Patiromer induces rapid and sustained potassium lowering in patients with chronic kidney disease and hyperkalemia.
ABSTRACT: Patients with chronic kidney disease (CKD) have a high risk of hyperkalemia, which increases mortality and can lead to renin-angiotensin-aldosterone system inhibitor (RAASi) dose reduction or discontinuation. Patiromer, a nonabsorbed potassium binder, has been shown to normalize serum potassium in patients with CKD and hyperkalemia on RAASi. Here, patiromer's onset of action was determined in patients with CKD and hyperkalemia taking at least one RAASi. After a 3-day potassium- and sodium-restricted diet in an inpatient research unit, those with sustained hyperkalemia (serum potassium 5.5 - under 6.5?mEq/l) received patiromer 8.4?g/dose with morning and evening meals for a total of four doses. Serum potassium was assessed at baseline (0?h), 4?h postdose, then every 2-4?h to 48?h, at 58?h, and during outpatient follow-up. Mean baseline serum potassium was 5.93?mEq/l and was significantly reduced by 7?h after the first dose and at all subsequent times through 48?h. Significantly, mean serum potassium under 5.5?mEq/l was achieved within 20?h. At 48?h (14?h after last dose), there was a significant mean reduction of 0.75?mEq/l. Serum potassium did not increase before the next dose or for 24?h after the last dose. Patiromer was well tolerated, without serious adverse events and no withdrawals. The most common gastrointestinal adverse event was mild constipation in two patients. No hypokalemia (serum potassium under 3.5?mEq/l) was observed. Thus, patiromer induced an early and sustained reduction in serum potassium and was well tolerated in patients with CKD and sustained hyperkalemia on RAASis.
Project description:INTRODUCTION:Hyperkalemia (potassium >5.0 mEq/L) affects heart failure patients with renal disease regardless of the use of renin-angiotensin-aldosterone system inhibitors (RAASi). The open-label TOURMALINE study showed that patiromer, a sodium-free, nonabsorbed potassium binder, lowers serum potassium of hyperkalemic patients similarly when given with or without food; unlike prior studies, patients were not required to be taking RAASi. We conducted post hoc analyses to provide the first report of patiromer in patients not taking RAASi. METHODS:Hyperkalemic patients received patiromer, 8.4 g/d to start, adjusted to achieve and maintain serum potassium of 3.8 to 5.0 mEq/L. If taking RAASi, stable doses were required. The primary end point was the proportion of patients with serum potassium 3.8 to 5.0 mEq/L at week 3 or 4. This analysis presents data by patients taking or not taking RAASi. RESULTS:Demographics and baseline characteristics were similar in patients taking (n = 67) and not taking RAASi (n = 45). Baseline mean (SD) serum potassium was 5.37 (0.37) mEq/L and 5.42 (0.43) mEq/L in patients taking and not taking RAASi, respectively. Mean (SD) daily patiromer doses were similar (10.7 [3.2] and 11.5 [4.0] g, respectively). The primary end point was achieved in 85% (95% confidence interval [CI]: 74-93) of patients taking RAASi and in 84% (95% CI: 71-94) of patients not taking RAASi. From baseline to week 4, the mean (SE) change in serum potassium was -0.67 (0.08) mEq/L in patients taking RAASi and -0.56 (0.10) mEq/L in patients not taking RAASi (both P < .0001 vs baseline, P = nonsignificant between groups). Adverse events were reported in 26 (39%) patients taking RAASi and 25 (54%) not taking RAASi; the most common adverse event was diarrhea (2% and 11%, respectively; no cases were severe). Five patients (2 taking RAASi) reported 6 serious adverse events; none considered related to patiromer. CONCLUSIONS:Patiromer was effective and generally well-tolerated for hyperkalemia treatment, whether or not patients were taking RAAS inhibitors.
Project description:<h4>Aims</h4>We evaluated the effects of patiromer, a potassium (K(+))-binding polymer, in a pre-specified analysis of hyperkalaemic patients with heart failure (HF) in the OPAL-HK trial.<h4>Methods and results</h4>Chronic kidney disease (CKD) patients on renin-angiotensin-aldosterone system inhibitors (RAASi) with serum K(+) levels ?5.1 mEq/L to <6.5 mEq/L (n = 243) received patiromer (4.2 g or 8.4 g BID initially) for 4 weeks (initial treatment phase); the primary efficacy endpoint was mean change in serum K(+) from baseline to week 4. Eligible patients (those with baseline K(+) ?5.5 mEq/L to <6.5 mEq/L and levels ?3.8 mEq/L to <5.1 mEq/L at the end of week 4) entered an 8-week randomized withdrawal phase and were randomly assigned to continue patiromer or switch to placebo; the primary efficacy endpoint was the between-group difference in median change in the serum K(+) over the first 4 weeks of that phase. One hundred and two patients (42%) had heart failure (HF). The mean [± standard error (SE)] change in serum K(+) from baseline to week 4 was -1.06 ± 0.05 mEq/L [95% confidence interval (CI), -1.16,-0.95; P < 0.001]; 76% (95% CI, 69,84) achieved serum K(+), 3.8 mEq/L to <5.1 mEq/L. In the randomized withdrawal phase, the median increase in serum K(+) from baseline of that phase was greater with placebo (n = 22) than patiromer (n = 27) (P < 0.001); recurrent hyperkalaemia (serum K(+), ?5.5 mEq/L) occurred in 52% on placebo and 8% on patiromer (P < 0.001). Mild-to-moderate constipation was the most common adverse event (11%); hypokalaemia occurred in 3%.<h4>Conclusion</h4>In patients with CKD and HF who were hyperkalaemic on RAASi, patiromer was well tolerated, decreased serum K(+), and, compared with placebo, reduced recurrent hyperkalaemia.
Project description:BACKGROUND:While chronic kidney disease (CKD) is common in resistant hypertension (RHTN), prior studies -evaluating mineralocorticoid receptor antagonists excluded patients with reduced kidney function due to risk of hyperkalemia. AMBER (ClinicalTrials.gov identifier NCT03071263) will evaluate if the potassium-binding polymer patiromer used concomitantly with spironolactone in patients with RHTN and CKD prevents hyperkalemia and allows more persistent spironolactone use for hypertension management. METHODS:Randomized, double-blind, placebo-controlled parallel group 12-week study of patiromer and spironolactone versus placebo and spironolactone in patients with uncontrolled RHTN and CKD. RHTN is defined as unattended systolic automated office blood pressure (AOBP) of -135-160 mm Hg during screening despite taking ?3 antihypertensives, including a diuretic, and an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker -(unless not tolerated or contraindicated). The CKD inclusion criterion is an estimated glomerular filtration rate (eGFR) of 25 to ?45 mL/min/1.73 m2. Screening serum potassium must be 4.3-5.1 mEq/L. The primary efficacy endpoint is the between-group difference (spironolactone plus patiromer versus spironolactone plus placebo) in the proportion of patients remaining on spironolactone at Week 12. RESULTS:Baseline characteristics have been analyzed as of March 2018 for 146 (of a targeted 290) patients. Mean (SD) baseline age is 69.3 (10.9) years; 52.1% are male, 99.3% White, and 47.3% have diabetes. Mean (SD) baseline serum potassium is 4.68 (0.25) mEq/L, systolic AOBP is 144.3 (6.8) mm Hg, eGFR is 35.7 (7.7) mL/min/1.73 m2. CONCLUSION:AMBER will define the ability of patiromer to facilitate the use of spironolactone, an effective antihypertensive therapy for patients with RHTN and CKD.
Project description:<h4>Introduction</h4>Patiromer is a potassium (K<sup>+</sup>) binding polymer indicated for treating hyperkalemia. Among patients receiving chronic hemodialysis (HD), this study aimed to identify patient characteristics associated with patiromer initiation, describe patiromer utilization, and analyze serum K<sup>+</sup> pre- and post-patiromer initiation.<h4>Methods</h4>In a retrospective cohort study, using electronic health record data from a large dialysis provider in the United States (study period: December 21, 2015, to December 20, 2016), HD patients were included who had a medication order for patiromer, sodium polystyrene sulfonate (SPS), or laboratory evidence of hyperkalemia (no K<sup>+</sup> binder [NoKb] cohort). The index date was the first order for patiromer/SPS, or the first K<sup>+</sup> ?5.0 mEq/l (NoKb cohort), respectively. Using multivariable logistic regression, we identified patient characteristics associated with patiromer initiation. We evaluated patiromer utilization using Kaplan-Meier methodology and proportion of days covered. Serum K<sup>+</sup> concentrations were assessed pre- versus post-patiromer initiation.<h4>Results</h4>Study cohorts included 527 (patiromer), 852 (SPS), and 8747 (NoKb) HD patients. Median follow-up was 141 days. Patiromer initiators were 2.6 times more likely to have had multiple prior episodes of hyperkalemia (odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.8-3.7). Most (61%) commenced patiromer on 8.4 g once daily; 60% of patients' first patiromer order remained open after 180 days. Statistically significant reductions in K<sup>+</sup>, averaging approximately -0.5 mEq/l, were observed post-patiromer initiation (48% pre-patiromer vs. 22% post-patiromer had K<sup>+</sup> ?6.0 mEq/l [<i>P</i> < 0.001]).<h4>Conclusion</h4>Patiromer initiators receiving chronic hemodialysis had comparatively more severe, uncontrolled baseline hyperkalemia. Medication order data show long-term patiromer use was associated with significantly reduced K<sup>+</sup>.
Project description:Data on hyperkalemia frequency among chronic kidney disease (CKD) patients receiving renin-angiotensin aldosterone system inhibitors (RAASis) and its impact on subsequent RAASi treatment are limited. This population-based cohort study sought to assess the incidence of clinically significant hyperkalemia among adult CKD patients who were prescribed a RAASi and the proportion of patients with RAASi medication change after experiencing incident hyperkalemia. We conducted a retrospective, population-based cohort study (1 January 2013-30 June 2017) using Australian national general practice data from the NPS MedicineWise's MedicineInsight program. The study included adults aged ?18 years who received ?1 RAASi prescription during the study period and had CKD (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73m2). Study outcomes included incident clinically significant hyperkalemia (serum potassium >6 mmol/L or a record of hyperkalemia diagnosis) and among patients who experienced incident hyperkalemia, the proportion who had RAASi medication changes (cessation or dose reduction during the 210-day period after the incident hyperkalemia event). Among 20,184 CKD patients with a median follow-up of 3.9 years, 1,992 (9.9%) patients experienced an episode of hyperkalemia. The overall incidence rate was 3.1 (95% CI: 2.9-3.2) per 100 person-years. Rates progressively increased with worsening eGFR (e.g. 3.5-fold increase in patients with eGFR <15 vs. 45-59 ml/min/1.73m2). Among patients who experienced incident hyperkalemia, 46.6% had changes made to their RAASi treatment regimen following the first occurrence of hyperkalemia (discontinuation: 36.6% and dose reduction: 10.0%). In this analysis of adult RAASi users with CKD, hyperkalemia and subsequent RAASi treatment changes were common. Further assessment of strategies for hyperkalemia management and optimal RAASi use among people with CKD are warranted.
Project description:AIMS:Hyperkalaemia risk precludes optimal renin-angiotensin-aldosterone system inhibitor use in patients with heart failure (HF), particularly those with chronic kidney disease (CKD). Patiromer is a sodium-free, non-absorbed potassium (K+ )-binding polymer approved for the treatment of hyperkalaemia. In PEARL-HF, patiromer 25.2 g (fixed dose) prevented hyperkalaemia in HF patients with or without CKD initiating spironolactone. The current study evaluated the effectiveness of a lower starting dose of patiromer (16.4 g/day) followed by individualized titration in preventing hyperkalaemia and hypokalaemia when initiating spironolactone. METHODS AND RESULTS:This open-label 8-week study enrolled 63 patients with CKD, serum K+ 4.3-5.1 mEq/L, and chronic HF, who, based on investigator opinion, should receive spironolactone. Eligible patients started spironolactone 25 mg/day and patiromer 16.8 g/day (divided into two doses), with patiromer titrated to maintain serum K+ 4.0-5.1 mEq/L. Mean (standard deviation) serum K+ was 4.78 (0.51) mEq/L at baseline; weekly values were 4.48-4.70 mEq/L during treatment. Serum K+ of 3.5-5.5 mEq/L at the end of study treatment (primary endpoint) was achieved by 57 (90.5%) patients; 53 (84.1%) had serum K+ 4.0-5.1 mEq/L. One patient (1.6%) developed hypokalaemia, and two patients (3.2%) developed hypomagnesaemia. Spironolactone was increased to 50 mg/day in all patients; 43 (68%) patients required one or more patiromer dose titration. Adverse events (AEs) occurred in 36 (57.1%) patients, with a low rate of discontinuations [four (6.3%) patients]. The most common AE was mild to moderate abdominal discomfort [four (6.3%) patients]. CONCLUSIONS:In this open-label study, patiromer 16.8 g/day followed by individualized titration maintained serum K+ within the target range in the majority of patients with HF and CKD, all of whom were uptitrated to spironolactone 50 mg/day, patiromer was well tolerated, with a low incidence of hyperkalaemia, hypokalaemia, and hypomagnesaemia.
Project description:To compare and contrast the efficacy and safety of patiromer and sodium zirconium cyclosilicate (ZS-9) in the treatment of hyperkalemia.A systematic review and meta-analysis of phase II and III clinical trial data was completed.Eight studies (two phase II and four phase III trials with two subgroup analyses) were included in the qualitative analysis, and six studies (two phase II and four phase III trials) were included in the meta-analysis.Significant heterogeneity was found in the meta-analysis with an I2 value ranging from 80.6-99.6%. A random-effects meta-analysis was applied for all end points. Each clinical trial stratified results by hyperkalemia severity and dosing; therefore, these were considered separate treatment groups in the meta-analysis. For patiromer, a significant -0.70 mEq/L (95% confidence interval [CI] -0.48 to -0.91 mEq/L) change was noted in potassium at 4 weeks. At day 3 of patiromer treatment, potassium change was -0.36 mEq/L (range of standard deviation 0.07-0.30). The primary end point for ZS-9-change in potassium at 48 hours-was -0.67 mEq/L (95% CI -0.45 to -0.89 mEq/L). By 1 hour after ZS-9 administration, change in potassium was -0.17 mEq/L (95% CI -0.05 to -0.30). Analysis of pooled adverse effects from these trials indicates that patiromer was associated with more gastrointestinal upset (7.6% constipation, 4.5% diarrhea) and electrolyte depletion (7.1% hypomagnesemia), whereas ZS-9 was associated with the adverse effects of urinary tract infections (1.1%) and edema (0.9%).Patiromer and ZS-9 represent significant pharmacologic advancements in the treatment of hyperkalemia. Both agents exhibited statistically and clinically significant reductions in potassium for the primary end point of this meta-analysis. Given the adverse effect profile and the observed time-dependent effects, ZS-9 may play more of a role in treating acute hyperkalemia.
Project description:<h4>Importance</h4>Renin angiotensin aldosterone system inhibitors (RAASIs) benefit individuals with chronic kidney disease (CKD). Elevations in serum creatinine and potassium levels are common reasons for discontinuation of this therapy, but their incidence and risks are not well characterized in community practice.<h4>Objective</h4>To evaluate associations of increased creatinine levels, hyperkalemia, and therapy continuation with the risk of emergency department (ED) visits, hospitalizations, and mortality within 1 year after RAASI therapy initiation in individuals with CKD.<h4>Design, setting, and participants</h4>This prospective cohort study included 4661 individuals with nondialysis CKD newly prescribed a RAASI or a diuretic who were treated at 36 outpatient primary care offices affiliated with Brigham & Women's Hospital and Massachusetts General Hospital, Boston, from January 1, 2009, through December 31, 2011. Individuals receiving a new prescription for a diuretic were used to provide context. All participants had a baseline measure of renal function and at least 1 follow-up measurement of creatinine and potassium levels within 90 days of the prescription. Data were analyzed from January 1, 2009, through December 31, 2012.<h4>Exposures</h4>Changes in creatinine and potassium levels within 90 days after the prescription date and therapy discontinuation.<h4>Main outcomes and measures</h4>Emergency department visits, hospitalizations, and mortality within 1 year.<h4>Results</h4>A total of 4661 individuals were included in the analysis (2506 [53.8%] women; mean [SD] age, 71?; 3931 [84.3%] white; and 4198 [90.1%] with CKD stage 3). Of these, 2354 individuals (50.5%) received RAASIs and 2307 (49.5%) received diuretics. Creatinine level increase of at least 30% after RAASI therapy initiation was found in 158 of 2354 individuals (6.7%); hyperkalemia of greater than 5.0 mEq/L, in 251 of 2354 (10.7%). Increases in creatinine level of at least 30% (unadjusted odds ratio [OR], 1.40; 95% CI, 0.89-2.21), hyperkalemia (unadjusted OR, 1.15; 95% CI, 0.64-2.06), and therapy discontinuation (unadjusted OR, 1.01; 95% CI, 0.71-1.46) were not associated with ED visits or hospitalizations, which was consistent with results from competing risk analyses. Initial increases in creatinine level of at least 30% were associated with mortality in the total cohort (adjusted OR [aOR], 2.17; 95% CI, 1.45-3.25). However, the effect was only independent for diuretics (aOR, 2.27; 95% CI, 1.41-3.66) and not for RAASIs (aOR, 1.82; 95% CI, 0.83-3.99).<h4>Conclusions and relevance</h4>Acute creatinine and potassium level disturbances after initiation of RAASI therapy in individuals with CKD appear to be sustained often often not sustained and not associated with ED visits or hospitalizations, despite therapy continuation. Findings from this study suggest that increases in creatinine level were independently associated with mortality among individuals prescribed diuretics but not RAASIs. Structured laboratory monitoring during RAASI therapy initiation may guide appropriate continuation of therapy in the outpatient setting.
Project description:Renin-angiotensin-aldosterone system inhibitor (RAASi) therapy has been shown to improve outcomes among patients with congestive heart failure, diabetes, or renal dysfunction. These patients are also at risk for the development of hyperkalemia (HK), often leading to down-titration and/or discontinuation of RAASi therapy. Patiromer is the first sodium-free, non-absorbed potassium (K+) binder approved for the treatment of hyperkalemia (HK) in over 50 years. We described the association between use of K+ binders (Patiromer and sodium polystyrene sulfonate [SPS]) and renin-angiotensin-aldosterone system inhibitor (RAASi), on healthcare resource utilization (HRU). The study population consisted of Medicare Advantage patients with HK (K+ ? 5.0 mmol/L) in Optum's Clinformatics® Data Mart between 1/1/2016-12/31/2017. Patiromer and (SPS) initiators, and HK patients not exposed to a K+ binder (NoKb) were included. The index date was the date of the first K+ binder dispensing or HK diagnosis. Outcomes assessed at 6 months post-index were: (1) K+ binder utilization, (2) RAASi continuation, and (3) HRU (pre- vs post-index). HRU change was analyzed using McNemar's statistical test. Study cohorts included 610 (patiromer), 5556 (SPS), and 21,282 (NoKb) patients. Overall baseline patient characteristics were: mean age 75 years; female 49%, low-income subsidy 29%, chronic kidney disease 48% (63% for patiromer cohort), and congestive heart failure 29%. At 6 months post-index, 28% (patiromer) and 2% (SPS) remained continuously exposed to the index K+ binder. RAASi continued for 78% (patiromer), 57% (SPS), and 57% (NoKb). The difference (pre- vs post-index) in hospitalized patients was: -9.4% (patiromer; P<0.05), -7.2% (SPS), and +16.8% (NoKb; P<0.001). Disparate K+ binder utilization patterns were observed. The majority of patiromer patients continued RAASi therapy while the percentage of SPS patients that continued RAASi therapy was lower, overlapping CIs were observed. Following continuous patiromer exposure, statistically significant reductions in hospital admissions and emergency department visits were observed, continuous SPS exposure observed no statistically significant reductions in either hospitalizations or ED visits, while NoKb patients with continuous exposure had statistically significant increases in both. Further research, with a larger sample size using comparative analytic methods, is warranted.
Project description:Introduction:An abnormal serum potassium (S-K) level is an important electrolyte disturbance. However, its relation to clinical outcomes in real-world patients, particularly hyperkalemia burden, is not extensively studied. Methods:An observational retrospective cohort study using a Japanese hospital claims database was done (April 2008-September 2017; N = 1,022,087). Associations between index S-K level and 3-year survival were modeled using cubic spline regression. Cox regression model was applied to estimate the time to death according to different S-K levels. Prevalence, patient characteristics, treatment patterns, and management of patients with hyperkalemia from first episode were assessed. Results:Hyperkalemia prevalence was 67.9 (95% confidence interval [CI]: 67.1-68.8) per 1000 and increased in patients with chronic kidney disease (CKD) (227.9; 95% CI: 224.3-231.5), heart failure (134.0; 95% CI: 131.2-136.8), and renin-angiotensin-aldosterone system inhibitor (RAASi) use (142.2; 95% CI: 139.6-144.7). U-shaped associations between S-K level and 3-year survival were observed with nadir 4.0 mEq/l. The risk of death was increased at S-K 5.1-5.4 mEq with hazard ratio of 7.6 (95% CI: 7.2-8.0). The 3-year mortality rate in patients with CKD stages 3a, 3b, 4, and 5 with normokalemia were 1.51%, 3.93%, 10.86%, and 12.09%, whereas that in patients with CKD stage 3a at S-K 5.1-5.4, 5.5-5.9, and ?6.0 mEq/l increased to 10.31%, 11.43%, and 22.64%, respectively. Despite treatment with loop diuretics (18.5%) and potassium binders (5.8%), >30% of patients had persistently high S-K (?5.1 mEq/l). Conclusion:This study provides real-world insight on hyperkalemia based on a large number of patients with various medical backgrounds.