Effect of Patiromer on Serum Potassium Level in Patients with Hyperkalemia and Diabetic Kidney Disease the AMETHYST-DN Randomized Clinical Trial

Research

Original Investigation Effect of Patiromer on Serum Potassium Level in Patients With Hyperkalemia and Diabetic Kidney Disease The AMETHYST-DN Randomized Clinical Trial

George L. Bakris, MD; Bertram Pitt, MD; Matthew R. Weir, MD; Mason W. Freeman, MD; Martha R. Mayo, PharmD; Dahlia Garza, MD; Yuri Stasiv, PhD; Rezi Zawadzki, DrPH; Lance Berman, MD; David A. Bushinsky, MD; for the AMETHYST-DN Investigators

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IMPORTANCE Hyperkalemia is a potentially life-threatening condition predominantly seen in Supplemental content at patients treated with renin-angiotensin-aldosterone system (RAAS) inhibitors with stage 3 or jama.com greater chronic kidney disease (CKD) who may also have diabetes, heart failure, or both.

OBJECTIVES To select starting doses for a phase 3 study and to evaluate the long-term safety and efficacy of a potassium-binding polymer, patiromer, in outpatients with hyperkalemia.

DESIGN, SETTING, AND PARTICIPANTS Phase 2, multicenter, open-label, dose-ranging, randomized clinical trial (AMETHYST-DN), conducted at 48 sites in Europe from June 2011 to June 2013 evaluating patiromer in 306 outpatients with type 2 diabetes (estimated glomerular filtration rate, 15 to <60 mL/min/1.73 m2 and serum potassium level >5.0 mEq/L). All patients received RAAS inhibitors prior to and during study treatment.

INTERVENTIONS Patients were stratified by baseline serum potassium level into mild or moderate hyperkalemia groups and received 1 of 3 randomized starting doses of patiromer (4.2 g [n = 74], 8.4 g [n = 74], or 12.6 g [n = 74] twice daily [mild hyperkalemia] or 8.4 g [n = 26], 12.6 g [n = 28], or 16.8 g [n = 30] twice daily [moderate hyperkalemia]). Patiromer was titrated to achieve and maintain serum potassium level 5.0 mEq/L or lower.

MAIN OUTCOMES AND MEASURES The primary efficacy end point was mean change in serum potassium level from baseline to week 4 or prior to initiation of dose titration. The primary safety end point was adverse events through 52 weeks. Secondary efficacy end points included mean change in serum potassium level through 52 weeks.

RESULTS A total of 306 patients were randomized. The least squares mean reduction from baseline in serum potassium level at week 4 or time of first dose titration in patients with mild hyperkalemia was 0.35 (95% CI, 0.22-0.48) mEq/L for the 4.2 g twice daily starting-dose group, 0.51 (95% CI, 0.38-0.64) mEq/L for the 8.4 g twice daily starting-dose group, and 0.55 (95% CI, 0.42-0.68) mEq/L for the 12.6 g twice daily starting-dose group. In those with moderate hyperkalemia, the reduction was 0.87 (95% CI, 0.60-1.14) mEq/L for the 8.4 g twice daily starting-dose group, 0.97 (95% CI, 0.70-1.23) mEq/L for the 12.6 g twice daily starting-dose group, and 0.92 (95% CI, 0.67-1.17) mEq/L for the 16.8 g twice daily starting-dose group (P < .001 for all changes vs baseline by hyperkalemia starting-dose groups within strata). From week 4 through week 52, statistically significant mean decreases in serum potassium levels were observed at each monthly point in patients with mild and moderate hyperkalemia. Author Affiliations: Author affiliations are listed at the end of this Over the 52 weeks, hypomagnesemia (7.2%) was the most common treatment-related article. adverse event, mild to moderate constipation (6.3%) was the most common gastrointestinal Group Information: The adverse event, and hypokalemia (<3.5 mEq/L) occurred in 5.6% of patients. AMETHYST-DN Investigators are listed in Supplement 2. CONCLUSIONS AND RELEVANCE Among patients with hyperkalemia and diabetic kidney Corresponding Author: George L. disease, patiromer starting doses of 4.2 to 16.8 g twice daily resulted in statistically significant Bakris, MD, ASH Comprehensive Hypertension Center, Division of decreases in serum potassium level after 4 weeks of treatment, lasting through 52 weeks. Endocrinology, Diabetes, and Metabolism, Department of TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01371747 Medicine, University of Chicago Medicine, 5841 S Maryland Ave, JAMA. 2015;314(2):151-161. doi:10.1001/jama.2015.7446 Chicago, IL 60637 (gbakris@gmail Corrected on July 20, 2015. .com).

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yperkalemia is a potentially life-threatening principles, and local or national independent ethics commit- condition.1,2 Patients at the highest risk for hyperka- tee requirements (study protocol available in Supplement 1). H lemia are those taking renin-angiotensin-aldoste- The study was conducted in accordance with the European rone system (RAAS) inhibitors with stage 3 or greater chronic Union Clinical Trials Directive 2001/20/EC (European Union kidney disease (CKD) who also have diabetes mellitus, heart common technical document) for sites in the European Union. failure, or both.3-8 Owing to the limited utility of current op- All patients provided written informed consent before any tions to manage hyperkalemia, particularly over the long term, study-specific procedures were performed. clinicians frequently must either avoid using RAAS inhibitors or use them at lower than recommended doses.9-11 Participants Patiromer for oral suspension is an orally administered The first patient was enrolled in June 2011 and the last patient drug being investigated for the treatment of hyperkalemia. completed the study in June 2013. Patients aged 30 to 80 years The active moiety, patiromer, is a nonabsorbed polymer that were eligible if they had type 2 diabetes and CKD, with or with- binds potassium throughout the gastrointestinal tract, thus out hypertension. Based on data suggesting differences in hy- increasing fecal excretion of potassium and lowering serum perkalemia by race,16-18 information on race/ethnicity was col- potassium levels.12 Patiromer consists of smooth, spherical lected by patient self-report from a selection of fixed categories. beads approximately 100 μm in diameter that do not swell Chronic kidney disease was defined as an estimated glomer- appreciably in liquids.13 Prior patiromer clinical trials have ular filtration rate of 15 mL/min/1.73 m2 to less than demonstrated the drug’s utility in treating hyperkalemia in 60 mL/min/1.73 m2 at screening (calculated using either the at-risk populations for periods ranging from a few days to Chronic Kidney Disease Epidemiology Collaboration equation19 up to 12 weeks.12,14 PEARL-HF (N = 105) demonstrated the or the Modification of Diet in Renal Disease Study equation). efficacy and safety of patiromer (15 g twice daily, equivalent All patients had been receiving an ACE inhibitor, ARB, or both to 12.6 g twice daily using the updated dosing nomencla- foratleast28dayspriortoscreening. ture) in preventing the development of hyperkalemia over 4 weeks in normokalemic patients with heart failure, with or Study Design without kidney disease, who were started on spironolac- The open-label study consisted of a screening visit, a run-in tone therapy.15 OPAL-HK (N = 243) showed the efficacy and period of up to 4 weeks’ duration, an 8-week treatment phase safety of patiromer starting doses, 4.2 or 8.4 g twice daily, in followed by a long-term maintenance phase of up to 44 weeks’ treating mild or moderate-to-severe hyperkalemia, respec- duration (up to 52 weeks of total treatment), and a posttreat- tively, over 4 weeks in patients with CKD maintained while ment follow-up period of up to 4 weeks’ duration (eFigure 1 receiving RAAS inhibitors.12 OPAL-HK further demonstrated in Supplement 2). Patients with serum potassium levels of 4.3 that when patiromer treatment was stopped at the end of to 5.0 mEq/L (ie, normokalemic) at the screening visit and who the active treatment period, hyperkalemia rapidly recurred had uncontrolled blood pressure (average sitting systolic blood over 8 weeks, indicating the need for persistent treatment pressure >130 to ≤180 mm Hg and diastolic blood pressure >80 to maintain normokalemia.12 We present a study evaluating to ≤110 mm Hg) were entered into the run-in period and ran- the effects of a range of starting doses of patiromer on domly assigned in a 3:1 ratio into cohort 1 or cohort 2. A run-in serum potassium levels after 4 weeks in outpatients with period was conducted to identify patients without hyperka- hyperkalemia as well as patiromer safety and efficacy over a lemia who could potentially benefit from initiation or optimi- 52-week period. zation of RAAS therapy. At the start of the run-in, patients in cohort 1 discontinued use of ACE inhibitor therapy, ARB therapy, or both and started losartan (100 mg/d), with the ad- Methods dition of spironolactone (25 mg/d) at the week 2 run-in visit if a blood pressure target of 130/80 mm Hg was not attained. Pa- Study Objectives tients in cohort 2 remained taking prescribed ACE inhibitor, The AMETHYST-DN phase 2 multicenter, open-label, dose- ARBs, or both and started spironolactone (25 mg/d). In both ranging randomized clinical trial was conducted to inform dose cohort 1 and cohort 2, the dose of spironolactone could be in- selection for a phase 3 study using data from patients evalu- creased to 50 mg/d if needed for blood pressure control. Pa- ated through 4 weeks, as well as to evaluate the 52-week safety tients who developed hyperkalemia at any time during the and efficacy of patiromer in patients with diabetes and CKD 4-week run-in were eligible to be randomized into the treat- receiving therapy with an angiotensin-converting enzyme ment phase. (ACE) inhibitor, angiotensin receptor blocker (ARB), or both, During the initial study enrollment, many patients who with or without spironolactone. otherwise met the eligibility criteria were excluded from participation because they were hyperkalemic. The protocol was Study Oversight therefore amended to add a third cohort to allow inclusion of The study was conducted at 48 sites in 5 European countries. eligible patients with preexisting hyperkalemia. For cohort 3, The protocol was approved by local or national independent eligible patients with serum potassium levels greater than 5.0 ethics committees at each study site and performed in accor- to less than 6.0 mEq/L at screening continued the use of pre- dance with the International Conference on Harmonisation E6 scribed ACE inhibitor, ARBs, or both, skipped the run-in, and Guideline for Good Clinical Practice, the Declaration of Helsinki were randomized directly into the treatment phase. After the

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protocol amendment, all eligible patients without hyperkale- through the end of the maintenance phase at week 52. Sec- mia entered cohort 1 only, while enrollment into cohort 2 was ondary efficacy end points included mean changes in serum discontinued. potassium level from baseline to other postbaseline visits. Base- Eligible patients from all 3 cohorts were stratified by baseline was the last available measurement taken prior to the start line serum potassium level (stratum 1: >5.0-5.5 mEq/L [mild of administration of patiromer. Adverse events, laboratory as- hyperkalemia]; stratum 2: >5.5-<6.0 mEq/L [moderate hyper- sessments, electrocardiograms, and vital signs were summa- kalemia]) and randomly assigned in a 1:1:1 ratio to 1 of 3 pati- rized descriptively for the entire study period. Analysis of the romer starting doses per stratum (mild hyperkalemia: 4.2 g, primary and secondary efficacy end points and safety was 8.4 g, or 12.6 g twice daily [8.4 g/d, 16.8 g/d, 25.2 g/d]; moder- based on the intention-to-treat population, which included all ate hyperkalemia: 8.4 g, 12.6 g, or 16.8 g twice daily [16.8 g/d, patients who were randomized and received a dose of pati- 25.2 g/d, 33.6 g/d]). A validated interactive web response sys- romer. tem was used to assign patients to cohorts and starting doses Prior to database lock and after the last patient’s using computer-generated randomization lists stratified by co- follow-up visits were completed, a safety review board was hort, with a block size of 3. convened to independently review all deaths occurring After the baseline visit (day 1), patients returned for an within the study. Adjudication was performed for cause of assessment at day 3 (48 hours after the first patiromer dose), death and whether the death was related to hypokalemia or week 1, and weekly thereafter during the 8-week treatment hyperkalemia.21 phase. During the 44-week maintenance phase, patients were seen monthly, unless more frequent monitoring was required Sample Size Calculations and Statistics per protocol. The patiromer dose could be titrated upward or A sample size of 42 patients for each patiromer starting-dose downward in a stepwise fashion to the individualized effec- group provided 90% power to detect an effect size of 0.5 (as- tive dose to maintain control of serum potassium level (eFig- suming a mean change of 0.3 [SD, 0.6] mEq/L), for the mean ure 2A-D in Supplement 2). All patients (those who com- change in serum potassium level from baseline to week 4 or pleted the entire 52-week treatment and those who withdrew prior to the initiation of dose titration of patiromer. The ef- early from the study) continued into the posttreatment fect size is based on the variability in serum potassium levels follow-up period. observed in a phase 2 hyperkalemia prevention study,15 as well Non–RAAS inhibitor antihypertensive drug changes were as consideration of a clinically meaningful difference for the allowed throughout the study if additional blood pressure re- mean change in serum potassium levels in a hyperkalemia duction was required to achieve target levels (<130/80 mm Hg). treatment study, as estimated by the authors responsible for At the beginning of the follow-up period, patiromer was the study concept and design. The test was based on a 2-sided, stopped, as were all RAAS inhibitor medications for patients 1-sample paired t test and a significance level of α = .05. Ap- with serum potassium levels greater than 5.0 mEq/L; these pa- proximately 50 patients were to be randomized to each start- tients were followed up for 2 visits within 7 days of complet- ing dose (300 total), assuming a 15% nonevaluable rate. ing treatment or from early termination of study participa- A parallel-lines analysis of covariance model, with treat- tion (day 3 and week 1 posttreatment). Patients with serum ment factor and baseline serum potassium level as the covar- potassium levels of 5.0 mEq/L or less stopped patiromer but iate, was used for the analysis of the primary efficacy mea- continued receiving RAAS inhibitor medications; these pa- sure within each stratum. For patients who required dose tients were followed up for 4 weeks (day 3 and weekly visits titration or who discontinued before week 4, the primary ef- through week 4 posttreatment). ficacy end point was the last observed data prior to titration On study visit days, patients were instructed to take the or discontinuation. For the prespecified secondary end points, morning patiromer dose before the visit. Blood was drawn for the mean changes in serum potassium level from baseline to measurement of serum potassium level at approximately the postbaseline visits were analyzed according to observed data same time on the morning of each study visit and tested by both at the time point of interest using t tests. No adjustment of type local and central laboratories. Local laboratory measure- I error for multiple comparisons was applied because the pur- ments were used for assessments of serum potassium inclu- pose of the study was to determine a starting dose and not to sion criteria and for testing related to the clinical care of pa- assess superiority between 2 or more treatment groups. In a tients. Central laboratory measurements were used for post hoc analysis, changes in serum potassium levels at post- assessments of baseline values and efficacy and safety analy- baseline time points through week 52 were estimated for each ses. Adverse events and other safety data were obtained at each stratum using a mixed-effects repeated-measures model with visit. Patients were counseled at each visit to restrict their in- central laboratory serum potassium value as the dependent take of high-potassium foods (>250 mg/100 g) and to main- variable, time point and starting dose as fixed-effect predic- tain a low-potassium diet (potassium intake of ≤3 g/d).20 tors, baseline central laboratory serum potassium value as a continuous covariate, and patient as a random effect. An un- Study End Points structured correlation matrix was fit. The primary efficacy end point was the mean change in cen- All analyses were conducted using SAS version 9.3 (SAS In- tral laboratory serum potassium level from baseline to week stitute Inc). A prespecified interim analysis was conducted to 4 or prior to the initiation of dose titration. The primary safety support dose selection for the phase 3 patiromer trial. The sta- end point was the frequency and severity of adverse events tistical analysis plan is available in Supplement 1.

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with mild hyperkalemia (8.4 g/d) and those with moderate Results hyperkalemia (16.8 g/d) for the phase 3 patiromer trial. Results for the prespecified analysis (observed cases) of A total of 324 patients were enrolled; 222 patients entered stra- mean serum potassium level over the entire study, including tum 1 (mild hyperkalemia) and 84 entered stratum 2 (moder- posttreatment follow-up, are shown in eFigure 5 in Supplement ate hyperkalemia), for a total of 306 randomized patients 2. Results of a post hoc, mixed-model, repeated-measures (Figure 1). Disposition by cohort is shown in eFigures 3A and analysis that included all available potassium measurements 3B in Supplement 2; 77% of patients entering run-in became are shown in Figure 3 and were consistent with the prespeci- hyperkalemic; the median time to hyperkalemia after initia- fied analysis. Significant (P < .001) reductions in mean serum tion of RAAS inhibitor therapy was 15 days (95% CI, 14-22 days) potassium level were seen at the first postbaseline assess- (see eFigure 4 in Supplement 2 for additional details on the sta- ment, approximately 48 hours after patiromer initiation, in bility of potassium values during the run-in). Two patients with both stratum 1 (mild hyperkalemia) and stratum 2 (moderate mild hyperkalemia did not receive patiromer and therefore hyperkalemia). From baseline least squares means of were not included in the efficacy or safety analyses. Of the 304 5.2 mEq/L (stratum 1) and 5.7 mEq/L (stratum 2), mean serum patients evaluated at week 4 or time of first dose titration, 300 potassium levels below 5.0 mEq/L were seen by 48 hours were analyzed for the primary efficacy end point. One pa- (stratum 1) and week 1 (stratum 2). eFigures 6 and 7 in tient each with mild hyperkalemia in the patiromer 8.4 g/d and Supplement 2 show the time to normal serum potassium 25.2 g/d groups and 1 patient with moderate hyperkalemia in level, by stratum, in the 8-week treatment phase. the patiromer 25.2 g/d group were excluded from the analysis From week 4 through week 52, significant (P < .001) mean because of missing baseline values. A patient with mild hy- decreases from baseline in serum potassium levels were ob- perkalemia in the patiromer 33.6 g/d group was excluded be- served at each monthly time point in patients with mild and cause of a lack of available central laboratory results. Dispo- moderate hyperkalemia (Figure 3). Similar results were seen sition for the entire study is presented in Figure 1. by starting-dose group within each stratum and by cohort (eFig- Mean baseline age of the study population was 66.3 years; ures 8-10 in Supplement 2). 63.2% were men and 100% were white (Table 1). All patients The majority of patients who entered the maintenance had hypertension and type 2 diabetes; 65% had stage 3 CKD phase had serum potassium levels within the target range and 22% had stage 4 CKD; 35% had heart failure. Median ratio (3.8-5.0 mEq/L). The proportion of patients with potassium of albumin to creatinine was 300 (interquartile range, 50-1490) levels within target range at each scheduled visit of the mg/g. Mean serum potassium level at baseline was 5.3 mEq/L. maintenance phase through week 52 ranged from 83.1% to For patients who were hyperkalemic at screening, serum po- 92.7% in patients with mild hyperkalemia (n = 180) and tassium level was confirmed by a second value; mean data for from 77.4% to 95.1% in patients with moderate hyperkale- each value are shown in eTable 1 in Supplement 2. Baseline mia (n = 66). characteristics by starting-dose group were generally bal- Patients discontinuing patiromer (either prematurely or anced within each stratum (Table 1). Baseline characteristics at the end of the maintenance phase [week 52]) were to be for patients who prematurely discontinued and for those who followed up for up to 28 days to assess changes in serum completed the study are shown in eTable 2 in Supplement 2. potassium levels and potential safety concerns in this with- As described in the methods, all patients received RAAS in- drawal period. A total of 238 patients (172 with mild hyper- hibitor medications during the treatment and maintenance kalemia and 66 with moderate hyperkalemia at baseline) phases of the study. entered the posttreatment follow-up. Significant (P < .001) increases in least squares mean serum potassium levels Efficacy were seen by day 3 posttreatment in patients with mild The least squares mean reduction from baseline in serum hyperkalemia (0.25 [95% CI, 0.19-0.31] mEq/L) (n = 63) and potassium level at week 4 or at the time of first dose titration moderate hyperkalemia (0.33 [95% CI, 0.20-0.46] mEg/L) in patients with mild hyperkalemia was 0.35 (95% CI, 0.22- (n = 58). Twenty-eight days following the cessation of pati- 0.48) mEq/L for the 8.4 g/d group, 0.51 (95% CI, 0.38-0.64) romer treatment, the least squares mean increase in serum mEq/L for the 16.8 g/d group, and 0.55 (95% CI, 0.42-0.68) potassium level was 0.39 (95% CI, 0.32-0.46) mEq/L in mEq/L for the 25.2 g/d group. In those with moderate hyper- patients with mild hyperkalemia (n = 126) and 0.48 (95% CI, kalemia, the least squares mean reduction from baseline in 0.31-0.62) mEq/L in those with moderate hyperkalemia serum potassium level at week 4 or at the time of first dose (n=47)(P < .001 for both strata). titration was 0.87 (95% CI, 0.60-1.14) mEq/L for the 16.8 g/d group, 0.97 (95% CI, 0.70-1.23) mEq/L for the 25.2 g/d group, Patiromer Dosing During the Treatment Phase and 0.92 (0.67-1.17) mEq/L for the 33.6 g/d group) (P < .001 for Mean daily doses at week 4 and week 4 through 8, respec- all changes compared with baseline by hyperkalemia strata tively, were 18.5 (SD, 7.5) g/d and 19.6 (SD, 9.3) g/d in patients and by starting-dose groups within strata) (Figure 2). Change with mild hyperkalemia and 26.9 (SD, 8.3) g/d and from baseline at week 8 (end of treatment phase) is also 28.0 (SD, 12.4) g/d in patients with moderate hyperkalemia. shown in Figure 2. Based in part on the prespecified interim In both strata, the majority of patients in all starting-dose analysis of the primary efficacy end point (see Supplement 1 groups had either no titrations or 1 titration during the treat- for details) the lowest starting doses were chosen for patients ment phase, with a dose increase being more common than

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Figure 1. Patient Disposition by Assigned Strata (Mild or Moderate Hyperkalemia) and Starting Dose Over 52 Weeks

535 Patients screened

211 Excluded 98 Noneligible eGFR a 52 Noneligible serum potassium level 43 Noneligible ACR a 8 Withdrew consent 7 Did not meet other eligibility criteria 3 Other

324 Enrolled

4-Week run-in period No run-in period 79 With serum potassium 4.3 to 5.0 mEq/L (normokalemic) 245 With serum potassium >5.0 to <6.0 mEq/L (cohort 3) and uncontrolled blood pressure b continued current RAAS inhibitor 76 Randomized to cohort 1 (discontinued RAAS inhibitor and started losartan plus spironolactone after 2 wk if needed for blood pressure control) 3 Randomized to cohort 2 (continued current RAAS inhibitor and added spironolactone)

18 Excluded 17 Serum potassium ≤5.0 mEq/L 1 Serum potassium 6.2 mEq/L

306 Randomized and stratified by baseline serum potassium

Stratum 1 Stratum 2 222 Mild hyperkalemia (serum potassium 84 Moderate hyperkalemia (serum >5.0 to 5.5 mEq/L) potassium >5.5 to <6.0 mEq/L)

74 Randomized to receive 74 Randomized to receive 74 Randomized to receive 26 Randomized to receive 28 Randomized to receive 30 Randomized to receive 8.4 g/d patiromer 16.8 g/d patiromer 25.2 g/d patiromer 16.8 g/d patiromer 25.2 g/d patiromer 33.6 g/d patiromer 74 Received patiromer 73 Received patiromer 73 Received patiromer 26 Received patiromer 28 Received patiromer 30 Received patiromer as randomized as randomized as randomized as randomized as randomized as randomized 1 Did not receive 1 Did not receive patiromer patiromer

18 Discontinued 23 Discontinued 24 Discontinued 9 Discontinued 7 Discontinued 14 Discontinued patiromer treatment patiromer treatment patiromer treatment patiromer treatment patiromer treatment patiromer treatment 6 Withdrew consent 12 Withdrew consent 5 Withdrew consent 2 Withdrew consent 2 Withdrew consent 4 Withdrew consent 4 Adverse event 2 Adverse event 7 Adverse event 2 Adverse event 2 Adverse event 2 Adverse event 3 Nonadherence 4 Nonadherence 3 Nonadherence 2 High serum 2 Died 2 High serum 1 Died 1 High serum 4 Died potassium 1 Investigator potassium 1 High serum potassium 1 High serum 1 Low serum decision 3 Low serum potassium 1 Low serum potassium potassium potassium 1 Low serum potassium 1 Low serum 1 Died 1 Abnormal renal potassium 2 Abnormal renal potassium 1 Abnormal renal function 2 Other function 3 Other function 1 Nonadherence 1 Other 1 Other

56 Completed treatment 51 Completed treatment 50 Completed treatment 17 Completed treatment 21 Completed treatment 16 Completed treatment

73 Included in primary 72 Included in primary 72 Included in primary 26 Included in primary 27 Included in primary 30 Included in primary analysis analysis analysis analysis analysis analysis 1 Excluded (week 4 2 Excluded 2 Excluded 1 Excluded (week 4 results available but 1 Did not receive 1 Did not receive results available but missing baseline patiromer patiromer missing baseline data) 1 No central 1 Excluded (week 4 data) laboratory results available results available but missing before titration baseline data)

ACR indicates albumin-to-creatinine ratio; eGFR, estimated glomerular filtration rate. a Only if serum potassium level was eligible at screening visit 1.

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Table 1. Demographic and Clinical Characteristics at Screening or Baseline by Baseline Potassium Level and Patiromer Starting Dosea

Stratum 1 (Mild Hyperkalemia)b Stratum 2 (Moderate Hyperkalemia)b (n = 220) (n = 84) Patiromer Dose, g/d Patiromer Dose, g/d 8.4 16.8 25.2 16.8 25.2 33.6 Overall Characteristic (n = 74) (n = 73) (n = 73) (n = 26) (n = 28) (n = 30) (n = 304) Age at screening, mean (SD), y 66.7 (7.55) 65.9 (9.67) 66.9 (9.01) 66.2 (5.58) 66.3 (9.61) 65.0 (8.98) 66.3 (8.61) ≥75 y, No. (%) 14 (18.9) 14 (19.2) 21 (28.8) 1 (3.8) 5 (17.9) 5 (16.7) 60 (19.7) Men, No. (%) 45 (60.8) 47 (64.4) 47 (64.4) 18 (69.2) 15 (53.6) 20 (66.7) 192 (63.2) White, No. (%) 74 (100) 73 (100) 73 (100) 26 (100) 28 (100) 30 (100) 304 (100) Body mass index at screening, 29.6 (4.3) 29.3 (3.9) 29.5 (4.0) 30.2 (4.6) 29.6 (5.0) 30.7 (4.4) 29.7 (4.2) mean (SD)c Sitting blood pressure at screening, mean (SD), mm Hg Systolic 155.6 (11.1) 155.1 (11.1) 154.7 (11.6) 157.4 (13.7) 158.7 (13.6) 153.7 (14.1) 155.5 (12.0) Diastolic 85.2 (10.5) 83.3 (12.2) 84.8 (9.8) 80.2 (11.8) 86.5 (11.3) 81.9 (13.6) 84.0 (11.3) Time since diabetes diagnosis 13.0 (7.7) 12.2 (8.3) 12.5 (7.1) 14.6 (8.0) 13.6 (8.5) 15.3 (9.8) 13.1 (8.0) at screening, mean (SD), y Time since CKD diagnosis at 1.8 (1.0-3.6) 2.0 (1.0-4.0) 1.5 (1.0-3.0) 2.2 (1.1-5.0) 1.8 (1.0-4.0) 2.0 (1.0-5.8) 1.9 (1.0-4.0) screening, median (IQR), y eGFR at screening, mean (SD), 41.1 (14.6) 42.5 (15.3) 43.3 (15.4) 37.0 (18.0) 37.4 (13.8) 34.1 (17.5) 40.6 (50.7) mL/min/1.73 m2 CKD stage (eGFR) at screening, No. (%) 1 (≥90 mL/min/1.73 m2) 0 0 1 (1.4) 0 0 0 1 (0.3) 2 (60-89 mL/min/1.73 m2) 7 (9.5) 8 (11.0) 7 (9.6) 2 (7.7) 2 (7.1) 3 (10.0) 29 (9.5) 3a (45-59 mL/min/1.73 m2) 24 (32.4) 18 (24.7) 26 (35.6) 6 (23.1) 6 (21.4) 5 (16.7) 85 (28.0) 3b (30-44 mL/min/1.73 m2) 24 (32.4) 35 (47.9) 25 (34.2) 8 (30.8) 11 (39.3) 8 (26.7) 111 (36.5) 4 (15-29 mL/min/1.73 m2) 14 (18.9) 12 (16.4) 13 (17.8) 8 (30.8) 7 (25.0) 12 (40.0) 66 (21.7) 5 (<15 mL/min/1.73 m2) 2 (2.7) 0 0 2 (7.7) 1 (3.6) 1 (3.3) 6 (2.0) NYHA class at screening, No. (%) I 5 (6.8) 6 (8.2) 7 (9.6) 3 (11.5) 4 (14.3) 1 (3.3) 26 (8.6) II 21 (28.4) 17 (23.3) 21 (28.8) 5 (19.2) 7 (25.0) 8 (26.7) 79 (26.0) None 48 (64.9) 50 (68.5) 45 (61.6) 18 (69.2) 17 (60.7) 21 (70.0) 199 (65.5) RAAS inhibitor use at baseline, No. (%) ACE inhibitor 32 (43.2) 37 (50.7) 34 (46.6) 17 (65.4) 17 (60.7) 13 (43.3) 140 (49.3) Angiotensin receptor blocker 21 (28.4) 15 (20.5) 14 (19.2) 7 (26.9) 5 (17.9) 12 (40.0) 74 (24.3) Aldosterone antagonist 1 (1.4) 000001(0.3) Non-RAAS inhibitor diuretic use 35 (47) 24 (33) 36 (49) 13 (50) 8 (29) 14 (47) 130 (42.8) at baseline, No. (%) Serum values at baseline, mean (SD) Potassium, mEq/L 5.1 (0.3) 5.2 (0.2) 5.1 (0.2) 5.7 (0.4) 5.7 (0.3) 5.6 (0.4) 5.3 (0.4) Calcium, mg/dL 9.4 (0.7) 9.3 (0.6) 9.6 (0.6) 9.4 (0.8) 9.4 (0.6) 9.3 (0.6) 9.4 (0.7) Magnesium, mg/dL 2.0 (0.3) 2.0 (0.3) 2.0 (0.2) 2.1 (0.3) 2.0 (0.3) 2.1 (0.3) 2.0 (0.3) Phosphate, mEq/L 3.6 (0.6) 3.8 (0.8) 3.6 (0.7) 4.1 (0.7) 3.9 (0.6) 4.1 (0.8) 3.7 (0.7) Creatinine, mg/dL 1.8 (0.8) 1.7 (0.6) 1.7 (0.7) 2.1 (1.1) 1.9 (0.9) 2.3 (1.2) 1.8 (0.8) Urine albumin–to-creatinine ratio 207 491 131 259 411 906 300 at screening, median (IQR), mg/g (38-1165) (61-1504) (34-1316) (32-646) (110-1646) (123-3246) (50-1490) Abbreviations: ACE, angiotensin-converting enzyme; CKD, chronic kidney screening in patients with hyperkalemia at screening [cohort 3]) was based on disease; eGFR, estimated glomerular filtration rate; IQR, interquartile range; the local laboratory calculation. NYHA, New York Heart Association; RAAS, renin-angiotensin-aldosterone b Stratum 1 (mild hyperkalemia) defined as potassium concentrations greater system. than 5.0 mEq/L through 5.5 mEq/L; stratum 2 (moderate hyperkalemia) SI conversion factors: To convert calcium values to mmol/L, multiply by 0.25; defined as potassium concentrations greater than 5.5 mEq/L to less than creatinine values to μmol/L, multiply by 88.4. 6.0 mEq/L. a All laboratory parameters are from the central laboratory (eGFR eligibility at c Calculated as weight in kilograms divided by height in meters squared.

a dose decrease. Overall, the mean number of titrations the 25.2 g/d group had no dose adjustments. In patients with across the dose groups in each stratum was similar. Through moderate hyperkalemia, 53.8% in the 16.8 g/d group, 50.0% week 4, in patients with mild hyperkalemia, 47.3% in the in the 25.2 g/d group, and 33.3% in the 33.6 g/d group had 8.4 g/d group, 58.9% in the 16.8 g/d group, and 65.8% in no dose adjustments. In patients with mild hyperkalemia,

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Figure 2. Least Squares Mean Reduction in Serum Potassium Level From Baseline to Weeks 4 and 8 or Time of First Patiromer Titration, by Starting Dose

Baseline to week 4 Baseline to week 8 0 0

–0.5 –0.5

–1.0 –1.0 From Baseline, mEq/L From Baseline, mEq/L From Change in Serum Potassium Change in Serum Potassium

–1.5 –1.5 8.4 16.8 25.2 16.8 25.2 33.6 8.4 16.8 25.2 16.8 25.2 33.6

Stratum 1 Stratum 2 Stratum 1 Stratum 2 (mild hyperkalemia) (moderate hyperkalemia) (mild hyperkalemia) (moderate hyperkalemia) Starting Patiromer dose, g/d Starting Patiromer dose, g/d

No. of patients 73 72 72 26 27 30 No. of patients 73 72 72 26 27 30

P < .001 for all changes compared with baseline by hyperkalemia strata and by (serum potassium level >5.0 to 5.5 mEq/L); stratum 2, moderate hyperkalemia starting dose groups within strata. Stratum 1 indicates mild hyperkalemia (serum potassium level >5.5 to <6.0 mEq/L). Error bars indicate 95% CIs.

Figure 3. Least Squares Mean (95% CI) Serum Potassium Levels Over 52 Weeks and During Posttreatment Follow-up in Patients With Mild or Moderate Hyperkalemia (Post Hoc Mixed-Effects Models for Repeated-Measures Analysis)

5.8 Hyperkalemia 5.6 Mild Moderate 5.4

5.2

5.0

4.8

Serum Potassium, mEq/L 4.6

4.4

4.2 Baseline 1 4 8 12 16 20 24 28 32 36 40 44 48 52 2 4 Day 3 a Study Visit, wk 1 c 3 d Day 3 b

Treatment Follow-up No. of patients Hyperkalemia Mild 218 204 199 192 175 168 161 161 163 158 156 151 148 149 145 131 126 Moderate 83 83 73 70 65 62 62 62 61 53 53 53 52 49 49 48 47

All serum potassium analyses are based on central laboratory values; 3 patients continuous covariate, and patient as a random effect. An unstructured correlation (2 with mild hyperkalemia [potassium concentration >5.0 to 5.5 mEq/L] and 1 with matrix was fit. Least squares means and their 95% CIs for the follow-up moderate hyperkalemia [potassium concentration >5.5 to <6.0 mEq/L]) did not period are based on the same model above, while the baseline covariate used have a central laboratory serum potassium value at baseline and therefore are not was the last potassium value before study termination. Tinted region indicates included in the analysis at this time point. At all points, P < .001 (2-sided t test) for serum potassium reference range. aAt treatment day 3, there were 202 patients least squares mean changes from baseline and week 52 (or from last dose of with mild hyperkalemia and 82 with moderate hyperkalemia. bAt follow-up patiromer received during the study). Least squares means and their 95% CIs are day 3, there were 163 patients with mild hyperkalemia and 58 with based on a mixed-effects repeated-measures model with central laboratory serum moderate hyperkalemia. cAt follow-up week 1, there were 154 patients with mild potassium value as the dependent variable, time point and starting dose as hyperkalemia and 57 with moderate hyperkalemia. dAt follow-up week 3, there fixed-effect predictors, baseline central laboratory serum potassium value as a were 126 patients with mild hyperkalemia and 48 with moderate hyperkalemia.

35.1% in the 8.4 g/d group, 26.0% in the 16.8 g/d group, and Mean daily doses at week 4 and weeks 4 through 8 were 31.5% in the 25.2 g/d group had 1 dose adjustment. In patients similar to the assigned starting dose in each dose group in with moderate hyperkalemia, 26.9% in the 16.8 g/d group, both strata. Over the entire 52-week study, mean daily pati- 32.1% in the 25.2 g/d group, and 36.7% in the 33.6 g/d group romer doses were similar to those at week 4 through week 8 had 1 dose adjustment. (19.4 [SD, 9.1] g/d and 27.2 [SD, 10.8] g/d in patients with

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Table 2. Most Common Adverse Events Over 52 Weeks by Starting Dose Within Each Stratuma

No. (%) Stratum 1 (Mild Hyperkalemia)b Stratum 2 (Moderate Hyperkalemia)b Patiromer Dose, g/d Patiromer Dose, g/d 8.4 16.8 25.2 Overall 16.8 25.2 33.6 Overall Total Adverse Event (n = 74) (n = 73) (n = 73) (n = 220) (n = 26) (n = 28) (n = 30) (n = 84) (n = 304) Worsening of CKD 5 (6.8) 6 (8.2) 3 (4.1) 14 (6.4) 3 (11.5) 4 (14.3) 7 (23.3) 14 (16.7) 28 (9.2) Hypomagnesemiac 4 (5.4) 5 (6.8) 6 (8.2) 15 (6.8) 2 (7.7) 4 (14.3) 5 (16.7) 11 (13.1) 26 (8.6) Worsening of hypertension 5 (6.8) 7 (9.6) 2 (2.7) 14 (6.4) 4 (15.4) 2 (7.1) 4 (13.3) 10 (11.9) 24 (7.9) Constipation 4 (5.4) 3 (4.1) 4 (5.5) 11 (5.0) 2 (7.7) 1 (3.6) 5 (16.7) 8 (9.5) 19 (6.3) Diarrhea 6 (8.1) 5 (6.8) 1 (1.4) 12 (5.5) 3 (11.5) 1 (3.6) 1 (3.3) 5 (6.0) 17 (5.6) Hypoglycemiac 1 (1.4) 2 (2.7) 1 (1.4) 4 (1.8) 2 (7.7) 1 (3.6) 3 (10.0) 6 (7.1) 10 (3.3)

Abbreviation: CKD, chronic kidney disease. c Based on investigators’ assessment; may not have correlated with laboratory a Occurring in 5.0% or more of patients in either baseline hyperkalemia stratum. values below the lower limit of normal; 4 additional patients had reported adverse events of decreased blood magnesium level. b Stratum 1 (mild hyperkalemia) defined as potassium concentrations greater than 5.0 mEq/L through 5.5 mEq/L; stratum 2 (moderate hyperkalemia) defined as potassium concentrations greater than 5.5 mEq/L to less than 6.0 mEq/L.

mild and moderate hyperkalemia, respectively), suggesting At least 1 adverse event leading to patiromer discontinu- that there was minimal additional dose titration to maintain ation occurred in 28 patients (9.2%) overall (20 patients [9.1%] control of serum potassium levels after week 8. Across with mild hyperkalemia and 8 [9.5%] with moderate hyper- starting-dose groups and strata, adherence over the entire kalemia). The most common adverse events leading to treat- study ranged from 86.7% to 95.9%. ment discontinuation were worsening of CKD (8 patients [2.6%]) and hypokalemia (5 patients [1.6%]; none with serum Safety potassium level <3.0 mEq/L). A single patient discontinued due Over the 52 weeks, 69% of patients reported at least 1 to a hypertension-related adverse event (hypertensive cri- treatment-emergent adverse event, with 20% reporting an sis). This event was not related to patiromer, per the investi- adverse event considered by the investigator to be related to gator. No patient discontinued patiromer because of hypo- patiromer. The most frequently reported adverse events magnesemia. (≥5.0% of patients, regardless of stratum or starting-dose Serious adverse events were reported for 44 patients group) were worsening of CKD (9.2%), hypomagnesemia (14.5%); none were attributed to patiromer by the investiga- (8.6%), worsening of hypertension (7.9%), constipation tor. The most common serious adverse event was worsening (6.3%), and diarrhea (5.6%) (Table 2). Among treatment- of CKD (6 patients [2.0%]) (eTable 4 in Supplement 2). Over related adverse events, the most frequently reported were 52 weeks, 15 patients (4.9%) died; 11 of the 15 deaths were hypomagnesemia (7.2%), constipation (4.6%), and diarrhea assessed by the safety review board as related to cardiovas- (2.7%). The adverse event of worsening of hypertension was cular causes (sudden cardiac death in 7 patients and acute considered related to patiromer in 1 patient (0.3%). No myocardial infarction in 4 patients; 10 had a prior history of adverse events of worsening CKD were considered by study either atherosclerotic heart disease, heart failure, or both). investigators to be related to study drug. Mean serum mag- No deaths were considered by study investigators to be nesium level remained in the normal range (1.5-2.4 mg/dL) related to patiromer, and none were considered by the safety throughout the 52-week treatment period and was relatively review board to be related to hyperkalemia or hypokalemia. constant. Mean change from baseline to week 4 ranged from None of the patients who died had a last observed potassium −0.10 to −0.20 mg/dL in patients with mild hyperkalemia value below the normal limit. Among 7 patients who experi- and from −0.10 to −0.30 in patients with moderate hyperka- enced sudden cardiac death, none had serum magnesium lemia, with mean changes from baseline at subsequent visits levels less than 1.58 mg/dL, measured at the last observation in a similar range and independent of dose, including at (Supplement 2). week 52 (end of treatment) (eTable 3 in Supplement 2). No Reductions in systolic and diastolic blood pressure patient developed severe hypomagnesemia (<1.0 mg/dL), were observed in all starting-dose groups in both strata. and no patient had cardiac arrhythmias or neuromuscular Mean blood pressure at baseline was 153.5/83.6 mm Hg in abnormalities that were temporally associated with hypo- patients with mild hyperkalemia and 153.8/81.9 mm Hg magnesemia (Supplement 2). in patients with moderate hyperkalemia. Mean blood pres- All cases of constipation were mild to moderate, and only sure decreases from baseline were seen as early as day 3 2 patients discontinued as a result of this event. Over the 52 (9.1/4.5 mm Hg in patients with mild hyperkalemia and weeks, hypokalemia (serum potassium <3.5 mEq/L) occurred 8.0/4.0 mm Hg in patients with moderate hyperkalemia) in 17 patients (5.6%), with no patients developing a serum po- (eTable 5 in Supplement 2). Reductions were observed at 4 tassium level less than 3.0 mEq/L. weeks in both strata (11.2/6.8 mm Hg and 8.0/5.8 mm Hg,

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respectively) and were similar at 8 weeks (14.2/7.3 mm Hg ney function as well as increase the risk of diabetes and gout, and 7.9/4.7 mm Hg, respectively). The mean reductions from they are not ideal agents for lowering serum potassium levels baseline continued into the maintenance phase. Mean over the long term. Other approaches have included chronic reductions in blood pressure from baseline to week 52 in sodium bicarbonate therapy with diuretics; however, this com- patients with mild (15.7/8.0 mm Hg) and moderate bination has other unintended consequences, such as meta- (17.1/9.2 mm Hg) hyperkalemia were similar to or larger than bolic alkalosis and sodium retention. the changes at the end of the treatment phase (week 8). No Sodium polystyrene sulfonate is the only drug specifi- apparent dose effect was observed within either stratum. cally indicated for the treatment of hyperkalemia in the United Mean blood pressure decreases persisted during posttreat- States.25 Use of this compound has been problematic because ment follow-up (18.4/8.5 mm Hg and 15.0/9.1 mm Hg in of concerns over questionable efficacy in removing potas- patients with mild and moderate hyperkalemia, respectively, sium and poor gastrointestinal tolerability.26,27 Although rare, at the 28-day posttreatment follow-up visit) (eTable 5 in bowel necrosis has been reported and is associated with a rela- Supplement 2). tively high mortality rate28-31 and has led to warnings in the There were no clinically meaningful changes in mean es- prescribing information about this complication.25,32 In addi- timated glomerular filtration rate and albuminuria in this tion, given that sodium is the counter exchange ion, caution heterogeneous patient population (eTable 6 in Supplement 2) is advised when sodium polystyrene sulfonate is adminis- Mean serum calcium, sodium, and phosphate levels re- tered to patients who cannot tolerate even a small increase in mained within normal range during the study (eTable 3 in sodium load (ie, those with severe congestive heart failure, se- Supplement 2). No dose-related edema was observed over the vere hypertension, or marked edema).25 52 weeks of treatment. Patiromer, a novel potassium-binding polymer, uses calcium rather than sodium as the counter ion exchange, thus avoiding the risk of a sodium load in patients. No dose- Discussion related edema was observed in this trial, nor were any clinically relevant changes in serum calcium or phosphate levels This study demonstrated that patiromer significantly detected after 52 weeks of treatment. reduced serum potassium levels across dose groups (8.4-33.6 Reductions in mean systolic and diastolic blood pressure g/d) through week 4 in patients with a varying severity of were observed in all starting-dose groups in both strata. Al- hyperkalemia. The significant reductions in serum potassium though there is no direct pharmacological mechanism to ex- level at 4 weeks, in concert with low incidence of hypokale- plain this magnitude of blood pressure reduction, a possible mia in the 8.4 g/d and 16.8 g/d groups, informed the selection reason is that control of potassium allowed for continuation of these doses as the starting doses for the phase 3 study of of RAAS inhibitor therapy, maximal dosing, or both. Addition- patiromer. ally, better blood pressure control may reflect a combination Because the AMETHYST-DN study adhered to clinical of better patient adherence to antihypertensive medications guideline recommendations for patients with CKD, type 2 dia- as an effect of study participation, close monitoring by clini- betes, or hypertension, all patients in the study received RAAS cal sites, and effects of blood pressure medication adjust- inhibitor therapy.3,8,22 Hyperkalemia is a major limitation to ments. It is also acknowledged that this study was not de- the use of RAAS inhibitors in patients with stage 3 or greater signed to assess the effects of patiromer on blood pressure. CKD.1,2 Hyperkalemia develops in approximately 10% of out- Without a placebo control, these blood pressure changes are patients within 1 year after initiation of RAAS inhibitor difficult to interpret and may represent, at least in part, re- therapy.23 AMETHYST-DN was designed to assess the effi- gression to the mean. In spite of this decrease in mean blood cacy of patiromer in high-risk patients for development of hy- pressure over time, adverse events of worsening hyperten- perkalemia at 4 weeks as well as long-term safety. sion were reported in 7.9% of patients. None appeared to be Patiromer consistently maintained normal serum potas- associated with a persistent serum potassium level less than sium levels over 52 weeks, with few patients requiring dose 4.0 mEq/L but were generally ascribed to worsening of the un- titration. Over this period, patiromer use demonstrated high derlying CKD. adherence, low risk of hypokalemia, and minimal discon- Worsening of CKD was the most frequently reported tinuations because of adverse events. Treatment discon- adverse event during the trial and the most common tinuations were largely driven by withdrawal of consent, adverse event leading to discontinuation. However, most of which may be attributable in part to study duration and fre- these adverse events occurred during the long-term mainte- quency of study visits during the treatment period, both of nance phase, suggesting that the progression of underlying which are potentially burdensome to patients. CKD may have been contributory. Consistent with this find- We believe that patient selection was clinically relevant, ing, the proportion of patients with more severe CKD because patients at greatest risk for hyperkalemia include those (ie, stages 4-5) at baseline was higher among those who dis- with diabetes and those with impaired renal function.24 Di- continued the study (32.3%) than among those who com- uretics are frequently used to prevent the increase in serum pleted the study (19.9%) (eTable 2 in Supplement 2). One potassium levels and control volume in patients with ad- possible explanation for the higher rate of discontinuation vanced CKD.1,2 However, because these agents can induce in- among patients with advanced CKD is that continuation of travascular volume depletion, leading to a reduction in kid- RAAS inhibitor therapy will reduce GFR by as much as 20%

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to 30% from baseline if blood pressure is lowered. However, lemia on cessation of treatment.12 This study was designed in long-term outcome studies in CKD stage 3, RAAS inhibi- to find an appropriate dose for a phase 3 trial. Additionally, tor therapy has slowed CKD progression.33,34 it was designed to assess the long-term safety of varying Study limitations include the lack of blinding, which doses. may have affected data recording and reporting through Based on the findings of this study, a phase 3 study was observer bias allowing for underreporting of adverse events; performed in which patiromer demonstrated consistent effi- and the lack of a comparator, which raises the possibility of cacy as shown in our study.12 The consistency of results regression to the mean contributing to apparent reductions across the secondary end points supports the conclusions in serum potassium level. However, the stability of multiple regarding long-term efficacy. The 52-week data support the screening measures for serum potassium level in cohort 3, finding of OPAL-HK, demonstrating that long-term manage- the increase in serum potassium level after initiation of ment of serum potassium level is needed in patients with RAAS inhibitor therapy in cohorts 1 and 2, and the increase CKD taking RAAS inhibitors to reduce recurrence of hyperka- in potassium level during the follow-up period after discon- lemia. Whether control of hyperkalemia and continued use of tinuation of patiromer argue against regression to the mean. RAAS inhibitors (including dual RAAS inhibition) in stages 4 Alternatives to this design were considered, but the study and 5 CKD will improve long-term outcomes remains to be investigators did not think it clinically appropriate to use a established. placebo control in this long-term trial as this would subject study participants to the potentially life-threatening risks of hyperkalemia. The chronic use of polystyrene sulfonate Conclusions compounds as blinded, active-control agents would have been difficult, given their poor gastrointestinal tolerability Among patients with hyperkalemia and diabetic kidney dis- and unpleasant taste.35 The efficacy of patiromer was dem- ease, patiromer starting doses of 4.2 to 16.8 g twice daily onstrated in previously reported placebo-controlled trials (8.4-33.6 g/d) resulted in statistically significant decreases (PEARL-HF and OPAL-HK),12,15 and the need for persistent in serum potassium levels after 4 weeks of treatment, last- therapy with the drug was evidenced by recurrent hyperka- ing through 52 weeks.

ARTICLE INFORMATION receiving personal fees from Relypsa, Pfizer, BA (Relypsa), and Cole Brown, MD (AlphaBioCom), Author Affiliations: ASH Comprehensive Bayer, AstraZeneca, Tricida, scPharmaceuticals, provided additional editorial support. Ms Obeid and Dr Hypertension Center, Division of Endocrinology, DaVinci Therapeutics, Stealth Peptides, Brownreceivednocompensationfortheircontributions. Diabetes, and Metabolism, Department of Aura Sense, Sarfez, Novartis, Johnson & Johnson, Correction: This article was corrected online on Medicine, University of Chicago Medicine, Chicago, Oxygen Biotherapeutics, and Eli Lilly and holding July 20, 2015, to correct a reported dose in a figure. Illinois (Bakris); University of Michigan, Ann Arbor patent EFS ID: 14916043, application (Pitt); Division of Nephrology, Department of 61762661,/UM-33001/US-1PRO pending. Dr Weir REFERENCES reported receiving personal fees from Relypsa, Medicine, University of Maryland School of 1. Perazella MA, Mahnensmith RL. Hyperkalemia in Medicine, Baltimore (Weir); Department of ZS Pharma Akebia, Janssen, AstraZeneca, Otsuka, Amgen, MSD, AbbVie, Novartis, Boston Scientific, the elderly: drugs exacerbate impaired potassium Medicine, Massachusetts General Hospital, Boston homeostasis. J Gen Intern Med. 1997;12(10):646-656. (Freeman); Relypsa, Redwood City, California and Sandoz. Dr Freeman reported receiving (Mayo, Garza, Stasiv, Zawadzki, Berman); Division personal fees from Relypsa and receiving stock 2. Einhorn LM, Zhan M, Hsu VD, et al. The of Nephrology, Department of Medicine, University option grants for involvement in helping design the frequency of hyperkalemia and its significance in of Rochester, Rochester, New York (Bushinsky). overall clinical trial program for patiromer. Dr chronic kidney disease. Arch Intern Med. 2009;169 Zawadzki reported receiving personal fees from (12):1156-1162. Author Contributions: Dr Bakris had full access to Relypsa. Dr Berman reported holding patent 3. KDOQI. KDOQI Clinical Practice Guidelines and all of the data in the study and takes responsibility WO 2014/058905 pending. Dr Bushinsky reported for the integrity of the data and the accuracy of the Clinical Practice Recommendations for Diabetes receiving personal fees from Relypsa. No other and Chronic Kidney Disease. Am J Kidney Dis.2007; data analysis. authors reported disclosures. Study concept and design: Bakris, Pitt, Weir, 49(2)(suppl 2):S12-S154. Freeman, Stasiv, Berman, Bushinsky. Funding/Support: This study was sponsored and 4. Kidney Disease: Improving Global Outcomes Acquisition, analysis, or interpretation of data: Pitt, funded by Relypsa. (KDIGO) CKD Work Group. KDIGO 2012 Clinical Weir, Freeman, Mayo, Garza, Zawadzki, Berman, Role of the Funder/Sponsor: Relypsa and the Practice Guideline for the Evaluation and Bushinsky. steering committee designed the study. Relypsa Management of Chronic Kidney Disease. Kidney Int. Drafting of the manuscript: Bakris, Pitt, Freeman, conducted the study, data collection, and 2013;3:S1-S150. Mayo, Berman. management analysis. Relypsa, with the steering 5. Inzucchi SE, Bergenstal RM, Buse JB, et al; Critical revision of the manuscript for important committee, was responsible for the interpretation American Diabetes Association (ADA); European intellectual content: All authors. of the data; preparation, review, or approval of the Association for the Study of Diabetes (EASD). Statistical analysis: Mayo, Zawadzki. manuscript; and decision to submit the manuscript Management of hyperglycemia in type 2 diabetes: Obtained funding: Mayo. for publication. The funder/sponsor did not have a patient-centered approach: position statement of Administrative, technical, or material support: the ability to veto publication of study results. the American Diabetes Association (ADA) and the Bakris, Mayo, Stasiv, Berman, Bushinsky. Additional Contributions: Mark Mortier, PhD European Association for the Study of Diabetes Study supervision: Bakris, Garza, Berman, Bushinsky. (Agility Clinical Inc), and Carol Francisco, PhD (EASD). Diabetes Care. 2012;35(6):1364-1379. Conflict of Interest Disclosures: All authors have (consultant to Relypsa), contributed to the 6. American Diabetes Association. Standards of completed and submitted the ICMJE Form for finalization of the statistical analysis plan and the medical care in diabetes—2014. Diabetes Care. Disclosure of Potential Conflicts of Interest. Dr analysis of data and were funded by Relypsa. 2014;37(suppl 1):S14-S80. Bakris reported receiving personal fees from Robert E. Lamb, PharmD (REL & Associates LLC), AbbVie, Takeda, Medtronic, Relypsa, developed the first draft of the Methods and 7. Yancy CW, Jessup M, Bozkurt B, et al; WRITING Daiichi-Sankyo, Janssen, Novartis, and Bayer and Results sections under the direction of the first COMMITTEE MEMBERS; American College of receiving grants from Takeda. Dr Pitt reported author and was funded by Relypsa. Julie Ann Obeid, Cardiology Foundation/American Heart Association

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