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Effect of Patiromer on Hyperkalemia Recurrence in Older Chronic Kidney Disease Patients Taking RAAS Inhibitors

Open AccessPublished:November 24, 2017DOI:https://doi.org/10.1016/j.amjmed.2017.11.011

      Abstract

      Background

      Older people are predisposed to hyperkalemia because of impaired renal function, comorbid conditions, and polypharmacy. Renin–angiotensin–aldosterone system inhibitors (RAASi), which are recommended to treat chronic kidney disease and heart failure augment the risk. Patiromer, a nonabsorbed potassium binder, was shown in the phase 3 OPAL-HK study to decrease serum potassium in patients with chronic kidney disease taking RAASi. We studied the efficacy and safety of patiromer in a prespecified subgroup of patients aged ≥65 years from OPAL-HK.

      Methods

      Chronic kidney disease patients with mild or moderate-to-severe hyperkalemia received patiromer, initially 8.4 g/d or 16.8 g/d, respectively, for 4 weeks (treatment phase, part A). Eligible patients entered an 8-week randomized withdrawal phase (part B) and continued patiromer or switched to placebo.

      Results

      Mean ± standard error change in serum potassium from baseline to week 4 of part A (primary endpoint) in patients aged ≥65 years was −1.01 ± 0.05 mEq/L (P < .001); 97% achieved serum potassium 3.8-<5.1 mEq/L. The serum potassium increase during the first 4 weeks of part B was greater in patients taking placebo than in those taking patiromer (P < .001). Fewer patients taking patiromer (30%) than placebo (92%) developed recurrent hyperkalemia (serum potassium ≥5.1 mEq/L). Mild-to-moderate constipation occurred in 15% (part A) and 7% (part B) of patients aged ≥65 years. Serum potassium <3.5 mEq/L and serum magnesium <1.4 mg/dL were infrequent (4% each in patients aged ≥65 years in part A).

      Conclusions

      Patiromer reduced recurrent hyperkalemia and was well tolerated in older chronic kidney disease patients taking RAASi.

      Keywords

      See related Commentary, p. 459
      Clinical Significance
      • Because of age, comorbidity, and polypharmacy, older patients are particularly predisposed to risk of hyperkalemia.
      • Patiromer significantly decreased serum K+ in hyperkalemic patients aged ≥65 years with chronic kidney disease taking renin–angiotensin–aldosterone system inhibitors (RAASi) and reduced the risk of recurrent hyperkalemia.
      • A significantly larger proportion of patients taking patiromer continued to receive RAASi medications compared with those receiving placebo.
      • Patiromer was well tolerated in patients aged ≥65 years and <65 years.

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      • Bakris G.L.
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      • et al.
      Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors.
      Here, we studied the efficacy and safety of patiromer in a prespecified subgroup of patients aged ≥65 years from OPAL-HK.

      Methods

       Study Design and Patient Population

      The OPAL-HK study has been described previously.
      • Weir M.R.
      • Bakris G.L.
      • Bushinsky D.A.
      • et al.
      Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors.
      Briefly, 243 patients were enrolled in a 4-week initial treatment phase (part A). Eligible patients were adults (18-80 years old) with chronic kidney disease stage 3 or 4 (estimated GFR [eGFR] 15-<60 mL/min/1.73 m2) and hyperkalemia (serum K+ 5.1-<6.5 mEq/L by local laboratory measurement) who were taking a stable dose of ≥1 RAASi medication(s) for ≥28 days at screening.
      At the beginning of part A, patients with mild hyperkalemia (serum K+ 5.1-<5.5 mEq/L) at screening were assigned to patiromer 8.4 g/d; those with moderate-to-severe hyperkalemia (5.5-<6.5 mEq/L) were assigned to patiromer 16.8 g/d (all doses were given twice daily). The patiromer dose was adjusted according to a prespecified titration algorithm to maintain serum K+ within the range of 3.8-<5.1 mEq/L. During this phase, RAASi therapy was not allowed to be adjusted unless medically necessary but could be discontinued if serum K+ was ≥6.5 mEq/L (or ≥5.1 mEq/L for patients on maximum patiromer dose).
      Patients who had serum K+ ≥5.5 mEq/L at baseline of part A and were normokalemic (serum K+ 3.8-<5.1 mEq/L) while receiving patiromer and taking ≥1 RAASi medication(s) at the end of part A were eligible to enter part B (8-week, placebo-controlled, randomized withdrawal phase). Patients meeting these criteria (n = 107) were randomized 1:1 to continue patiromer at the daily dose they were receiving at week 4 of part A or to switch to placebo. Recurrence of hyperkalemia (serum K+ ≥5.5 mEq/L) during part B was managed with a prespecified algorithm as described previously.
      • Weir M.R.
      • Bakris G.L.
      • Bushinsky D.A.
      • et al.
      Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors.
      Laboratory assessments, conducted at baseline (day 1), day 3 of each phase, and weekly thereafter, included serum K+ and serum chemistry (including creatinine and eGFR). Sitting blood pressure was measured in triplicate at each visit.

       Efficacy and Safety Assessments

      Analysis of the primary efficacy endpoints for part A and part B were prespecified by age (≥65 years, <65 years): part A, change in serum K+ from baseline to week 4 of the initial treatment phase; part B, between-group difference in change in serum K+ from start to week 4 of the randomized withdrawal phase. During the first 4 weeks of part B, changes in patiromer or RAASi doses were not permitted unless serum K+ was ≥5.5 mEq/L, to facilitate interpretation of the primary endpoint (see the online Supplementary Material to Weir et al
      • Weir M.R.
      • Bakris G.L.
      • Bushinsky D.A.
      • et al.
      Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors.
      for details). Analysis of the secondary efficacy endpoint in part B was prespecified by age group: proportion of patients with serum K+ ≥5.5 mEq/L and serum K+ ≥5.1 mEq/L at any time during part B.
      • Weir M.R.
      • Bakris G.L.
      • Bushinsky D.A.
      • et al.
      Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors.
      Other efficacy endpoints were assessed post hoc by age group, including the following: part A, proportion of patients with serum K+ in the normal range (3.8-<5.1 mEq/L) at any time; and part B, time to recurrent hyperkalemia; time to RAASi discontinuation; proportion of patients requiring intervention to manage hyperkalemia (defined as patiromer dose increase or RAASi discontinuation for patients taking patiromer and RAASi dose decrease of ≥50% or RAASi discontinuation for patients taking placebo); and proportion of patients taking RAASi at the end of the withdrawal phase.
      Safety was evaluated in each age group by adverse events, change in blood pressure, change in serum magnesium (Mg2+), and proportions of patients with serum Mg2+ <1.4 mg/dL or serum K+ <3.5 mEq/L.

       Statistical Analyses

       Initial Treatment Phase (Part A)

      Mean change in serum K+ from baseline to week 4 was assessed in enrolled patients who received ≥1 dose of patiromer and had ≥1 postbaseline weekly serum K+ measurement. The mean changes in serum K+ (± standard error [SE]) and 95% confidence intervals (CIs) were estimated separately by age group using longitudinal repeated-measures models that included presence or absence of heart failure, presence or absence of type 2 diabetes, and baseline serum K+.

       Randomized Withdrawal Phase (Part B)

      Change in serum K+ at week 4 or first local serum K+ <3.8 or ≥5.5 mEq/L was compared between treatment groups, separately for each age group, using ranked values of change in serum K+ and an analysis of variance model that included treatment group, level of serum K+ at the start of the initial treatment phase (<5.8 mEq/L or ≥5.8 mEq/L), and presence or absence of type 2 diabetes. The difference and 95% CI between the treatment groups in median change from baseline were estimated, within age group, using a Hodges-Lehmann estimator.
      Proportions of subjects with recurrent hyperkalemia (serum K+ ≥5.5 mEq/L and ≥5.1 mEq/L) at any time during the withdrawal phase were stratified by serum K+ level at the start of the initial phase of the study (<5.8 mEq/L or ≥5.8 mEq/L) and by presence or absence of type 2 diabetes. Treatment groups were compared, separately by age group, using the Mantel-Haenszel test.
      Kaplan-Meier methods were used to estimate the time to recurrent hyperkalemia and time to discontinuation of RAASi during the withdrawal phase. Additional details regarding statistical methods were published previously.
      • Weir M.R.
      • Bakris G.L.
      • Bushinsky D.A.
      • et al.
      Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors.

      Results

       Patient Disposition

      Of patients enrolled in part A, 131 (54%) were aged ≥65 years and 112 (46%) <65 years; 87% and 94%, respectively, completed part A. The 2 most common reasons for discontinuation were adverse events (7 [5%] ≥65 years and 3 [3%] <65 years) and consent withdrawal (4 [3%] and 1 [1%], respectively).
      Of 107 patients who met eligibility criteria to enter part B, 60 (56%) were aged ≥65 years and 47 (44%) <65 years. Among patients who completed part A, the most common reason for ineligibility for part B was serum K+ level <5.5 mEq/L at baseline of part A (48 [42%] ≥65 years and 49 [47%] <65 years). A total of 40 patients (67%) ≥65 years (22 of 29 [76%] taking patiromer and 18 of 31 [58%] taking placebo) and 35 patients (74%) <65 years (23 of 26 [88%] taking patiromer and 12 of 21 [57%] taking placebo) completed the study. The most common reason for discontinuation was high serum K+ level meeting protocol-specified withdrawal criterion, occurring in 2 patients (4%) taking patiromer and 14 (27%) taking placebo.

       Baseline Demographic and Clinical Characteristics in Part A

      Mean (standard deviation [SD]) age was 71.7 (4.4) years for patients aged ≥65 years and 55.5 (8.6) years for those <65 years (Table 1). Approximately 24% of patients ≥65 years and 29% <65 years had stage 3B chronic kidney disease; 43% and 47%, respectively, had stage 4/5 chronic kidney disease (Table 1). There was no difference in mean (SD) eGFR between the 2 subgroups, whereas serum creatinine was lower in patients ≥65 years (P < .01; Table 1). Heart failure was present in 52% of patients ≥65 years and in 30% of those <65 years. The mean (SD) serum K+ was similar by age group (≥65 years: 5.59 [0.54] mEq/L; <65 years: 5.56 [0.49] mEq/L). Patients ≥65 years were taking 6.7 concomitant medications on average at baseline, and those <65 years were taking 5.8; all were taking RAASi medications (primarily angiotensin-converting enzyme inhibitors), and a majority were taking non-RAASi, nondiuretic antihypertensives, and non-RAASi diuretics (Supplementary Table 1, available online).
      Table 1Baseline Demographic and Clinical Characteristics at Baseline in the Initial Treatment Phase (Part A) by Age Group
      Parameter≥65 y (n = 131)<65 y (n = 112)
      Male, n (%)76 (58.0)64 (57.1)
      Age (y), mean (SD)71.7 (4.4)55.5 (8.6)
       <65 y (%)46.1
       65-69 y (%)18.5
       70-74 y (%)18.5
       ≥75 y (%)16.8
      White, n (%)129 (98.5)110 (98.2)
      Chronic kidney disease stage (eGFR in mL/min/1.73 m2), n (%)
      Classification of chronic kidney disease stage at baseline was determined by central laboratory eGFR values. None of the patients had stage 1 chronic kidney disease.
       Stage 2
      Approximately 9% of patients in each subgroup who met the entry criteria on the basis of their local laboratory eGFR values were reclassified on the basis of their central eGFR values as having stage 2 chronic kidney disease at baseline.
      (60-<90)
      12 (9.2)10 (8.9)
       Stage 3A (45-<60)32 (24.4)17 (15.2)
       Stage 3B (30-<45)31 (23.7)32 (28.6)
       Stage 4/5 (<30)56 (42.7)53 (47.3)
      Type 2 diabetes mellitus, n (%)78 (59.5)61 (54.5)
      Heart failure, n (%)68 (51.9)34 (30.4)
       Time since diagnosis (y), mean (SD)4.0 (5.0)2.7 (3.2)
      Myocardial infarction, n (%)34 (26.0)26 (23.2)
      Hypertension, n (%)127 (96.9)109 (97.3)
      eGFR (mL/min/1.73 m2), mean (SD)36.8 (16.1)
      P = nonsignificant and §P < .01 for difference between age groups (one-way analysis of variance).
      33.9 (16.3)
      P = nonsignificant and §P < .01 for difference between age groups (one-way analysis of variance).
      Serum blood urea nitrogen (mg/dL), mean (SD)37.0 (17.0)41.8 (19.1)
      Serum creatinine (mg/dL), mean (SD)1.92 (0.8)§2.34 (1.2)§
      Serum K+ (mEq/L), mean (SD)
      By central laboratory measurements.
      5.59 (0.54)5.56 (0.49)
      n130108
      eGFR = estimated glomerular filtration rate; K+ = potassium; SD = standard deviation.
      * Classification of chronic kidney disease stage at baseline was determined by central laboratory eGFR values. None of the patients had stage 1 chronic kidney disease.
      Approximately 9% of patients in each subgroup who met the entry criteria on the basis of their local laboratory eGFR values were reclassified on the basis of their central eGFR values as having stage 2 chronic kidney disease at baseline.
      P = nonsignificant and §P < .01 for difference between age groups (one-way analysis of variance).
      By central laboratory measurements.

       Efficacy

       Initial Treatment Phase (Part A)

      The estimated mean ± SE change in serum K+ from baseline to week 4 in patients who received ≥1 dose of patiromer and had ≥1 serum K+ measurement after day 3 was −1.01 ± 0.05 mEq/L (95% CI, −1.10, −0.92) for patients ≥65 years (n = 126) and −0.96 ± 0.05 mEq/L (95% CI, −1.05, −0.88) for those <65 years (n = 111; P < .001 for both); P = .50 for difference between age groups. The estimated mean ± SE serum K+ for patients aged ≥65 years and <65 years during part A is shown in Figure 1.
      Figure 1
      Figure 1Effect of patiromer on serum K+ in patients aged ≥65 and <65 years during the initial treatment phase (part A). Estimates of mean (standard error [SE]) serum potassium (K+) by visit were based on models that included presence or absence of heart failure and presence or absence of type 2 diabetes. The postbaseline models also included the baseline serum K+ value. Baseline and day 3 means were estimated using analysis of variance models; estimates at weeks 1-4 were based on mixed models with repeated measures.
      Among patients with ≥1 centrally measured serum K+ value after baseline, the proportion that achieved normokalemia (serum K+ 3.8-<5.1 mEq/L) at any time during part A was 97%, both for patients aged ≥65 years (122 of 126) and for those <65 years (108 of 111).
      The mean daily dose of patiromer during part A was 17.5 g in patients aged ≥65 years and 19.0 g in patients <65 years. Of the 78 of 131 patients ≥65 years and the 69 of 112 patients <65 years who required a dose adjustment, the majority (53 [68%] and 38 [55%], respectively) required only 1 adjustment.

       Randomized Withdrawal Phase (Part B)

      Mean (SD) serum K+ for patients aged ≥65 years who entered part B was 4.51 (0.42) mEq/L. During the first 4 weeks of this phase, serum K+ levels remained stable in patiromer-treated patients and increased in placebo-treated patients. Differences between the patiromer versus placebo groups in the median (95% CI) change in serum K+ were 0.81 (0.49, 1.14) mEq/L (P < .001) in patients ≥65 years and 0.57 (0.11, 1.03) mEq/L (P = .006) in patients <65 years (Supplementary Figure 1, available online).
      Among patients aged ≥65 years taking patiromer versus placebo, 11% versus 64% (P < .001) had at least 1 serum K+ value ≥5.5 mEq/L, and 30% versus 92% (P < .001) had at least 1 serum K+ value ≥5.1 mEq/L (Figure 2). Results for patients <65 years were generally similar, although the difference between treatment groups in the proportion with serum K+ ≥5.1 mEq/L was more pronounced in the older versus the younger age group (P < .05) (Figure 2). The time to first recurrence of hyperkalemia is shown in Supplementary Figure 2, available online (panels A and B, time to first serum K+ level >5.5 mEq/L; panels C and D, time to first serum K+ level >5.1 mEq/L).
      Figure 2
      Figure 2Proportion of patients with recurrent hyperkalemia (HK) (A, ≥5.5 mEq/L; B, ≥5.1 mEq/L) at any time through 8 weeks of the randomized withdrawal phase (part B). K+ = potassium.
      The proportion of patients aged ≥65 years who required an intervention to manage hyperkalemia was 10% for patiromer versus 71% for placebo (Figure 3A). All patients ≥65 years (100%) receiving patiromer, compared with 48% of those taking placebo, continued to be receiving RAASi at the end of part B (Figure 3B). Results for patients <65 years were similar (Figure 3). Time to RAASi discontinuation is shown in Figure 4.
      Figure 3
      Figure 3Proportion of patients who required management of recurrent hyperkalemia (HK) and who continued taking renin–angiotensin–aldosterone-system inhibitors (RAASi) at the end of the randomized withdrawal phase (part B). *The protocol required different interventions for the management of recurrent hyperkalemia (ie, RAASi dose reduction or discontinuation in the placebo group and patiromer dose increase or RAASi discontinuation in the patiromer group). Could be at the final visit (week 8) or earlier if the patient discontinued. K+ = potassium.
      Figure 4
      Figure 4Time to renin–angiotensin–aldosterone-system inhibitors (RAASi) discontinuation during the randomized withdrawal phase (part B). Circles indicate censored observations.
      During part A, mean daily patiromer doses were similar in patients subsequently randomized to continue patiromer (18.7 g/d for those aged ≥65 years and 21.6 g/d for those <65 years) or to switch to placebo (21.2 g/d for both patients ≥65 and <65 years). During part B, the mean daily dose in the patiromer group was 19.9 g/d in patients ≥65 years and 22.7 g/d in patients <65 years. During part B, dose titrations were permitted only in the patiromer group (and during the first 4 weeks when the primary efficacy endpoint was under evaluation, only if serum K+ was <3.8 mEq/L or >5.5 mEq/L). Over the entire phase, patiromer dose increases were reported in 3 patients (10%) ≥65 years and in 5 (19.2%) patients <65 years.

       Safety

      During part A and its safety follow-up period, 47% of the patients aged ≥65 years and 46% of those <65 years reported ≥1 adverse event (Table 2). A total of 10 patients (7.6%) ≥65 years and 5 patients (4.5%) <65 years reported an adverse event that led to study discontinuation during the initial treatment phase. Two patients (1.5%) ≥65 years and 1 patient (0.9%) <65 years reported a total of 6 nonfatal serious adverse events; none of these were considered by the investigator as related to patiromer.
      Table 2Adverse Events During Initial Treatment Phase (Part A) and Its Safety Follow-Up by Age Group
      Adverse Event
      Based on safety population.
      ≥65 y (n = 131)<65 y (n = 112)
      At least 1 adverse event62 (47.3)52 (46.4)
      Most common adverse events
      Occurring in >3% of patients in either subgroup; presented by descending number of patients for both subgroups combined.
       Constipation19 (14.5)7 (6.3)
       Diarrhea7 (5.3)1 (0.9)
       Hypomagnesemia5 (3.8)3 (2.7)
       Nausea5 (3.8)3 (2.7)
       Anemia4 (3.1)3 (2.7)
       Worsening of chronic kidney disease2 (1.5)5 (4.5)
       Hyperkalemia4 (3.1)2 (1.8)
       Left ventricular hypertrophy2 (1.5)4 (3.6)
       Reduced GFR0 (0)4 (3.6)
      Most common patiromer-related adverse events
      Occurring in >3% of patients in either subgroup; presented by descending number of patients for both subgroups combined.
       Any patiromer-related adverse event36 (27.5)17 (15.2)
       Constipation17 (13)7 (6.3)
       Diarrhea6 (4.6)1 (0.9)
       Hypomagnesemia5 (3.8)2 (1.8)
      Other adverse events of interest
       Edema (peripheral)1 (0.8)0 (0)
      At least 1 serious adverse event2 (1.5)1 (0.9)
      Prespecified electrolytes of interest
      Available for 126 patients aged ≥65 years and 111 patients aged <65 years.
       Serum K+ <3.5 mEq/L5 (4.0)2 (1.8)
       Serum Mg2+
        <1.4 mg/dL5 (4.0)3 (2.7)
        <1.2 mg/dL00
      Values are number (percentage). GFR = glomerular filtration rate; K+ = potassium; Mg2+ = magnesium.
      * Based on safety population.
      Occurring in >3% of patients in either subgroup; presented by descending number of patients for both subgroups combined.
      Available for 126 patients aged ≥65 years and 111 patients aged <65 years.
      The proportions of patients who reported at least 1 adverse event during part B and its safety follow-up period were generally similar in patients taking patiromer versus placebo (Table 3). Two (6.9%) patients aged ≥65 years who were taking patiromer reported constipation; in both, the adverse event was related to patiromer but was not severe or serious. Two patients (3.3%) ≥65 years (1 patiromer, 1 placebo) and none <65 years reported an adverse event that led to study discontinuation during the withdrawal phase. One patient ≥65 years who was taking placebo during part B reported a serious adverse event (mesenteric vessel thrombosis) that led to death; the serious adverse event was reported 36 days after the last dose of patiromer in part A and was considered by the investigator as not related to patiromer and by the Safety Review Board as not related to hypokalemia or hyperkalemia.
      Table 3Adverse Events During Withdrawal Phase (Part B) and Its Safety Follow-Up by Age Group
      Adverse Event
      Based on safety population.
      ≥65 y<65 y
      Patiromer (n = 29)Placebo (n = 31)Patiromer (n = 26)Placebo (n = 21)
      At least 1 adverse event15 (51.7)17 (54.8)11 (42.3)9 (42.9)
      Most common adverse events
      Occurring in ≥2 patients in any subgroup; presented in descending order of incidence in patients aged ≥65 taking patiromer.
       Constipation2 (6.9)000
       Nausea2 (6.9)000
       Headache1 (3.4)2 (6.5)1 (3.8)2 (9.5)
       Influenza1 (3.4)1 (3.2)02 (9.5)
       Hyperkalemia02 (6.5)1 (3.8)0
       Hepatic enzyme increased02 (6.5)1 (3.8)0
       Hypertension0003 (14.3)
      Most common patiromer-related adverse events
      Occurring in ≥2 patients in any subgroup; presented in descending order of incidence in patients aged ≥65 taking patiromer.
       Any patiromer-related adverse event4 (13.8)2 (6.5)00
       Constipation2 (6.9)000
      Adverse events of interest
       Edema (peripheral)0000
      At least 1 serious adverse event01 (3.2)00
      Prespecified electrolytes of interest
       Serum K+ <3.8 mEq/L
      During the withdrawal phase and its follow-up period, hypokalemia was predefined as serum K+ <3.8 mEq/L, the protocol-specified criterion for study withdrawal.
      2 (6.9)1 (3.2)1 (3.9)0
       Serum Mg2+
        <1.4 mg/dL0000
        <1.2 mg/dL0000
      Values are number (percentage). K+ = potassium; Mg2+ = magnesium.
      * Based on safety population.
      Occurring in ≥2 patients in any subgroup; presented in descending order of incidence in patients aged ≥65 taking patiromer.
      During the withdrawal phase and its follow-up period, hypokalemia was predefined as serum K+ <3.8 mEq/L, the protocol-specified criterion for study withdrawal.
      Mean serum Mg2+ remained within the normal range during the study. Predefined measures of serum Mg2+ <1.4 mg/dL and serum K+ <3.5 mEq/L (part A) and <3.8 mEq/L (part B) were infrequent (Table 2, Table 3). In the 8 patients with serum Mg2+ <1.4 mg/dL during patiromer treatment, Mg2+ levels increased during follow-up after patiromer was discontinued, regardless of age group. Hypomagnesemia was reported as an adverse event in part A for 8 patients (5 patients aged ≥65 years and 3 patients <65 years; Table 2); and blood Mg2+ decrease was reported as an adverse event in 1 patient <65 years of age. Of note, only 2 (both ≥65 years) of the 9 patients with these adverse events had prespecified serum Mg2+ <1.4 mg/dL (1.3 mg/dL in both patients at or after the adverse events were recorded). All 9 patients received Mg2+ supplementation, and none were discontinued from part A owing to adverse events. In part B, as shown in Table 3, no patients had serum Mg2+ <1.4 mg/dL. Hypomagnesemia was reported as an adverse event in 3 patients (serum Mg2+ 1.7-1.8 mg/dL at the time of the event; 2 patients were ≥65 years [1 taking patiromer, 1 taking placebo], and 1 patient was <65 years and taking placebo); and a decrease in blood Mg2+ was reported in 1 patient ≥65 years receiving placebo (serum Mg2+ 1.7 mg/dL at the time of the event). Three of these 4 patients received Mg2+ supplementation, and none were discontinued from part B owing to adverse events. No patient had both hypokalemia and hypomagnesemia at any time during the study.

      Discussion

      This prespecified subgroup analysis of patients aged ≥65 years from the OPAL-HK study shows that patiromer is effective in managing hyperkalemia in patients with chronic kidney disease taking RAASi, regardless of age. The effect on lowering serum K+ during the initial treatment phase was similar in patients ≥65 years and <65 years, and >96% of all patients achieved normokalemia (serum K+ 3.5-<5.1 mEq/L) at some point during the phase. The magnitude of serum K+ decrease in response to patiromer in patients aged ≥75 years seems to be consistent with the current findings.
      • Kumar R.
      • Kanev L.
      • Woods S.D.
      • et al.
      Managing hyperkalemia in high-risk patients in long-term care.
      Of note, more than 50% of patients in each age subgroup were taking loop or thiazide diuretics at baseline; however, a previously published analysis of OPAL-HK data showed similar magnitude and time course of reductions in serum K+ in patients taking and not taking diuretics.
      • Weir M.R.
      • Mayo M.R.
      • Garza D.
      • et al.
      Effectiveness of patiromer in the treatment of hyperkalemia in chronic kidney disease patients with hypertension on diuretics.
      Patients aged ≥65 years are more likely to have multiple risk factors for hyperkalemia as a result of age-related comorbidities—such as chronic kidney disease, diabetes, and heart failure—and the use of guideline-recommended RAASi therapy for these conditions.
      • Stevens L.A.
      • Viswanathan G.
      • Weiner D.E.
      Chronic kidney disease and end-stage renal disease in the elderly population: current prevalence, future projections, and clinical significance.
      • Curtis L.H.
      • Whellan D.J.
      • Hammill B.G.
      • et al.
      Incidence and prevalence of heart failure in elderly persons, 1994-2003.
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: an update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.
      • Ponikowski P.
      • Voors A.A.
      • Anker S.D.
      • et al.
      2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
      Patients in both groups were at similar risk for persistent hyperkalemia: they had similarly low eGFRs, similar proportions of patients in both groups had type 2 diabetes, and all were taking RAASi at baseline. The study population represents a real-world population at risk for hyperkalemia who can benefit from RAASi therapy.
      Our result that the median serum K+ increased in patients—both ≥65 and <65 years of age—who switched to placebo, but not in those who continued patiromer, during the randomized withdrawal phase demonstrates that daily patiromer is needed to maintain normokalemia. Consistent with this, fewer recurrent hyperkalemia events occurred in patients in both age groups who continued patiromer compared with those who switched to placebo. The rate of recurrent hyperkalemia was lower in older versus younger patients when defined as serum K+ ≥5.1 mEq/L; however, given that there was no difference between age groups in the rate of recurrent hyperkalemia based on serum K+ ≥5.5 mEq/L, this difference is likely not clinically relevant. As a result of the reduced rate of recurrent hyperkalemia, more patients who continued patiromer in both age groups were able to maintain their RAASi therapy. These exploratory data suggest that patiromer may enable patients with chronic kidney disease, including older patients, to maintain their guideline-recommended RAASi therapy. In the present analysis, more than 50% of patients aged ≥65 years had heart failure; in a previous report, heart failure patients treated with patiromer in OPAL-HK showed decreases in serum K+ similar to those seen in the present analysis, with similar proportions of patients achieving normokalemia and continuing to take RAASi at study end.
      • Pitt B.
      • Bakris G.L.
      • Bushinsky D.A.
      • et al.
      Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney disease on RAAS inhibitors.
      Hyperkalemia also likely contributes to the cost of managing patients with chronic kidney disease and/or heart failure, both directly (more hospital visits and longer inpatient stays) and indirectly (RAASi discontinuation or dose reduction).
      • Epstein M.
      • Alvarez P.J.
      • Reaven N.L.
      • et al.
      Evaluation of clinical outcomes and costs based on prescribed dose level of renin-angiotensin-aldosterone system inhibitors.
      • Ouwerkerk W.
      • Voors A.A.
      • Anaker S.D.
      • et al.
      Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study.
      • Polson M.
      • Evangelatos T.
      • Lord T.
      • et al.
      Clinical and economic impact of hyperkalemia in patients with chronic kidney disease and heart failure (abstract).
      The ability of patiromer to lower serum K+ and to prevent recurrent hyperkalemia may also provide economic value.
      Patiromer was well tolerated in patients regardless of age. During the initial treatment phase, mild-to-moderate gastrointestinal events (eg, constipation, diarrhea, nausea) were the most frequently reported class of adverse events in both subgroups, whereas the specific events of constipation and diarrhea occurred more frequently in patients aged ≥65 years. All other adverse events and events leading to study drug discontinuation occurred at similarly low rates in both groups. As described previously, few serious adverse events occurred during the study; none were related to patiromer.
      • Weir M.R.
      • Bakris G.L.
      • Bushinsky D.A.
      • et al.
      Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors.
      The mean serum Mg2+ levels remained relatively unaltered in patients ≥65 years and <65 years throughout both phases of study; occurrences of serum Mg2+ <1.4 mg/dL were infrequent, and in all cases serum Mg2+ increased during follow-up after patiromer was discontinued. Although adverse events of hypomagnesemia or blood Mg2+ decrease occurred in 5 patients ≥65 years and 4 patients <65 years in part A, only 2 of these patients had serum Mg2+ <1.4 mg/dL at any time during the study. Patients who are at an increased risk for hypomagnesemia (eg, those with diabetes and those treated with loop diuretics or proton pump inhibitors) may warrant closer attention during patiromer treatment. The prescribing information for patiromer recommends that magnesium supplementation be considered for patients who develop low serum Mg2+ levels during treatment.
      • Relypsa, Inc.
      Veltassa (patiromer) for oral suspension [package insert].
      Serum K+ levels <3.8 mEq/L (predefined as hypokalemia in part A) occurred at low frequency, 4% and 2% in patients ≥65 years and <65 years, respectively, and was reversible by patiromer dose adjustment.
      Finally, as noted previously, patiromer uses calcium as the counter-exchange ion, with approximately 1.6 g of calcium per 8.4 g of patiromer.
      • Bakris G.
      • Weir M.
      • Epstein M.
      Letter to the editor.
      As reported by Bushinsky et al,
      • Bushinsky D.A.
      • Spiegel D.M.
      • Gross C.
      • et al.
      Effect of patiromer on urinary ion excretion in healthy adults.
      at the maximal recommended daily dose (25.2 g/d), patiromer administration in healthy adults increased urine calcium by 73 mg/d, suggesting that only a small fraction of the calcium released from patiromer is available for absorption. At the same time, urine phosphate decreased by 64 mg/d, suggesting that some of the released calcium may bind phosphate, which is then excreted in the stool as relatively insoluble salts.
      • Bushinsky D.A.
      • Spiegel D.M.
      • Gross C.
      • et al.
      Effect of patiromer on urinary ion excretion in healthy adults.
      Nonetheless, clinicians will need to weigh the risk of a potential small increase in calcium absorption compared with the risk of hyperkalemia in patients with chronic kidney disease.
      Limitations of OPAL-HK have been described previously.
      • Weir M.R.
      • Bakris G.L.
      • Bushinsky D.A.
      • et al.
      Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors.
      Briefly, this was a short-term and single-blind study, and the number of patients in the 2 age groups that received patiromer or placebo during the randomized withdrawal phase was relatively small. However, similar reductions in serum K+ in patients aged ≥65 years (n = 182) and in those <65 years (n = 122) were observed in a larger, phase 2 trial of patiromer (personal communication, M. Weir, August 17, 2017).

      Conclusions

      Treatment with patiromer significantly reduced serum K+ and maintained normokalemia in hyperkalemic patients aged ≥65 years with chronic kidney disease who were taking RAASi. As a consequence, significantly more patiromer-treated patients were able to continue guideline-recommended RAASi therapy. Patiromer was well tolerated in patients aged ≥65 years, with low rates of discontinuations.

      Acknowledgments

      Editorial assistance was provided by Narender Dhingra, MBBS, PhD, and was funded by Relypsa, Inc.
      Conflict of Interest: MRW reports personal fees for scientific advisory boards from Relypsa, Inc. and Vifor Pharma Management Ltd., both Vifor Pharma Group Companies; and from ZS Pharma, Akebia, Janssen, AstraZeneca, Sanofi, MSD, AbbVie, and Boston Scientific outside the submitted work. DAB reports personal fees from and past stock ownership of Relypsa, Inc., a Vifor Pharma Group Company; personal fees outside the submitted work from Amgen, Sanofi/Genzyme, OPKO, and Tricida; and stock outside of the submitted work in Amgen and Tricida. He reports research support from the National Institutes of Health and from the Renal Research Institute outside of the submitted work. WWB reports employment by Relypsa, Inc., a Vifor Pharma Group Company, when the study was conducted. SDW, MRM, and SPA report employment by and past stock ownership of Relypsa, Inc., a Vifor Pharma Group Company. BP reports personal fees for consulting with Sanofi, Relypsa, Inc., a Vifor Pharma Group Company, Merck, Bayer, AstraZeneca, Boehringer Ingelheim, Forest Laboratories, scPharmaceuticals, PharMain, Tricida, DaVinci Therapeutics, KBP Biosciences, Stealth Peptides, and AuraSense. He has stock options with scPharmaceuticals, PharMain, DaVinci Therapeutics, Tricida, KBP Biosciences, and AuraSense. He serves on a data safety monitoring committee for and receives personal fees from Johnson & Johnson, Novartis, and Tenax Pharmaceuticals. He serves on a clinical events committee and receives personal fees from Juventas Therapeutics. In addition, he has a pending patent EFS ID 14916043, application number 61762661/UM-33001/US-1PRO, for the site-specific delivery of eplerenone to the myocardium. GLB reports personal fees and other from Relypsa, Inc., a Vifor Pharma Group Company; and grants from AbbVie, Janssen, and Bayer.

      Appendix

      Supplemetary Figure 1
      Supplemetary Figure 1Change in serum potassium (K+) from baseline to week 4 of the randomized withdrawal phase (part B) by age group. *For comparison between treatment groups in mean rank change.
      Supplementary Figure 2
      Supplementary Figure 2Time to first serum potassium level ≥5.5 mEq/L (A, B) and ≥5.1 mEq/L (C, D) by age subgroup.
      Supplementary Table 1Concomitant Medications at Baseline in the Initial Treatment Phase (Part A) by Age Group
      Concomitant Medication≥65 y<65 y
      Mild HK (n = 53)Moderate/Severe HK

      (n = 78)
      Total (n = 131)Mild HK (n = 39)Moderate/Severe HK (n = 73)Total (n = 112)
      No. of medications, mean (SD)6.8 (2.9)6.6 (2.9)6.7 (2.9)6.1 (3.5)5.6 (2.9)5.8 (3.1)
      RAASi medication, n (%)53 (100)78 (100)131 (100)39 (100)73 (100)112 (100)
       ACE inhibitor38 (71.7)52 (66.7)90 (68.7)30 (76.9)50 (68.5)80 (71.4)
       ARB19 (35.8)29 (37.2)48 (36.6)14 (35.9)30 (41.1)44 (39.3)
       Aldosterone antagonist10 (18.9)7 (9.0)17 (13.0)1 (2.6)4 (5.5)5 (4.5)
       Renin inhibitor1 (1.9)01 (0.8)01 (1.4)1 (0.9)
       Dual RAASi
      Any combination of 2 or more of the following: ACE inhibitor, ARB, aldosterone antagonist, and renin inhibitor.
      13 (24.5)10 (12.8)23 (17.6)6 (15.4)12 (16.4)18 (16.1)
       On maximal RAASi dose
      As assessed by the investigator in accordance with local standards of care.
      27 (50.9)37 (47.4)64 (48.9)15 (38.5)27 (37.0)42 (37.5)
      Non-RAASi, nondiuretic antihypertensives, n (%)40 (75.5)67 (85.9)107 (81.7)23 (59.0)56 (76.7)79 (70.5)
       Beta-blocker30 (56.6)45 (57.7)75 (57.3)16 (41.0)37 (50.7)53 (47.3)
       Calcium channel blocker18 (34.0)43 (55.1)61 (46.6)19 (48.7)32 (43.8)51 (45.5)
       Alpha-blocker8 (15.1)8 (10.3)16 (12.2)2 (5.1)4 (5.5)6 (5.4)
      Non-RAASi diuretics, n (%)28 (52.8)41 (52.6)69 (52.7)22 (56.4)41 (56.2)63 (56.3)
       Thiazide or thiazide-like12 (22.6)21 (26.9)33 (25.2)13 (33.3)24 (32.9)37 (33.0)
       Loop18 (34.0)26 (33.3)44 (33.6)11 (28.2)22 (30.1)33 (29.5)
      Insulin, n (%)12 (22.6)11 (14.1)23 (17.6)8 (20.5)24 (32.9)32 (28.6)
       Long-acting4 (7.5)6 (7.7)10 (7.6)4 (10.3)8 (11.0)12 (10.7)
       Intermediate-acting2 (3.8)2 (2.6)4 (3.1)1 (2.6)8 (11.0)9 (8.0)
       Short-acting6 (11.3)3 (3.8)9 (6.9)6 (15.4)20 (27.4)26 (23.2)
       Combination4 (7.5)3 (3.8)7 (5.3)0 (0)2 (2.7)2 (1.8)
      Noninsulin antidiabetic, n (%)23 (43.4)33 (42.3)56 (42.7)11 (28.2)19 (26.0)30 (26.8)
       Biguanides10 (18.9)14 (17.9)24 (18.3)4 (10.3)6 (8.2)10 (8.9)
       Sulfonylureas15 (28.3)25 (32.1)40 (30.5)7 (17.9)17 (23.3)24 (21.4)
       Others3 (5.7)3 (3.8)6 (4.6)3 (7.7)03 (2.7)
      Magnesium supplementation, n (%)5 (9.4)8 (10.3)13 (9.9)3 (7.7)8 (11.0)11 (9.8)
      Warfarin, n (%)5 (9.4)8 (10.3)13 (9.9)3 (7.7)03 (2.7)
      ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; HK = hyperkalemia; RAASi = renin–angiotensin–aldosterone system inhibitors; SD = standard deviation.
      * Any combination of 2 or more of the following: ACE inhibitor, ARB, aldosterone antagonist, and renin inhibitor.
      As assessed by the investigator in accordance with local standards of care.

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      Linked Article

      • Patiromer: Can Less Be Better than More?
        The American Journal of MedicineVol. 131Issue 5
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          In 2015, patiromer was approved by the Food and Drug Administration for hyperkalemia on the basis of a study showing that patiromer allows patients to continue renin-angiotensin-aldosterone-system inhibitors, which were otherwise stopped because of hyperkalemia.1,2 Patiromer has replaced kayexalate (sodium polystyrene), an inferior agent that has been used for more than 50 years for hyperkalemic patients who do not respond to diuretics.3 Because kayexalate does not reduce potassium reliably and may cause bowel necrosis, particularly in combination with sorbitol,1,3 the addition of patiromer is particularly welcome by nephrologists and cardiologists who now can administer renin-angiotensin-aldosterone-system inhibitors continuously for cardiorenal protection without worrying life-threatening hyperkalemia.
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