Long-term effects of patiromer for hyperkalaemia treatment in patients with mild heart failure and diabetic nephropathy on angiotensin-converting enzymes/angiotensin receptor blockers: results from AMETHYST-DN.
ABSTRACT: AIMS:Chronic kidney disease (CKD) in heart failure (HF) increases the risk of hyperkalaemia (HK), limiting angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) use. Patiromer is a sodium-free, non-absorbed potassium binder approved for HK treatment. We retrospectively evaluated patiromer's long-term safety and efficacy in HF patients from AMETHYST-DN. METHODS AND RESULTS:Patients with Type 2 diabetes, CKD, and HK [baseline serum potassium >5.0-5.5 mmol/L (mild) or >5.5-<6.0 mmol/L (moderate)], with or without HF (New York Heart Association Class I and II, by investigator judgement), on ACE-I/ARB, were randomized to patiromer 8.4-33.6 g to start, divided twice daily. Overall, 105/304 (35%) patients had HF (75%, Class II). Mean (standard deviation) ejection fraction (EF) was 44.9% (8.2) (n = 81) in patients with HF; 26 had EF ≤40%. In HF patients, mean serum potassium decreased by Day 3 through Week 52. At Week 4, estimated mean (95% confidence interval) change in serum potassium was -0.64 mmol/L (-0.72, -0.55) in mild and -0.97 mmol/L (-1.14, -0.80) in moderate HK (both P < 0.0001). Most HF patients with mild (>88%) and moderate (≥73%) HK had normokalaemia at each visit from Weeks 12 to 52. Three HF patients were withdrawn because of high (n = 1) or low (n = 2) serum potassium. The most common patiromer-related adverse event was hypomagnesaemia (8.6%). CONCLUSIONS:In patients with a clinical diagnosis of HF, diabetes, CKD, and HK on ACE-I/ARB, patiromer was well tolerated and effective for HK treatment over 52 weeks.
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:OBJECTIVE:To assess the patterns of angiotensin converting enzyme inhibitors and angiotensin receptor blockers (ACE-I/ARB) discontinuation in the setting of chronic kidney disease (CKD) progression in real-world clinical practice. PATIENTS AND METHODS:We identified incident ACE-I/ARB users with a baseline estimated glomerular filtration rate (eGFR) ?15 mL/min/1.73 m2 and without end-stage renal disease in the Geisinger Health System between January 1, 2004, and December 31, 2015. We investigated the associations of CKD stage, hospitalizations with and without acute kidney injury (AKI), serum potassium, bicarbonate level, thiazide, and loop diuretic use with ACE-I/ARB discontinuation. RESULTS:Among the 53,912 ACE-I/ARB users, the mean age was 59.9 years, and 50.6% were female. More than half of users discontinued ACE-I/ARB within 5 years of therapy initiation. The risk of ACE-I/ARB discontinuation increased with more advanced CKD stage. For example, patients who initiated ACE-I/ARB with CKD stage G4 (eGFR: 15-29 mL/min/1.73 m2) were 2.09-fold (95% CI, 1.87-2.34) more likely to discontinue therapy than those with eGFR ? 90 mL/min/1.73 m2. Potassium level greater than 5.3 mEq/L, systolic blood pressure ? 90 mm Hg, bicarbonate level < 22 mmol/L, and intervening hospitalization-particularly AKI-related-were also strong risk factors for ACE-I/ARB discontinuation. Thiazide diuretic use was associated with lower risk, whereas loop diuretic use was associated with higher risk of discontinuation. CONCLUSION:In a real-world cohort, discontinuation of ACE-I/ARB was common, particularly in patients with lower eGFR. Hyperkalemia, hypotension, low bicarbonate level, and hospitalization (AKI-related, in particular) were associated with a higher risk of ACE-I/ARB discontinuation. Additional studies are needed to evaluate the risk-benefit balance of discontinuing ACE-I/ARB in the setting of CKD progression.
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:OBJECTIVES:The first phase of the published OPAL-HK study was a single-group treatment phase, which showed that patiromer normalised serum potassium at 4weeks in patients with chronic kidney disease stages 3-4 who were receiving renin-angiotensin-aldosterone inhibitors. We utilised real-world data to provide a control comparison to evaluate patiromer's efficacy in lowering serum potassium. MATERIALS AND METHODS:The Salford Kidney Study (SKS) in the United Kingdom provided a matched cohort. After applying OPAL-HK inclusion and exclusion criteria, patients with an outpatient potassium level between 5.1mmol/L to <6.5mmol/L and whose next outpatient level was checked 24-42 days later were selected. Patients underwent 1:1 matching with the 243 OPAL-HK patients using propensity matching based on 6 variables: age, gender, estimated glomerular filtration rate, diabetes, heart failure and potassium level. The study outcomes aligned with the OPAL-HK treatment phase: mean change in baseline potassium, and the proportion of patients with a potassium of 3.8 to <5.1mmol/L at follow-up. RESULTS:The study comprised 87 precisely matched patients. The mean follow-up in the 87 SKS patients was 31±5 days. At baseline, matched patients had a mean potassium of 5.5±0.3mmol/L. At follow-up, the mean level was unchanged in SKS patients but was 4.5±0.5mmol/L in the OPAL-HK group (p<0.001), a mean (±SE) change of -1.00±0.06mmol/L. The target range of 3.8 to <5.1mmol/L was reached in 80% of OPAL-HK patients compared with 0% in the SKS cohort. There were very few interventions undertaken to reduce hyperkalaemia in SKS patients. CONCLUSIONS:Using real-world data as a matched control arm for the first phase of the OPAL-HK study, we highlight a potential role for patiromer in lowering potassium levels in patients with CKD 3-4 receiving renin-angiotensin-aldosterone inhibitors.
Project description:OBJECTIVES:To investigate healthcare costs associated with hyperkalaemia (HK) among patients with chronic kidney disease (CKD), heart failure (HF) or diabetes. DESIGN:Before-after cohort study of patients with HK and matched patients without HK. SETTING:Population-based databases covering primary and secondary care for the entire of Northern Denmark. PARTICIPANTS:Patients with a first incident record of CKD (n=78 372), HF (n=14 233) or diabetes (n=37 479) during 2005-2011. Among all patients experiencing a first HK event (potassium level >5.0 mmol/L), healthcare costs were compared during 6 months before and 6 months after the HK event. The same cost assessment was conducted 6 months before and after a matched index date in a comparison cohort of patients without HK. PRIMARY AND SECONDARY OUTCOME MEASURES:Mean costs of hospital care, general practice and dispensed drugs converted to 2018 Euros. RESULTS:Overall, 17 747 (23%) CKD patients, 5141 (36%) HF patients and 4183 (11%) diabetes patients with a first HK event were identified. More than 40% of all HK patients across the patient groups had subsequent HK events with successively shorter times between the events. In CKD patients, overall mean costs were €5518 higher 6 months after versus before first HK, while €441 higher in matched CKD patients without HK, yielding HK-associated costs of €5077. Corresponding costs associated with a HK event were €6018 in HF patients, and €4862 in diabetes patients. CONCLUSIONS:Among CKD, HF and diabetes patients, an incident HK event was common, and a large proportion of the patients experienced recurrent HK events. Substantial increase in healthcare costs associated with a HK event was observed in the HK patients compared with non-HK patients. These results are important to better understand the potential economic impact of HK among high-risk comorbid patients in a real-wold setting and help inform decision-making for clinicians and healthcare providers.
Project description: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: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:Hypokalemia and hyperkalemia are often noted in chronic kidney disease (CKD) patients, but their impact on mortality and end-stage renal disease (ESRD) is less well understood. We aimed at studying the associations between potassium disorders, and mortality and progression to ESRD in a CKD population.Using our electronic health record-based CKD registry, 36,359 patients with eGFR <60 ml/min/1.73 m(2) and potassium levels measured from January 1, 2005 to September 15, 2009 were identified. We examined factors associated with hypokalemia (<3.5 mmol/l) and hyperkalemia (>5.0 mmol/l) using logistic regression models and associations between serum potassium levels (both as continuous and categorical variables) and all-cause mortality or ESRD using Cox-proportional hazards models.Serum potassium <3.5 mmol/l was noted among 3% and >5.0 mmol/l among 11% of the study population. In the multivariable logistic regression analysis, lower eGFR, diabetes and use of ACE inhibitors or Angiotensin-Receptor Blockers were associated with higher odds of having hyperkalemia. Heart failure and African American race were factors associated with higher odds of hypokalemia. After adjustment for covariates including kidney function, serum potassium <4.0 and >5.0 mmol/l were significantly associated with increased mortality risk, but there was no increased risk for progression to ESRD. Time-dependent repeated measures analysis confirmed these findings. When potassium was examined as a continuous variable, there was a U-shaped association between serum potassium levels and mortality.In patients with stage 3-4 CKD, serum potassium levels <4.0 and >5.0 mmol/l are associated with higher mortality but not with ESRD.
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:Concerns about hyperkalemia limit the use of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs), but guidelines conflict regarding potassium-monitoring protocols. We quantified hyperkalemia monitoring and risks after ACE-I/ARB initiation and developed and validated a hyperkalemia susceptibility score.We evaluated 69 426 new users of ACE-I/ARB therapy in the Stockholm Creatinine Measurements (SCREAM) project with medication initiation from January 1, 2007 to December 31, 2010, and follow-up for 1 year thereafter. Three fourths (76%) of SCREAM patients had potassium checked within the first year. Potassium >5 and >5.5 mmol/L occurred in 5.6% and 1.7%, respectively. As a comparison, we propensity-matched new ACE-I/ARB users to 20 186 new ?-blocker users in SCREAM: 64% had potassium checked. The occurrence of elevated potassium levels was similar between new ?-blocker and ACE-I/ARB users without kidney disease; only at estimated glomerular filtration rate <60 mL/min per 1.73 m2 were risks higher among ACE-I/ARB users. We developed a hyperkalemia susceptibility score that incorporated estimated glomerular filtration rate, baseline potassium level, sex, diabetes mellitus, heart failure, and the concomitant use of potassium-sparing diuretics in new ACE-I/ARB users; this score accurately predicted 1-year hyperkalemia risk in the SCREAM cohort (area under the curve, 0.845, 95% CI: 0.840-0.869) and in a validation cohort from the US-based Geisinger Health System (N=19 524; area under the curve, 0.818, 95% CI: 0.794-0.841), with good calibration.Hyperkalemia within the first year of ACE-I/ARB therapy was relatively uncommon among people with estimated glomerular filtration rate >60 mL/min per 1.73 m2, but rates were much higher with lower estimated glomerular filtration rate. Use of the hyperkalemia susceptibility score may help guide laboratory monitoring and prescribing strategies.