managed in routine clinical practice without the stringent monitoring protocols of clinical trials.23 Predictors of hyperkalemia are shown in Table 1.22 These predictors reflect worse kidney function, advanced diabetes mellitus, or more severe heart failure.Table 1. Key Predictors of Hyperkalemia* in People With Chronic Kidney Disease With or Without Diabetes Mellitus or Heart FailureeGFR ≤45 mL/min per 1.73 m2 (regardless of pathogenesis)Initial serum potassium >4.5 mEq/L9BMI <25 g/m2*Hyperkalemia is defined as a [K+] >5.5 mEq/L where renin–angiotensin–aldosterone system inhibitors alone or in combination were given. eGFR indicates estimated glomerular filtration rate.Hyperkalemia is associated with an increased risk of death in patients with and without CKD.3 In an analysis of 15 803 patients with heart failure or hypertension treated with RAASi, twice as many deaths occurred in patients categorized as hyperkalemic (serum potassium >5 mEq/L, n=3868), although the absolute number of deaths was not reported.24 In a multiple logistic regression model, hyperkalemia was associated with an odds ratio for death of 1.56 (95% confidence interval, 1.30–1.88) in the total population and 1.63 (95% confidence interval, 1.04–2.55) among those with stages 3 to 5 CKD.24 The association between mortality risk and serum potassium among patients with stage 3 to 5 CKD is U-shaped, with an increased mortality risk at serum potassium >5.0 mEq/L and <4.1 mEq/L, even after adjustment for demographic characteristics and comorbidities.25 Patients ≥65 years of age and those with comorbidities (eg, heart failure, CKD, cardiovascular disease, or hypertension) have a greater mortality risk than younger patients or those without comorbid conditions.26In addition to the direct association between hyperkalemia and all-cause mortality, hyperkalemia may theoretically have an indirect impact on clinical outcomes because of the lost opportunity to treat patients with RAASi, either because of actual hyperkalemia or concerns about the risk of hyperkalemia.27 However, this theoretical effect has not been quantified.Dietary Management of HyperkalemiaRestriction of dietary potassium to <2.4 g/d is recommended in patients with stage 3 (eGFR <60 mL/min per 1.73 m2) or higher CKD.14 However, specific guideline-directed advice is lacking on dietary potassium intake for other patient groups at risk of hyperkalemia. In patients with heart failure in whom sodium restriction is frequently advised, the use of salt substitutes including potassium chloride may expose these patients to the risk of hyperkalemia, especially if they have concomitant CKD or diabetes mellitus. Although patients are often educated to avoid commonly recognized high-potassium foods, many high-potassium foods may remain unrecognized by patients and healthcare providers (Table S2). Patients at risk for hyperkalemia should receive comprehensive dietary potassium education. This recommendation may be especially important in patients who attempt the DASH (Dietary Approaches to Stop Hypertension) diet. Although the overall effects of the DASH diet seem beneficial, patients with CKD or diabetes mellitus may be placed at increased risk for hyperkalemia and its consequences.Novel Therapies in Development for HyperkalemiaOverviewThe majority of potassium is renally excreted, but ≈5% to 10% is secreted in the colon (Figure 1). Two new agents, patiromer and sodium zirconium cyclosilicate (ZS-9), are in the late stages of clinical development for the treatment of hyperkalemia. These agents may offer advantages over existing approaches to hyperkalemia treatment (Table 2). Both patiromer and ZS-9 act to remove potassium by exchanging cations (calcium and sodium for patiromer and ZS-9, respectively) for potassium in the distal colon, binding potassium, and increasing its fecal excretion.28Table 2. Comparison of Existing and New Potential Therapies for Chronic HyperkalemiaCharacteristicKayexylatePatiromerZS-9Clinical pharmacologyCation-exchange resin, exchanges sodium for H+ in stomach, then exchange for H+ for other cations in large intestineNonabsorbed organic polymer28,29; preferentially binds K+ in the colonInorganic polymer; negative charge to framework enables cation exchange28,29Clinical trialsNoYesYesEfficacyObserved decreases in serum potassium between 0.82 and 1.14 mEq/L depending on dose29Mean reduction in serum potassium at week 4 −1.01 mmol/L; 76% with normokalemia after 4 wk;17 60% placebo vs 15% patiromer had recurrent serum K+ ≥5.5 mmol/L during 8-week withdrawal phase17Mean initial reduction in serum potassium (48 h) −0.46 to −1.1 mEq/L depending on dose16,20; 98% achieved normokalemia within 48 h; 71%–85% depending on ZS-9 dose maintained normokalemia during 28 day follow-up vs 48% with placebo20SafetyRisk of acute bowel necrosis, hypernatremia, diarrhea, and gastrointestinal intolerance15Mild-to-moderate constipation most commonly reported (11% during initial treatment phase and 4% patiromer vs 0% placebo during 8-wk randomized withdrawal phase), hypokalemia (5%–6%), hypomagnesemia (3% in OPAL-HK, 7.2% in AMETHYST-DN, and 24% in PEARL-HF)Gastrointestinal disorder reported in 2.1%–8.7% of ZS-9 patients (depending on dose and period of study) vs 2.4%–7.4% of placebo patients, hypokalemia (≈10% depending on dose), edema (2.4%)Download figureDownload PowerPointFigure 1. Mechanisms involved in potassium secretion in colonic epithelial cells in response to an increase in serum potassium levels. In the colonic enterocytes potassium enters the cell via the Na+, K+-ATPase, and Na+-2Cl−-K+ cotransporter (NKCC1) of the basolateral membrane and leaves the cell into the colon lumen via apical large conductance Ca2+-dependent potassium (KCNMA or BK) channels. In the basolateral membrane, several potassium channels (KCNQ1/KCNE3, KCNN4, and probably KCNK5) facilitate the electrogenic transport by hyperpolarizing the membrane voltage. CFRT indicates epithelial (cystic fibrosis transmembrane regulator) chloride channels; and ENaC, apical epithelial sodium channels. Reprinted from Tamargo et al28 with permission of the publisher. Copyright © 2014, Discovery Medicine.Patiromer is an organic, nonabsorbed polymer (Figure 2) that increases fecal potassium excretion by exchanging potassium for calcium in the distal colon.17,18,29,30 It is a free-flowing, insoluble powder of small (≈100 µm) spherical beads with low viscosity.17,18,29,30 Sodium zirconium cyclosilicate (ZS-9) is an inorganic polymer, which selectively attracts potassium ions to its negatively charged crystalline lattice structure and exchanges them for sodium and hydrogen (Figure 3).16,28,29,31 It is formulated as a free-flowing, insoluble powder that is not absorbed systemically.31Download figureDownload PowerPointFigure 2. Properties of patiromer calcium. Reprinted from McCullough PA et al29 with permission of the publisher. Copyright © 2014, MedReviews ®, LLC.Download figureDownload PowerPointFigure 3. Structure of ZS-9. Pore detail with potassium ion (A), sodium ion (B), and calcium ion (C). Blue spheres indicates oxygen atoms; green spheres, silicon atoms; and red spheres, zirconium atoms. Reprinted from Stavros et al31 with permission of the publisher. Copyright © 2014, the Authors.Patiromer Clinical TrialsThe PEARL-HF study (Evaluation of RLY5016 in Heart Failure Patients) was a multicenter, randomized, double-blind, placebo-controlled parallel-group multiple-dose study to evaluate the effects of patiromer in patients with heart failure.18 A total of 120 patients with chronic heart failure who were treated with standard background therapy and had an indication for spironolactone were enrolled. Patients were required to have serum potassium between 4.3 and 5.1 mEq/L at screening. All patients had either an eGFR of <60 mL/min or a documented history of RAASi discontinuation because of hyperkalemia within 6 months. Patients were randomized to double-blind patiromer 15 g twice daily or placebo for 4 weeks; spironolactone 25 mg once daily was also initiated in all patients with plans to increase the dose to 50 mg once daily after 2 weeks if serum potassium was >3.5 to ≤5.1 mEq/L. The mean change in serum potassium from baseline to day 28 was the primary efficacy end point.18Mean serum potassium was 4.7 mEq/L at baseline in both the groups. At 28 days, serum potassium was significantly lower in the patiromer group compared with placebo.18 This reduction was evident regardless of eGFR. Fewer patients randomized to patiromer experienced serum potassium of >5.5 mEq/L (7% versus 25%; P=0.015), and more patiromer-treated patients had serum potassium of <3.5 mEq/L, but the difference was not significant (6% versus 0%; P=0.094). Hypomagnesemia (<1.8 mg/dL) was reported in 13 (24%) of the patiromer patients and 1 (2%) of the placebo patients (P=0.001). The mean serum magnesium value remained within normal limits, although the patiromer group had a statistically significant reduction in serum magnesium from baseline compared with the placebo group. These electrolyte changes were not associated with an increased risk of ventricular arrhythmias. No significant changes in serum phosphorous were noted. The spironolactone dose was increased in more patients randomized to patiromer than placebo (91% versus 74%; P=0.019). Gastrointestinal side effects were reported in 21% of patiromer-treated patients and 6% of placebo patients, but there was no difference in adverse events leading to study drug discontinuation (7% versus 6%).18 The PEARL-HF data suggested that patiromer was well tolerated and may be an effective therapy to prevent hyperkalemia in patients with heart failure who are at risk for hyperkalemia, and it may enable initiation, maintenance, or higher doses of mineralocorticoid receptor antagonists in addition to background RAASi therapy.18 Larger studies of this concept are warranted.Patiromer was studied in 304 patients with type 2 diabetes mellitus and CKD (eGFR, 15 to <60 mL/min per 1.73 m2) in the AMETHYST-DN (RLY5016 in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy) trial.19 In this multicenter, randomized, open-label, dose-ranging study, patients were enrolled who developed hyperkalemia in the setting of RAASi dose optimization for blood pressure control, or who were on an RAASi and hyperkalemic at the time of screening. Patients were stratified by baseline serum potassium, and those with serum potassium of >5 to 5.5 mEq/L (mild stratum) were equally randomized to patiromer 4.2, 8.4, or 12.6 g twice daily. Patients with serum potassium >5.5 to <6 mEq/L (moderate stratum) were randomized 1:1:1 to patiromer 8.4, 12.6, or 16.8 g twice daily. The study consisted of an 8-week treatment phase and a 44-week maintenance phase. The primary efficacy end point was the mean change in serum potassium from baseline to week 4. The mean baseline serum potassium was 5.3 mEq/L; 65% of patients had stage 3 CKD. Statistically significant reductions in mean serum potassium were observed within 48 hours, across the spectrum of baseline serum potassium levels. By week 4, the reduction from baseline in serum potassium was significant in both strata (mild, −0.47±0.04 mEq/L; moderate, −0.92±0.08 mEq/L) and for all dosing groups (all P<0.001). The reduction in serum potassium was maintained throughout the follow-up period. After patiromer discontinuation, serum potassium rose by 0.43±0.46 mEq/L in the mild stratum and 0.49±0.69 mEq/L in the moderate stratum during 28 days of follow-up.19 Serum potassium <3.5 mEq/L occurred in 17 patients (5.6%). Hypomagnesemia (7.2%), constipation (4.6%), and diarrhea (2.7%) were the most commonly reported treatment-related adverse events.19 Mean serum magnesium was in the normal range (1.5–2.4 mg/dL) during the treatment period. The mean change in serum magnesium from baseline to week 52 was −0.1 to −0.2 across all doses within all strata. Mean phosphate decreased slightly from baseline to 52 weeks, with a mean reduction of −0.1 to −0.2 mg/dL in all dosing groups, except for a decrease of −0.8±0.9 mg/dL at the 8.4 g twice daily starting dose in the moderate hyperkalemia stratum.The OPAL-HK (A Two-Part, Single-Blind, Phase 3 Study Evaluating the Efficacy and Safety of Patiromer for the Treatment of Hyperkalemia) trial was a 2-part, single-blind, phase 3 study, which evaluated the efficacy and safety of patiromer for the treatment of hyperkalemia in patients with stage 3 or 4 CKD (eGFR, 15 to <60 mL/min per 1.73 m2), on ≥1 RAASi, and serum potassium of 5.1 to <6.5 mmol/L.17 The first study phase consisted of a 4-week, single-group, single-blind treatment phase (patiromer 4.2 g twice daily for baseline potassium 5.1 to <5.5 mmol/L or 8.4 g twice daily for baseline potassium 5.5 to <6.5 mmol/L with subsequent dose adjustments made according to a prespecified algorithm), followed by an 8-week placebo-controlled, single-blind, randomized withdrawal phase in the patients whose serum potassium was ≥5.5 mmol/L at the first-phase baseline and 3.8 to <5.1 mmol/L at the end of the initial treatment period. Patients were randomized to continue patiromer at the same dose as their week 4 dose during the initial treatment phase, or placebo. The primary end points for the respective study phases were the mean change in serum potassium from baseline to week 4, and the between-group difference in the median serum potassium change from the beginning of the randomized withdrawal phase to week 4 of the withdrawal phase.In the initial treatment phase, 243 patients were enrolled. Of these, 107 continued into the randomized withdrawal phase. Comorbidities associated with hyperkalemia were common: 57% had type 2 diabetes mellitus, 42% had heart failure, 97% had hypertension, all were on an RAASi, 17% were on dual RAASi, and 44% were receiving maximal RAASi doses. The mean eGFR was 35 mL/min per 1.73 m2. Patiromer significantly reduced serum potassium from baseline during the initial treatment phase (−1.01±0.03 mmol/L; 95% confidence interval, −1.07 to −0.95). The majority of patients (76%) had serum potassium levels within the target range (3.8 to <5.1 mmol/L) at the end of the initial treatment phase, and this finding was consistent among patients with mild or moderate-to-severe hyperkalemia at baseline. Serum potassium increased in the placebo group but not in the patiromer group during the first 4 weeks of the randomized withdrawal phase, resulting in a between-group difference in serum potassium of 0.72 mmol/L (P<0.001). Potassium >5.5 mmol/L occurred in 15% of patients randomized to patiromer continuation compared with 60% of patients in the placebo group (P<0.001). Patiromer, although well tolerated, was associated with constipation in 11% of patients during the initial treatment phase, whereas there was no constipation in the placebo group. Study drug was discontinued because of adverse events in 1 (2%) patient each in the patiromer and placebo groups.17 Serum potassium of <3.5 mmol/L occurred in 3% of patients during the initial treatment phase. Hypokalemia was defined as serum potassium of <3.8 mmol/L during the randomized withdrawal phase, and it was observed in 5% and 2% of the patiromer and placebo groups, respectively.17 Changes in magnesium were similar to those observed in other patiromer studies. Patients maintained overall normal serum magnesium levels with small decreases from baseline in the range of −0.1 to −0.2 mg/dL. Hypomagnesemia occurred in 8 (3%) patients during the initial treatment phase. No clinically relevant changes in calcium were observed.Sodium Zirconium Cyclosilicate Clinical TrialsPackham et al16 conducted a 2-phase study of ZS-9 in patients with serum potassium of 5.0 to 6.5 mmol/L. Patients on dialysis were excluded, but no specific requirements for eGFR or RAASi use were specified. Patients were randomized to double-blind ZS-9 (1.25 g, 2.5 g, 5 g, or 10 g 3× daily) or placebo for 48 hours. Patients in the ZS-9 group whose serum potassium was 3.5 to 4.9 mmol/L at 48 hours were randomized to either continue their current ZS-9 dose once daily or placebo for 12 days. The primary end point of the initial phase was the between-group difference in the exponential rate of change in mean serum potassium during 48 hours. The maintenance phase primary end point was the between-group difference in mean serum potassium level during the 12-day treatment interval. A total of 754 patients entered the initial phase, and 543 patients continued to the 12-day maintenance phase. The population reflected patients with risk factors for hyperkalemia, including CKD (61%), heart failure (42%), diabetes mellitus (61%), and RAASi use (64%). The mean rate of change (decrease) in serum potassium from baseline was greater for the ZS-9 2.5, 5, and 10 g groups compared with placebo (P<0.001), and normokalemia was reached within 48 hours for all these dosing groups compared with placebo (P<0.001). During the maintenance phase, normokalemia was maintained in the ZS-9 5 g and 10 g dosing groups compared with patients who were subsequently randomized to placebo. Recurrent hyperkalemia was observed within 1 week among patients treated with ZS-9 10 g who discontinued study drug at the end of the study.16 Gastrointestinal side effects were the most commonly reported adverse events in both the initial treatment and maintenance phases. Hypokalemia <3.5 mmol/L was reported in 2 ZS-9 patients, 1 at the 2.5-g dose (maintenance) and 1 at the 10-g dose (initial treatment).16 A dose-dependent increase in serum bicarbonate was observed. There were no reports of hypomagnesemia.The Hyperkalemia Randomized Intervention Multidose ZS-9 Maintenance (HARMONIZE) study was a randomized, double-blind, placebo-controlled trial in patients with serum potassium of ≥5.1 mEq/L.20 Patients were treated with ZS-9 10 g 3× daily for 48 hours during an open-label initial phase, and patients who achieved serum potassium 3.5 to 5.0 mEq/L were randomized to double-blind ZS-9 (5, 10, or 15 g) or placebo for 28 days. The primary end point was the comparison of mean serum potassium levels between placebo and ZS-9 from days 8 through 29. A total of 258 patients entered the open-label phase, and 237 were randomized into the maintenance phase.20 The mean baseline serum potassium was 5.6 mEq/L, mean eGFR was 46 mL/min per 1.73 m2, and 69% had eGFR <60 mL/min per 1.73 m2. CKD was present in 66%, 36% had heart failure, 66% had diabetes mellitus, and 70% were treated with ≥1 RAASi. ZS-9 reduced serum potassium from baseline at 48 hours (−1.1 mEq/L, 95% confidence interval, −1.1 to −1.0; P<0.001), and normokalemia (serum potassium 3.5–5.0 mEq/L) was achieved in 84% and 98% within 24 and 48 hours, respectively. The median time to normokalemia was 2.2 hours. During the maintenance phase, mean serum potassium was lower in all the ZS-9 groups compared with placebo (P<0.001). ZS-9 was well tolerated. Gastrointestinal side effects were reported, but they did not differ between the placebo and ZS-9 groups (14% placebo, 7% 5 g, 2% 10 g, and 9% 15 g). During the maintenance phase, edema was reported in 2.4% of the placebo group and 2.2%, 5.9%, and 14.3% of the 5 g, 10 g, and 15 g dosing groups, respectively. Serum potassium of <3.5 mEq/L was observed in 10% of patients in the ZS-9 10 g group and 11% of patients in the ZS-9 15 g group versus no cases in the 5 g or placebo groups.20 No clinically significant changes in serum magnesium, phosphate, or bicarbonate were observed.Practical Clinical Management of HyperkalemiaAcute HyperkalemiaIn acute hyperkalemia, intravenous insulin or a β2-agonist can be used to shift potassium into cells. Sodium bicarbonate is indicated in the setting of metabolic acidosis. However, in patients with hypertension and in those with heart failure, the use of sodium bicarbonate may be contraindicated because of the risk of increasing sodium retention and volume overload. Hyperkalemic patients presenting with evidence of cardiac instability should receive rapid therapy to stabilize the myocardium according to the standard of care (eg, intravenous calcium chloride or gluconate).32 Dialysis may also be considered for the treatment of acute hyperkalemia.32Acute therapy is recommended when serum potassium is >6.5 mmol/L or when cardiac manifestations of hyperkalemia are present regardless of the serum potassium concentration.33 However, it is important to recognize that the ECG can be normal, even with severe hyperkalemia. In addition, ventricular fibrillation may develop without preceding cardiac rhythm abnormalities, and it is difficult to predict which patients are at risk for cardiac manifestations of hyperkalemia.33–35 The absolute level of serum potassium associated with an increased risk of ventricular arrhythmias and sudden cardiac death will, in part, depend on the rate of rise of serum potassium, the level of tissue potassium (as reflected by red blood cell potassium concentration), calcium concentration, pH, and other factors. These considerations support instituting acute therapy for patients with moderate-to-severe hyperkalemia according to the criteria specified above,33 although minimal evidence from clinical trials is available on the acute treatment of hyperkalemia.36Some data suggest that ZS-937 and patiromer38 may have an onset of action sufficient to allow the use of these agents in the acute setting. More data are needed to fully understand these findings and determine whether the observation of an early effect (1–4 hours with ZS-9) was because of shifting potassium (ie, because of postprandial insulin release in patients who were fasting before ZS-9 was administered or alkalization from the conversion of the sodium component of ZS-9 to bicarbonate), or to true potassium removal.Chronic HyperkalemiaTreatmentThe only available current treatment for chronic hyperkalemia is sodium or calcium polystyrene. Sodium or calcium polystyrene are cation-exchange resins, which exchange sodium (or calcium) for secreted potassium in the lumen of the colon. Although these agents are effective in reducing serum potassium, their effects are not predictable.15 The onset of action is delayed until the resin reaches the colon. In addition, sodium polystyrene has been associated with gastrointestinal toxicity limiting its chronic use.15 Sodium polystyrene when administered alone can cause severe constipation and impaction, which led to its administration with sorbitol. However, sorbitol is a suspected contributor to the colonic necrosis that has been observed in patients treated with sodium polystyrene.19 Because of these limitations, sodium polystyrene is not a viable option for routine chronic use, and discontinuation of RAASi is often the most clinically appropriate option for managing hyperkalemia.However, if approved, patiromer and ZS-9 could play an important role in the current management of hyperkalemia. Patiromer and ZS-9 have demonstrated both early reductions in potassium and an ability to maintain normokalemia over weeks of therapy with acceptable side effect profiles.16–20 Although head-to-head trials of patiromer or ZS-9 versus sodium polystyrene sulfonate have not been conducted, the theoretical advantages of the new agents over existing therapy are apparent (Table 2).Patient Selection and DosingAlthough the exact indication and labeling parameters will not be known until these drugs are approved, the patient selection criteria will probably mimic the eligibility criteria of the patiromer and ZS-9 clinical trials. Thus, patients presenting with elevated serum potassium of >5 mmol/L will likely be candidates for therapy. It is not expected that specific thresholds for eGFR would be required for treatment if hyperkalemia is present. However, patients with end-stage renal disease on dialysis were not included in clinical trials. The clinical trial data suggest that potassium-lowering effects are observed within several hours and normokalemia within 24 hours.20 However, these agents are not intended for acute lowering of serum potassium, and their onset of action should be considered when determining the need for acute treatment. Until more data become available, clinical trial protocols should be used to help guide initial and maintenance dosing strategies if these agents are approved for use.Treatment DurationPatiromer and ZS-9 are likely to be initially approved for relatively short treatment durations (30–60 days). However, the results of PEARL-HF and 1-year follow-up data with patiromer from AMETHYST-DN show effectiveness with no concerning safety signals when patiromer was administered daily for ≤1 year.18,19 A study with ZS-9 is also ongoing to gather 1-year data.MonitoringIn the patiromer and ZS-9 clinical trials, potassium was monitored at weekly intervals. Serum potassium values were relatively stable during maintenance therapy. Firm monitoring recommendations cannot be made at the present time in" @default.
• W1892570064 created "2016-06-24" @default.
• W1892570064 creator A5012514694 @default.
• W1892570064 creator A5042843111 @default.
• W1892570064 date "2015-10-01" @default.
• W1892570064 modified "2023-10-18" @default.
• W1892570064 title "New Potassium Binders for the Treatment of Hyperkalemia" @default.
• W1892570064 cites W122788210 @default.
• W1892570064 cites W1487934346 @default.
• W1892570064 cites W1581048864 @default.
• W1892570064 cites W1756552807 @default.
• W1892570064 cites W1970939567 @default.
• W1892570064 cites W1975828955 @default.
• W1892570064 cites W2006586291 @default.
• W1892570064 cites W2008452717 @default.
• W1892570064 cites W2041162893 @default.
• W1892570064 cites W2052349502 @default.
• W1892570064 cites W2057550912 @default.
• W1892570064 cites W2072577267 @default.
• W1892570064 cites W2093767567 @default.
• W1892570064 cites W2097640181 @default.
• W1892570064 cites W2100169278 @default.
• W1892570064 cites W2101879409 @default.
• W1892570064 cites W2111945961 @default.
• W1892570064 cites W2119340816 @default.
• W1892570064 cites W2126125759 @default.
• W1892570064 cites W2131066811 @default.
• W1892570064 cites W2138862624 @default.
• W1892570064 cites W2148910374 @default.
• W1892570064 cites W2152271789 @default.
• W1892570064 cites W2152594920 @default.
• W1892570064 cites W2154336683 @default.
• W1892570064 cites W2157267479 @default.
• W1892570064 cites W2167557672 @default.
• W1892570064 cites W2315765264 @default.
• W1892570064 cites W2319308197 @default.
• W1892570064 cites W2324948948 @default.
• W1892570064 cites W4233762550 @default.
• W1892570064 cites W4244540230 @default.
• W1892570064 doi "https://doi.org/10.1161/hypertensionaha.115.04889" @default.
• W1892570064 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26303290" @default.
• W1892570064 hasPublicationYear "2015" @default.
• W1892570064 type Work @default.
• W1892570064 sameAs 1892570064 @default.
• W1892570064 citedByCount "60" @default.
• W1892570064 countsByYear W18925700642015 @default.
• W1892570064 countsByYear W18925700642016 @default.
• W1892570064 countsByYear W18925700642017 @default.
• W1892570064 countsByYear W18925700642018 @default.
• W1892570064 countsByYear W18925700642019 @default.
• W1892570064 countsByYear W18925700642020 @default.
• W1892570064 countsByYear W18925700642021 @default.
• W1892570064 countsByYear W18925700642022 @default.
• W1892570064 countsByYear W18925700642023 @default.
• W1892570064 crossrefType "journal-article" @default.
• W1892570064 hasAuthorship W1892570064A5012514694 @default.
• W1892570064 hasAuthorship W1892570064A5042843111 @default.
• W1892570064 hasConcept C126322002 @default.
• W1892570064 hasConcept C191897082 @default.
• W1892570064 hasConcept C192562407 @default.
• W1892570064 hasConcept C2780243291 @default.
• W1892570064 hasConcept C517785266 @default.
• W1892570064 hasConcept C71924100 @default.
• W1892570064 hasConceptScore W1892570064C126322002 @default.
• W1892570064 hasConceptScore W1892570064C191897082 @default.
• W1892570064 hasConceptScore W1892570064C192562407 @default.
• W1892570064 hasConceptScore W1892570064C2780243291 @default.
• W1892570064 hasConceptScore W1892570064C517785266 @default.
• W1892570064 hasConceptScore W1892570064C71924100 @default.
• W1892570064 hasIssue "4" @default.
• W1892570064 hasLocation W18925700641 @default.
• W1892570064 hasLocation W18925700642 @default.
• W1892570064 hasOpenAccess W1892570064 @default.
• W1892570064 hasPrimaryLocation W18925700641 @default.
• W1892570064 hasRelatedWork W133937744 @default.
• W1892570064 hasRelatedWork W1983781786 @default.
• W1892570064 hasRelatedWork W2013215766 @default.
• W1892570064 hasRelatedWork W2032799877 @default.
• W1892570064 hasRelatedWork W2049058840 @default.
• W1892570064 hasRelatedWork W2063784476 @default.
• W1892570064 hasRelatedWork W2463234862 @default.
• W1892570064 hasRelatedWork W2474074509 @default.
• W1892570064 hasRelatedWork W2896448125 @default.
• W1892570064 hasRelatedWork W4245370611 @default.
• W1892570064 hasVolume "66" @default.
• W1892570064 isParatext "false" @default.
• W1892570064 isRetracted "false" @default.
• W1892570064 magId "1892570064" @default.
• W1892570064 workType "article" @default.