Potassium Binders Research Articles

Abstract 4113864: Hyperkalemia In Patients With Heart Failure Correlates to Worse Inpatient Outcomes

Background: Heart failure (HF) is one of the leading causes of hospitalizations in the States. Hyperkalemia is not an infrequent comorbidity in patients with HF, limiting the maximum benefits of guideline-directed medical therapy. This study evaluates the outcomes in patients admitted for HF with and without hyperkalemia. Methods: We used the Nationwide Readmissions Database (NRD) from 2016-2019, extracting adult patients with a primary diagnosis of HF who were admitted between January and November of each year. Survey procedures were applied using SAS 9.4. Results: We included 4,454,273 weighted hospitalizations due to HF for which 380,446 patients (8.5%) had a concurrent diagnosis of hyperkalemia. Overall, patients with hyperkalemia, compared to HF cases with hyperkalemia, were slightly younger (mean age 70 years vs. 72 years, p <0.01) with fewer women (47% vs.48%) respectively. Patients with hyperkalemia had a higher frequency of diabetes mellitus, hypertension, chronic liver disease, acute kidney injury, chronic kidney disease, end-stage renal disease, and acute encephalopathy (p<0.001). They had more inpatient complications including ventricular fibrillation and cardiac arrest (p <0.001) with longer mean lengths of stay (7 days vs. 5 days, p <0.001) and 30-day readmissions (28% vs. 22%, p<0.001). In-hospital mortality during index admission was significantly higher in the hyperkalemic group (6.4% vs. 2.5%, p < 0.001). Inpatient outcomes including mortality were also worse during first readmission (7% vs. 6%, p<0.01). Even after adjustment for the above-mentioned comorbidities, multivariable analysis reveals that hyperkalemia is an independent factor for inpatient mortality (adjusted OR 1.9 [1.8-2], p<0.001). Conclusion: Hyperkalemia in patients admitted with HF is associated with increased inpatient mortality and readmission. Further studies can investigate whether novel potassium binders may improve outcomes.

Abstract 4117180: Hyperkalemia-Related Hospitalization Associated with Short-Term vs. Long-Term Outpatient SZC Therapy Among RAASi Users: The GALVANIZE Outcome study

Introduction: Patients receiving renin-angiotensin-aldosterone system inhibitors (RAASi) are at increased risk of developing hyperkalemia (HK). Sodium zirconium cyclosilicate (SZC) is used to treat HK, but the impact of duration of SZC on healthcare resource utilization (HRU) in RAASi users is unknown. The GALVANIZE Outcome study compared HK-related HRU among RAASi users between long-term and short-term SZC users. Methods: Adults with ≥1 outpatient prescription for SZC (index date) and ≥1 RAASi prescription spanning the index date were identified from a large US insurance claims database (7/2018-12/2022) and were stratified based on duration of SZC use. Long-term SZC users (>90 days) and short-term SZC users (≤30 days) were exactly and propensity score matched on key baseline characteristics. Rates of HK-related hospitalizations or emergency department (ED) visits, HK-related ED visits, and HK-related hospitalizations were compared during follow-up from index to the earliest of 6 months post-index, end of data availability, other potassium binder use, or re-initiation of SZC post-discontinuation. Results: Among 1,586 matched pairs, the mean age was 65.5 years, 41.0% of patients were female, and most patients had any stage chronic kidney disease (91.9%), hypertension (90.8%), and diabetes (73.4%). Also, 30.0% of patients had heart failure. The most used RAASi therapies at index were angiotensin-converting enzyme inhibitors (57.3%) and angiotensin-receptor blockers (56.3%). Patients with long-term SZC use had a 44% lower rate of HK-related hospitalizations or ED visits, a 41% lower rate of HK-related hospitalizations and a 52% lower rate of HK-related ED visits than patients with short-term SZC use during follow-up (all p<0.01; Figure 1). Conclusions: Among patients with RAASi and SZC therapy use, long-term SZC use was associated with significantly lower rates of HK-related HRU compared to matched patients with short-term SZC use. Funding: AstraZeneca

Integrating the new pharmacological standard of care with traditional nutritional interventions in non-dialysis CKD.

Chronic kidney disease (CKD) is widely recognized as a leading and growing contributor to global morbidity and mortality worldwide. Nutritional therapy is the basic treatment for metabolic control, and may contribute to nephroprotection; however, the absence of solid evidence on slowing CKD progression together with poor adherence to dietary prescription limit de facto itsefficacy and prevent itsmore widespread use. Sodium-glucose transport protein 2 inhibitors (SGLT2is) are now considered the new standard of care in CKD; in addition, novel potassium binders, glucagon-like peptide-1 receptor antagonists (GLP1-RAs) and nonsteroidal mineralocorticoid receptor antagonists (nsMRAs) show either direct (SGLT2i, GLP1-RA, nsMRA) or indirect (potassium binders that enable the optimal use of renin-angiotensin-aldosterone system inhibitors) nephroprotective effects. These drugs could potentially lead to a more permissive diet, thereby allowing the patient to reap the benefits of this approach. In particular, SGLT2is, and to a lesser extent also GLP1-RAs and nsMRAsin patients with diabetic kidney disease, can counterbalance hyperfiltration as well as the higher protein intake often recorded in obese patients; on the other hand, potassium binders can facilitate following plant-based diets, which are considered healthy because of the high content of essential micronutrients such as antioxidant vitamins, minerals, alkalies, and fibers. In this review paper, we discuss the current pharmacological paradigm shift that places a new, broader standard of care in light of its interaction with nutritional therapy in order to optimize the global approach to patients with CKDnotondialysis.

Sodium Zirconium Cyclosilicate for Renin-Angiotensin-Aldosterone System Inhibitor Optimization in Patients with Heart Failure with Reduced Ejection Fraction: A Retrospective Analysis.

In this retrospective analysis, we evaluate the effectiveness of the potassium (K+) binder sodium zirconium cyclosilicate (SZC) in maintaining normokalemia and facilitating the initiation, optimization, and maintenance of renin-angiotensin-aldosterone system inhibitors (RAASi) in patients with heart failure (HF) with reduced ejection fraction (HFrEF). A total of 44 patients with HFrEF and a history of hyperkalemia who were receiving SZC to enable the prescription of RAASi were identified from two district general hospital sites. Retrospective analysis was performed to determine biochemical response, alterations in pharmacotherapy, and subsequent HF outcomes following initiation of SZC. Mean K+ was reduced by 0.9mmol/L within 1month of initiation of SZC; mean K+ after 12months of treatment was 4.8mmol/L with a median (interquartile range) duration of treatment of 13 (8.4-15.1) months. Following SZC treatment, 100% of patients received an angiotensin receptor-neprilysin inhibitor (18% increase) and 93% received a mineralocorticoid receptor antagonist (41% increase), with 59% and 37% achieving guideline-recommended dosing, respectively. Ninety-one percent of patients were able to receive triple or quadruple therapy with the addition of a beta-blocker and a sodium glucose co-transporter2 inhibitor. Reduced rates of hospitalization for HF (HHF) were observed with 12 episodes per 100 patient-years recorded (reduced from 21) in addition to improvements in mean left ventricular ejection fraction (29-36%) and median N-terminal pro-B-type natriuretic peptide (3458-2055ng/L, 45% median reduction). Renal function (creatinine clearance increased from 48.4 to 49.3ml/min) and systolic blood pressure (decreased from 124 to 122mmHg) were similar following optimization, and no tolerability issues were identified. Extended real-world treatment with the K+ binder SZC was effective at maintaining normokalemia, and was associated with a greater uptake of RAASi, a reduced rate of HHF, and improvements in cardiac biomarkers in patients with HFrEF.

Heart failure and advanced chronic kidney disease: differences in characteristics, treatment and outcomes in patients with glomerular filtration rate greater or less than 30 ml/minute/m2

Abstract Introduction Heart failure (HF) is a serious health problem and continues to have a high mortality and incidence of decompensation, despite advances in its management. Chronic kidney disease (CKD) is very prevalent in patients with HF, hinders their treatment and worsens their prognosis, especially when it is advanced CKD (glomerular filtration rate-GFR <30 ml(min/m2). It is important to know the differential characteristics of these patients to improve their management. Purpose To analyze in a contemporary registry of HF patients followed in specialized HF units in Spain the differences in clinical characteristics and treatment between patients with HF and advanced CKD. Methods We analyzed data from the registry of the SEC-Excelente-IC quality accreditation program of the Spanish Society of Cardiology, with 1716 patients with HF included between 2019 and 2021 by 45 specialized HF units accredited by the SEC. Patients were included consecutively in two 1-month cutoffs (March and October) in that period. The clinical and demographic characteristics and comorbidities of the patients were compared according to GFR < or > 30ml/min/m2. Results Of the 1,716 patients, 11.1% had a GFR<30 and 88.9% >30 mL/min/m2. Figure 1 shows the main clinical characteristics and comorbidities of the 2 groups. Median LVEF was similar in both groups: 42 (30-58) vs 38% (29-54). The group with advanced CKD was older (77±9.6 vs 70.5±12.6 years; p<0.001), had greater HF severity (more admissions for HF in the last year, worse NYHA functional class and longer evolution time), and a higher prevalence of coronary heart disease, hypertension, diabetes mellitus, cognitive impairment, anemia, iron deficiency and hyponatremia. There were no differences in sex, BMI, serum potassium or other comorbidities (Figure 1). Figure 2 shows the treatment received in each group. Patients with GFR <30 received in a significantly lower proportion all drugs for HF (p<0.001), except diuretics and potassium binders (ACEI/ARA, sacubitril-valsartan, MRA, beta-blockers, digoxin and SLGT2 inhibitors), and less cardiac rehabilitation (5.2 vs 10.4%; p=0.029). Incidence of one-year mortality was significantly higher in patients with GFR<30 ml/min/m2 (37.2 vs 14.4 per 100 persons-year, p<0.001), as were HF hospitalizations (61.3 vs 33.0; p<0.001) and HF decompensations without hospitalization (24.1 vs 11; p<0.001). Conclusions In our contemporary cohort of real-life HF patients, the prevalence of advanced CKD was 11.1%. These patients had a higher severity of HF, despite which, the utilization of HF drugs, including SGLT2 inhibitors was much lower than in those with GFR >30 ml/min/m2. One-year mortality, HF hospitalization and HF decompensations were almost 3-times higher. This treatment trend needs to be modified to improve the prognosis of these patients.

Hyperkalemia burden and treatment patterns in Chinese patients on hemodialysis: final analysis of a prospective multicenter cohort study (PRECEDE-K)

Objectives Patients with end-stage renal disease (ESRD) on hemodialysis (HD) are at risk for hyperkalemia (HK), associated with cardiac arrhythmia and sudden death. Data on the burden of HK and management techniques among HD patients in China are still scarce. This study assessed the treatment modalities, recurrence, and prevalence of HK in Chinese HD patients. Methods In this prospective cohort study conducted from May 2021 to July 2022, patients aged ≥18 years who had ESRD and were on HD were enrolled from 15 centers in China (up to 6 months). Results Overall, 600 patients were enrolled. At the baseline visit, mean (± standard deviation) urea reduction ratio was 68.0% ± 9.70 and Kt/V was 1.45 ± 0.496. Over 6 months, 453 (75.5%) patients experienced HK, of whom 356 (78.6%) recurred. Within 1, 2, 3, 4, 5, and 6 months, 203 (44.8%), 262 (57.8%), 300 (66.2%), 326 (72.0%), 347 (76.6%), and 356 (78.6%) patients had at least one HK recurrence event, respectively. The proportions of patients with ≥1, 2, 3, 4, 5, or 6 HK recurrence events were 356 (78.6%), 306 (67.5%), 250 (55.2%), 208 (45.9%), 161 (35.5%), and 110 (24.3%), respectively. Among the 453 patients who experienced HK, only 24 (5.3%) were treated with potassium binders: seven (1.5%) with sodium polystyrene sulfonate, 13 (2.9%) with calcium polystyrene sulfonate, and six (1.3%) with sodium zirconium cyclosilicate. Conclusion Since HK is a chronic illness, long-term care is necessary. Patients on HD should have effective potassium management on non-dialysis days, yet our real-world population rarely used potassium binders. Trial registration ClinicalTrials.gov Identifier NCT04799067

Novel Potassium Binders for Early Postoperative Hyperkalemia in Kidney Transplant Recipients: A Single-Center Experience

PurposeEvaluate the safety/efficacy of novel potassium binders (patiromer, sodium zirconium cyclosilicate [SZ-9]) for early postoperative hyperkalemia following kidney transplantation. MethodsRetrospective, single-center, cohort study of deceased-donor kidney recipients transplanted between 1/2018 and 12/2020. Potassium-binder use was evaluated from immediately posttransplant until discharge. Potassium binders were administered ≥2 hours before/after medications. ResultsA total of 179 patients were included, 24 (13%) of whom received potassium binders (16 [67%] patiromer, 7 [29%] SZ-9, 1 [4%] both) for a mean of 2.5 (±3.18) doses. Peak potassium levels were higher in the potassium-binder group (6.05 vs 5.35 mEq/L; P < .001). More patients on potassium binders transitioned to atovaquone than those on no binders (n = 21 [100%] vs n = 112 [75%], respectively; P = .005). Delayed graft function (DGF) was observed in 100 (56%) patients, with a higher proportion receiving potassium binders (18 [75%] vs 82 [53%], respectively; P = .042). There was no difference between groups in number of posttransplant dialysis sessions required in the general study population (P = .2), nor in the DGF group (P = .12). No difference was noted in the incidence of ileus (P = .2), or gastrointestinal symptoms (diarrhea, nausea, vomiting; P = .6). Of the 24 patients who received inpatient binders, 9 (37.5%) were discharged and remained on them for a mean of 46 (±49) days. ConclusionPatiromer and SZ-9 appear safe in the early posttransplant period, but larger prospective trials are needed. Potassium-binder use does not appear to be associated with fewer dialysis sessions in DGF patients, however, they may be used as additional tools for lowering potassium in these patients.

Patiromer-Facilitated Renin-Angiotensin-Aldosterone System Inhibitor Utilization in Patients with Heart Failure with or without Comorbid Chronic Kidney Disease: Subgroup Analysis of DIAMOND Randomized Trial

Plain Language SummaryPatients with chronic kidney disease (CKD) can develop high potassium (hyperkalemia) levels in their blood that can lead to complications such as heart issues. Renin-angiotensin-aldosterone system inhibitors (RAASis) are used as treatment for heart failure and CKD, but can also cause hyperkalemia, so are underutilized and used at lower than optimal doses. Patiromer is a potassium binder which was investigated in the DIAMOND trial to identify if it could reduce hyperkalemia in patients receiving RAASis. Lower kidney function (eGFR) has been associated with a greater likelihood of stopping treatment with RAASis; therefore, this analysis assessed the effect of patiromer on patients with varying eGFR levels. Patiromer enabled use of effective RAASi doses, controlled the serum potassium levels and minimized hyperkalemia in patients with heart failure and CKD.

Hyperkalemia and risk of chronic kidney disease progression: A propensity score matched analysis.

Hyperkalemia is a known complication of chronic kidney disease (CKD); however, it is not known whether hyperkalemia directly contributes to CKD progression and the risk of death. Clarifying the extent to which hyperkalemia is associated with CKD progression and mortality can inform clinical practice and guide future research. The objective of this study was to quantify the risks of CKD progression and mortality associated with hyperkalemia in patients with stages 3b/4 CKD. This was a real-world, exact and propensity score-matched, observational cohort study using data (January 2016-December 2021) from Optum's deidentified Market Clarity Data, a large US integrated insurance claims/electronic medical record database. The study included matched adult patients with stages 3b/4 CKD with and without hyperkalemia, not regularly treated with an intestinal potassium (K+) binder. Measured outcomes were CKD progression and all-cause mortality. CKD progression was defined as diagnosis of CKD stage 4 (if stage 3b at index), CKD stage 5 or kidney failure, or receipt of dialysis or kidney transplantation. After matching, there were 6,619 patients in each of the hyperkalemia and non-hyperkalemia cohorts, with a mean (standard deviation) follow-up time of 2.12 (1.42) years. Use of any renin-angiotensin-aldosterone system inhibitors (RAASi) during baseline was common (75.9%) and most patients had CKD stage 3b (71.2%). Patients with hyperkalemia had a 1.60-fold (95% confidence interval [CI] 1.50, 1.71) higher risk of CKD progression and a 1.09-fold (1.02, 1.16) higher risk of all-cause mortality relative to patients without hyperkalemia. Relative risks of CKD progression associated with hyperkalemia were similar within the subset of patients receiving RAASi and across CKD stages, and when alternative definitions of CKD progression were used. Patients with CKD stages 3b/4 and hyperkalemia experienced significantly higher risks of CKD progression and all-cause mortality than propensity score-matched patients without hyperkalemia.

Risk of Serious Adverse Gastrointestinal Events with Potassium Binders in Hospitalized Patients: A National Study.

Concerns about serious adverse gastrointestinal (GI) events with sodium polystyrene sulfonate (SPS) led to development of two new potassium binders, patiromer and sodium zirconium cyclosilicate (SZC), for treatment of hyperkalemia. To compare risk of intestinal ischemia/thrombosis or other serious GI events associated with SPS, patiromer, or SZC in hospitalized patients. Retrospective cohort study. National sample of 3,144,960 veterans hospitalized 2016-2022 in the U.S. Department of Veterans Affairs Healthcare System. Demographics, comorbidities, medications and outcomes were ascertained from the VA Corporate Data Warehouse. Exposures were SPS, patiromer, SZC. Outcomes were 30-day intestinal ischemia/thrombosis, and a composite of intestinal ischemia/thrombosis, peptic ulcer/perforation or bowel resection/ostomy. Potassium binders were used during 39,270 (1.3%) hospitalizations: SPS = 30,040 (1.0%), patiromer = 3,750 (0.1%), and SZC = 5,520 (0.2%). Intestinal ischemia/thrombosis occurred with 106/30,040 (0.4%) SPS, 12/3750 (0.3%) patiromer and 24/5520 (0.4%) SZC, vs. 6998/3,105,650 (0.2%) without potassium binder. Adjusted odds ratios (aOR) were 1.40 [95% CI, 1.16 to 1.69] with SPS, 1.36 [CI, 0.79 to 2.36] with patiromer, and 1.78 [CI, 1.21 to 2.63] with SZC exposures. Composite GI adverse events occurred with 754/30,040 (2.5%) SPS, 96/3750 (2.6%) patiromer, 2.6% SZC, vs. 144/5520 (2.4%) without binder; aOR were 1.00 [CI, 0.94 to 1.08] with SPS, 1.08 [CI, 0.89 to 1.32] with patiromer, and 1.08 [CI, 0.93 to 1.27] with SZC exposures. No statistical difference in intestinal ischemia/thrombosis between each new agent and SPS was seen (p = 0.274 for SPS vs. SZC; p = 0.916 for SPS vs. patiromer). Risk of intestinal ischemia/thrombosis or other serious adverse GI events was low and did not differ across three potassium-binding drugs.

Plant-based diet in hyperkalemic chronic kidney disease patients receiving sodium zirconium cyclosilicate: a feasibility clinical trial

BackgroundPlant-based diets (PBD) may induce hyperkalemia in chronic kidney disease (CKD) patients. ObjectivesWe explored the safety and feasibility of PBD in hyperkalemic CKD patients receiving the potassium binder sodium zirconium cyclosilicate (SZC). MethodsIn the current 6-wk trial, 26 hyperkalemic patients with CKD stage 4–5 not on dialysis received a low-protein low-potassium diet plus SZC for 3 wk and then a PBD with high potassium content delivered as a weekly food basket while continuing SZC for subsequent 3 wk. Plasma potassium was monitored weekly and SZC was titrated to achieve normokalemia. The 24-h urine excretion of potassium and sodium, 24-h food records, dietary quality, nutritional status, Bristol stool scale, Quality of life (QoL), and renal treatment satisfaction were assessed at baseline (week 0), week 3, and week 6. ResultsMean plasma potassium decreased from 5.5 to 4.4 mEq/L within 48–72 h after baseline, then rose to 4.7–5.0 mEq/L throughout the remaining study period following dose adjustments of SZC that matched the increased potassium intake of PBD from week 3 to week 6. Over the study period, 24-h urinary potassium excretion decreased from week 0 to week 3 and increased from week 3 to week 6. During the study, 58% of patients had fasting plasma potassium between 3.5 and 5.0 mEq/L and there was no episode of plasma potassium >6.5 mEq/L or <3.0 mEq/L during the study. P-carbon dioxide increased from baseline until week 6 (21 ± 2 to 23 ± 2 mEq/L; P = 0.002; mean ± SD), whereas remaining laboratory values remained unchanged. Fiber intake, dietary quality, the domain physical functioning from QoL, and 1 question of renal treatment satisfaction improved, whereas stool type and frequency did not change after starting PBD. ConclusionsPBD in hyperkalemia-prone CKD patients receiving SZC improved dietary quality and increased the intake of healthy foods, whereas plasma potassium concentration remained stable within normal values for most patients. Trial registration numberThis trial was registered at the https://clinicaltrials.gov/study/NCT04207203 as NCT04207203.

The Effect of Renastart Formula Supplementation in Serum Electrolytes in Children with Acute Kidney Injury

Abstract Background patients of renal disease suffer from electrolyte disturbances including hyperkalemia, hyperphosphatemia, hyponatremia, hypocalcemia and hypermagnesemia. Unfortunately, patients with kidney disease require close monitoring for serum electrolytes to maintain normal levels; with traditional nutritional interventions they may need receiving potassium and phosphorus binders Aim: This study will concentrate on the effect and tolerability of Renastart formula supplementation on correction and maintaining serum levels of electrolytes in AKI or AKI on top of CKD pediatric patients. Methods Double arm clinical convenient trial, conducted in Pediatric Nephrology Unit,Ain Shams University, Cairo, Egypt, where 24 participants who had AKI or AKI on top of CKD with hyperphosphatemia and / or hyperkalemia were recruited, the mean of age of participants was 4.1±3.15 years ranged from 0.5 to 10 years. Subjects were divided into two groups, 12 patients per group (group A received a calcium carbonate (phosphorus binder) (9 patients) with dosage 45-65 mg/kg/day orally alone or withsodium polystyrene sulfonate (potassium binder) (11 patients) with dosage 0.5-1mg/kg/day oral and group B received Renastart formula supplemented with breast milk, standard infant formula or diet), the dosage ratio was adjusted to be 1:3 (Renastart was 1/4 daily caloric intake) if serum potassium level ≥5.5 - &amp;lt;6 meq/L and / or serum phosphorus &amp;gt; 7mg/dl. But, if potassium level was ≥ 6 meq/L, the ratio was 1:1 (Renastart was ½ daily caloric intake). Readjusting dosage ratio was according to serum electrolyte levels response for treatment. Follow up of serum levels of potassium was every day until its serum level returned to normal then every month for three months and serum phosphorus was every month for three consecutive months. Results All the included subjects in both groups had high serum potassium (&amp;gt; 5.5 meq/L) and / or high serum phosphorus (&amp;gt;7 mg/dl) upon enrollment, mean serum potassium and serum phosphorus were (5.7±0.41 meq/L) (7.2±1.6 mg/dl) respectively. Regarding the decrease of serum potassium, Renastart formula supplementation in group B and potassium binders in group A resulted in equal decrease in serum potassium levels; Potassium after 3 months of management in group B was (4.22±0.28 mEq/L) (p value between 3rd month- baseline month in group B p &amp;lt; 0.01) and potassium binders in group A (4.48±0.27 mEq/L) (p value between 3rd month – baseline month in group A p &amp;lt; 0.01). Renastart formula in group B ((potassium after 1 month of management = 4.7±0.32 meq/L) (p value between 1st month – baseline month in group B p &amp;lt; 0.01)) had more rapid effect than potassium binders in group A during 1st month of the study ((potassium after 1 month of management =5.1±0.41 meq/L) (p value between 1st month – baseline month in group A p &amp;gt; 0.05). Regarding decrease in serum phosphorus, Renastart formula supplementation in group B resulted in more decrease in serum phosphorus levels though both showed significant drop in phosphorus level (( serum phosphorus after 3 months of management = 4.60±0.29 mg/dl (p value between 3rd month – baseline month in group B p = 0.002)) in comparison to that achieved by phosphorus binders in group A ((5.21±0.29mg/dl) (p value between 3rd month – baseline month in group A p = 0.01)), moreover Renastart supplementation in group B was more rapid than phosphorus binders in group A in decrease serum phosphorus (p value between 1st month and baseline in group B p = 0.002) (p value between 1st month and baseline in group A p = 0.17) Conclusion We can conclude that Renastart formula supplementation was more rapid than potassium binders in decreasing serum potassium levels in AKI pediatric patients, moreover more effective and rapid than phosphorus binders in decreasing serum phosphorus.

Comparative effectiveness of an individualized model of hemodialysis vs conventional hemodialysis: a study protocol for a multicenter randomized controlled trial (the TwoPlus trial)

BackgroundMost patients starting chronic in-center hemodialysis (HD) receive conventional hemodialysis (CHD) with three sessions per week targeting specific biochemical clearance. Observational studies suggest that patients with residual kidney function can safely be treated with incremental prescriptions of HD, starting with less frequent sessions and later adjusting to thrice-weekly HD. This trial aims to show objectively that clinically matched incremental HD (CMIHD) is non-inferior to CHD in eligible patients.MethodsAn unblinded, parallel-group, randomized controlled trial will be conducted across diverse healthcare systems and dialysis organizations in the USA. Adult patients initiating chronic hemodialysis (HD) at participating centers will be screened. Eligibility criteria include receipt of fewer than 18 treatments of HD and residual kidney function defined as kidney urea clearance ≥3.5 mL/min/1.73 m2 and urine output ≥500 mL/24 h. The 1:1 randomization, stratified by site and dialysis vascular access type, assigns patients to either CMIHD (intervention group) or CHD (control group). The CMIHD group will be treated with twice-weekly HD and adjuvant pharmacologic therapy (i.e., oral loop diuretics, sodium bicarbonate, and potassium binders). The CHD group will receive thrice-weekly HD according to usual care. Throughout the study, patients undergo timed urine collection and fill out questionnaires. CMIHD will progress to thrice-weekly HD based on clinical manifestations or changes in residual kidney function. Caregivers of enrolled patients are invited to complete semi-annual questionnaires. The primary outcome is a composite of patients’ all-cause death, hospitalizations, or emergency department visits at 2 years. Secondary outcomes include patient- and caregiver-reported outcomes. We aim to enroll 350 patients, which provides ≥85% power to detect an incidence rate ratio (IRR) of 0.9 between CMIHD and CHD with an IRR non-inferiority of 1.20 (α = 0.025, one-tailed test, 20% dropout rate, average of 2.06 years of HD per patient participant), and 150 caregiver participants (of enrolled patients).DiscussionOur proposal challenges the status quo of HD care delivery. Our overarching hypothesis posits that CMIHD is non-inferior to CHD. If successful, the results will positively impact one of the highest-burdened patient populations and their caregivers.Trial registrationClinicaltrials.gov NCT05828823. Registered on 25 April 2023.

#1802 Treatment with potassium binders in central Sweden—an observational study based on the DEMONSTRATE database

Abstract Background and Aims Hyperkalemia (HK), defined as a plasma potassium level (&amp;gt; 5.0 mmol/L), is associated with adverse outcomes, including cardiac arrhythmias and mortality. Until recently, HK was managed mainly with sodium polystyrene sulfonate (SPS) (first generation potassium binders) but concerns regarding the safety profile warranted new alternatives. The second-generation potassium binders, patiromer and sodium zirconium cyclosilicate (SZC) were introduced in Sweden in 2018 and 2019 respectively. The aim of this observational study was to understand the current use of new potassium binders, the related potassium values triggering treatment and to describe the clinical characteristics of patients treated with first- and second-generation potassium binders (SPS and patiromer/SZC respectively) in Sweden. Method An observational study based on laboratory data from six regions in central Sweden (18% of the Swedish population), linked to national health registry data, comprising information on clinical events and pharmacy drug dispensations. All treatment episodes of potassium binders between 01 July 2005 and 31 December 2022 were selected and restricted to patients with information on potassium values. A new treatment episode was defined as a gap of at least 120 days to the prior pharmacy dispensations of potassium binders. We analyzed potassium values (up to 60 days prior to initiation of potassium binders), demographics, comorbidities and treatments. Results are mainly presented by treatment episodes and strata of; (a) all, (b) first- and (c) second-generation potassium binders. Results In total, we identified 13 441 treatment episodes of which 13 218 episodes (n = 7086 individuals), were attributed to first generation potassium binders (throughout the study period) and 223 episodes (n = 151 individuals) to second-generation potassium binders (from 2018-2022) (Table 1). Baseline characteristics are presented by treatment episodes. Baseline potassium value prior to treatment was 5.6 (0.8) mmol/L for first and 5.6 (0.7) for second generation potassium binders. Mean eGFR prior to treatment was 22.3 (16.3) ml/min/1.73 m2 for first and 18.7 (16.0) for second-generation potassium binders. Compared to first generation, second-generation potassium binders were prescribed to patients with more comorbidities (41.7% vs 32.1% for heart failure, 88.3% vs 81.7% for hypertension, and 39.5% vs 28.9% for dialysis) and more frequently from cardiology/internal medicine units (41.7% vs 30.0%). Distribution of potassium levels at baseline is shown in Fig. 1. Conclusion Compared to first- generation potassium binder, we observed fewer treatment episodes with second generation potassium binders, of which majority had a more severe comorbidity profile. There was no difference in potassium values prior to treatment between first- and second-generation potassium-binders.

#1926 Persistence to first- and second- generation potassium binder treatment—an observational study based on the DEMONSTRATE database

Abstract Background and Aims Hyperkalemia (HK) is a common electrolyte abnormality mainly caused by reduced renal potassium excretion in patients with chronic kidney disease (CKD). Potassium binders, such as sodium polystyrene sulfonates (SPS) are widely used but may lead to adverse gastrointestinal (GI) symptoms, reducing their tolerability. Patiromer and sodium zirconium cyclosilicate (SZC) are newer ion exchange resins for treatment of HK which may cause fewer GI side-effects. This study aims to evaluate the persistence to first- (SPS) and second-generation potassium binder (patiromer and SZC) treatment and the related clinical characteristics. Method In this observational study based on the DEMONSTRATE database, a novel national and regional database comprising laboratory data from six regions in central Sweden (18% of the Swedish population), linked to the national health registry data, we selected all patients in Sweden having at least one pharmacy dispensation of either first (SPS) or second (patiromer or SZC) generation potassium binder between July 2005 and December 2022. By semi-automatically interpreting the prescribed dosages in combination with the amount of medical supply, duration for each dispensation was estimated and episodes of potassium binder treatments were established. For all potassium binder episodes, we described patient characteristics and persistence to treatment. Results are mainly presented by treatment episodes and by strata of (a) all, (b) first and (c) second generation potassium binders. Results Between July 2005 and December 2022, we identified 68 133 treatment episodes of potassium binders for 32 424 patients (Table 1). Of these, 31 730 individuals and 66 309 treatment episodes were attributed to first generation (throughout the study period), and 1,276 individuals and 1,824 treatment episodes to second-generation potassium binders (between 2018-2022) Mean (SD) age was slightly lower in patients initiating second compared to first generation potassium binders; 68.5 (15.6) vs 65.2 (16.6) years. Potassium binder treatment was more common in men compared to women (66.9% vs. 33.1%) with similar gender distribution between first- and second-generation potassium binders. Comorbidities were more common in patients initiating treatment with second than first generation potassium binders, notably for heart failure (40.0% vs. 29.7%) and dialysis (38.8% vs 29.2%). RAASi and MRA were more often prescribed to the second generation potassium binders vs first; 70.8% vs 62.9% for RAASi and 18.8% vs. 8.5% for MRA. Second generation potassium binders were more commonly initiated in cardiology/internal medicine units (41.7% vs. 34.8%) and dialysis (38.8% vs. 29.2%). Persistence was higher among patients treated with second generation potassium binders (Fig. 1). Conclusion Second generation potassium binders were more often prescribed to younger patients that had more co-morbidities being slightly more persistent to treatment when compared to patients on first generation potassium binders.

#2341 WS016, a novel potassium binder: safety, tolerability and pharmacodynamics in first-in-human phase 1 healthy volunteer study

Abstract Background and Aims Hyperkalemia is a common and potentially serious medical condition in patients with chronic kidney disease and is associated with high rates of mortality. Partiromer and Lokelma are available recently, however, edema is the common adverse event resulted from the exceed sodium exchanged by Lokelma and constipation, hypomagnesemia are frequently found using Partiromer because of the basic structure of them. WS016 is a highly selective, non-absorbed, cation-exchange polymer binder with the potential characteristics of no edema and hypomagnesemia. The objective of the trials was to assess the safety/tolerability and pharmacodynamics (PD) profiles of WS016. Method This is a randomized, double-blind, placebo-controlled phase 1 clinical trial. 40 healthy volunteers were randomized (6:2 randomization within a cohort) into five different cohorts administered with 6 g, 12 g, 24 g, 36 g, 48 g WS016 orally once daily for only one dose during the single dose ascending (SAD) stage and 24 healthy volunteers were randomized (6:2 randomization within a cohort) into three different cohorts administered with 12 g, 36 g, 48 g orally once daily for consecutive seven days during the multiple dose ascending(MAD) stage. Adverse events (AE) were collected, and physical examination, laboratory tests were done at baseline and different visits according to the protocol. Urinary potassium and fecal potassium were collected, tested and calculated per 24 hour. Serum potassium was evaluated alone with the timing after administration of WS016 in different cohort. Results Data of subjects from different placebo cohorts were pooled together for analysis in SAD and MAD stage. 40 healthy volunteers, including 6 in different WS016 cohorts and 10 in placebo cohort completed the SAD trial. 9, 5, 6, 7, 12 grade 1 AEs were reported from 12-48 g WS016 cohorts, respectively; 11 AEs were reported from placebo cohort and 1 is grade 2 AE. Totally, 5 cases with hypertriglyceridemia, 4 cases with prolonger activated partial thromboplastin time (APTT), 4 cases with decreased blood fibrinogen, 3 cases with sinus bradycardia were reported from WS016 cohort and 2 cases with hypertriglyceridemia, 1case with prolonged APTT, 1 case with decreased fibrinogen were reported from placebo cohort. 24 healthy volunteers, 6 from different WS016 cohorts and 6 from placebo cohort completed the MAD trial. 12, 10, 12 AEs were reported from 12 g, 24 g, 48 g cohort, respectively and 6 AEs were from placebo cohort. Only 1 AE as hypertriglyceridemia from 24 g cohort is grade 2, while others are grade 1. 5 cases with sinus bradycardia, 4 cases with hypertriglyceridemia, 3 cases with hyperuricacidemia, 3 cases with hypotension, 3 cases with prolonged APTT were reported from all WS016 cohort totally and 1 cases with hyperuricacidemia,1 cases with hypotension, 1 cases with prolonged APTT were reported from placebo cohort. There is no AE related to gastrointestinal tract and no side effects on the other electrolytes such as magnesium, calcium, sodium and phosphorus, reported from both SAD and MAD. It was found that fecal potassium excretion increased and urinary potassium decreased on D2 in SAD (Fig. 1) and on D7 in MAD (Fig. 2) compared to baseline. The serum potassium decreased quickly at about 1-2 hour after first administration of WS016 both in SAD and MAD (Figs 1 and 2) and the mean serum potassium of placebo cohort is higher than that in other WS016 cohorts during MAD (Fig. 2). Conclusion WS016 was generally well-tolerated following single doses and multiple doses. The AEs like constipation, hypomagnesemia commonly found in Patiromer and edema commonly found in Lokelma were not reported in WS016 cohorts. In accordance to the results from pre-clinical studies, the clinical pharmacodynamics characteristics was the increased fecal potassium along with the decreased urinary potassium, meanwhile the serum potassium decreased, especially during the first 4 hours after administration of WS016 although in the normal range among the healthy volunteers.

#1287 Duration of sodium zirconium cyclosilicate treatment and continuation of RAASi therapy after a hyperkalaemia episode

Abstract Background and Aims Renin-angiotensin-aldosterone system inhibitor (RAASi) therapy is foundational in the management of chronic kidney disease (CKD) and heart failure (HF) but increases the risk of hyperkalaemia (HK). Current guidelines recommend continuation of RAASi therapy while managing risk of HK using novel potassium binders, such as sodium zirconium cyclosilicate (SZC). This study describes the likelihood of continued RAASi therapy after a HK episode by SZC treatment duration in routine clinical practice across three countries. Method This observational study used contemporary data from healthcare registries and claims in the US, Japan and Spain, and included non-dialysis patients diagnosed with CKD and/or HF who initiated outpatient treatment with SZC while on RAASi therapy. The duration of SZC treatment and continuation of RAASi therapy were described using the Kaplan–Meier method. The association between time on SZC treatment and continuation of RAASi therapy is being analysed by applying Hernàn's randomised trial emulation approach (using cloning, censoring and weighting) to avoid the risk of immortal time bias. A weighted Kaplan–Meier method with bootstrapping will be used to estimate the likelihood of continued RAASi treatment at, e.g. 180 days by SZC treatment duration strategy, e.g. 1–30, 31–60 days, etc. The corresponding association will be evaluated using the z-test where the estimated probabilities are compared between strategies. Results This study included 4008 patients who initiated outpatient treatment with SZC, across the US (3137), Japan (655) and Spain (216). For the US, Japan and Spain, respectively, mean age was 72.9, 76.0 and 72.6 years; 54.4%, 62.9% and 58.3% were male; 95.8%, 71.9% and 94.4% had CKD; and 39.8%, 79.1% and 36.1% had HF. In the US, 31.5% (95% CI 29.8–33.2%) were treated with SZC for at least 60 days, and 14.4% (95% CI 13.1–15.8%) were treated for at least 120 days. Among US patients still on SZC treatment at 120 days, 84.0% (95% CI 81.2–86.8%) remained on RAASi therapy at that time, while the corresponding value for all SZC initiators, including those who discontinued SZC earlier, was 65.5% (63.7–67.3%). In Japan, 32.2% (95% CI 28.6–36.2%) were treated with SZC for at least 120 days and, of these, 92.3% (95% CI 89.3–95.4%) remained on RAASi therapy at that time. Among all SZC initiators (including the early discontinuers), 78.4% (95% CI 75.1–81.8%) remained on RAASi therapy at 120 days. In Spain, most patients (78.0% [95% CI 72.2–84.2%]) were treated with SZC for at least 120 days, and 84.6% (95% CI 79.4–90.2%) of these patients remained on RAASi therapy at that time. Analyses of the likelihood of continued RAASi treatment by SZC treatment duration strategy using Hernàn's approach are currently ongoing and will be presented at the congress. Conclusion This study provides contemporary insights into the management of HK with the novel potassium binder SZC across three different countries and demonstrates that duration of SZC treatment is positively associated with continued guideline-directed RAASi therapy after a HK episode.

#1302 Maintained renin-angiotensin-aldosterone system inhibitor therapy with sodium zirconium cyclosilicate in patients with chronic kidney disease

Abstract Background and Aims Hyperkalaemia is a barrier to achieving guideline-directed renin-angiotensin-aldosterone system inhibitor (RAASi) therapy. This observational cohort study compared the likelihood of maintained (stabilised or up-titrated) RAASi therapy at 6 months following an episode of hyperkalaemia in patients with chronic kidney disease (CKD) from the US and Japan, in patients who were treated with sodium zirconium cyclosilicate (SZC) for at least 120 days, relative to those with no potassium (K+) binder prescription. Method Using data from healthcare registers and hospital medical records, patients with CKD receiving RAASi therapy who had an episode of hyperkalaemia in an inpatient or outpatient care setting were identified. Propensity score (PS) matching (up to 1:4) was applied to balance the SZC cohort to a No K+ binder cohort on baseline characteristics. The proportions of patients in each cohort who had discontinued, down-titrated, stabilised or up-titrated their RAASi treatment at 6 months were described, with P values for differences between cohorts calculated using Chi-squared tests. Logistic regression analysis was performed to compare the odds of maintained RAASi therapy at 6 months in the SZC versus No K+ binder cohorts, and a meta-analysis across countries was performed using a random effects model. Results After PS-matching, the SZC cohorts included 530 (US) and 211 (Japan) patients, and the No K+ binder cohorts included 1937 and 711 patients, respectively. Mean ages of patients were 72 (US) and 74 (Japan) years, and 44% and 30% were females, respectively. Most US patients had CKD Stage 3−4 (∼89%), while CKD Stage 5 was more common in Japan (∼47% of patients). Comorbid heart failure was less common in the US than in Japan (∼33% versus ∼74%, respectively). The proportions who discontinued RAASi therapy at 6 months were consistently lower in the SZC cohorts than in the No K+ binder cohorts in both countries (Table). At 6 months, 69.8% (US) and 79.6% (Japan) of the SZC cohorts had maintained their RAASi therapy, while corresponding proportions for the No K+ binder cohorts were 53.6% (US) and 52.6% (Japan). The odds ratios (95% confidence interval) for maintained RAASi therapy in the SZC cohort versus the No K+ binder cohort were 2.09 (1.70–2.58) in the US and 3.54 (2.43–5.17) in Japan; the meta-analysed odds ratio was 2.65 (1.62–4.34). Conclusion In contemporary routine clinical practice of patients with CKD, the likelihood ofstabilised or up-titrated RAASi therapy at 6 months following an episode of hyperkalaemia was substantially higher in patients treated with SZC for at least 120 days versus those with no prescribed K+ binder treatment. These data demonstrate the potential for SZC to facilitate maintained, guideline-concordant RAASi therapy following an episode of hyperkalaemia to achieve optimal treatment outcomes in patients with CKD.

#1303 Hyperkalaemia-related RAASi reduction and estimated number needed to treat to avoid a first hospitalisation by maintaining RAASi

Abstract Background and Aims Guidelines recommend renin-angiotensin-aldosterone system inhibitor (RAASi) therapy at the maximum tolerated dose in patients with chronic kidney disease (CKD) and/or heart failure (HF). Hyperkalaemia (HK) may be a barrier to achieving guideline-directed targets, with RAASi treatment often being down-titrated or discontinued in patients who experience HK. Guidelines suggest targeted anti-HK management with potassium binders to facilitate maintained RAASi. In patients with CKD and/or HF, we describe the extent of HK-related RAASi reduction. To provide clinicians with a sense of magnitude of impact, we estimate the ‘number needed to treat’ (NNT) to avoid a first hospitalisation if RAASi had been maintained at prior dose. Method This observational cohort study used contemporary data from four European countries (Germany, Spain, Sweden, UK). The population included non-dialysis patients diagnosed with CKD and/or HF who had an index HK episode (defined as a recorded HK diagnosis or potassium &amp;gt;5.0 mmol/L) while on RAASi therapy. Patients were defined as having reduced (down-titrated or discontinued) vs maintained RAASi treatment based on their most recent prescriptions, or lack thereof, within 120 days before vs after the index HK episode. Those who died within the first 120 days post index HK were excluded to avoid misclassification bias. Propensity score (PS) matching was applied to balance the groups on baseline characteristics. Patients were followed for 6 months after the index HK event. The risk of an all-cause hospitalisation in patients who reduced vs maintained RAASi was assessed at 6 months using the Kaplan–Meier method. The NNT framework was applied to estimate the number of patients who would need to have maintained instead of reduced their RAASi therapy to avoid a firsthospitalisation during this period. Results By Dec 2023, the study includes a total of 33,009 patients with CKD and/or HF from Germany (N = 11,199), Spain (N = 4406) and Sweden (N = 17,404); UK data extraction is in progress. Presence of CKD at baseline was similar across countries (77–85%), while HF was more common in Germany (70%) and Sweden (55%) than in Spain (18%). After the index HK episode, RAASi therapy was reduced (down-titrated or discontinued) in 25–44% of patients. Following PS matching (available from Spain and Sweden), the 6-month risk of at least one all-cause hospitalisation was consistently higher in those with reduced relative to maintained RAASi (Table). Data suggest that a first hospitalisation within 6 months could potentially have been avoided if 20–24 patients had maintained instead of reduced their RAASi. Conclusion Despite current guidelines recommending targeted anti-HK management with potassium binders to facilitate maintained RAASi treatment, HK is still associated with frequent down-titration or discontinuation of RAASi therapy in clinical practice. Following PS matching and using the NNT framework, our data suggest a potential for avoiding a firsthospitalisation, even within a short time frame, by increasing guideline adherence to maintain instead of reducing RAASi after a HK episode.

#2011 Reduced hospitalisation or emergency department visits with long- versus short-term SZC in patients with history of hyperkalaemia: GALVANIZE Outcomes

Abstract Background and Aims Hyperkalaemia is associated with increased healthcare resource use and often requires long-term management. The GALVANIZE Outcomes study is a comparison of hyperkalaemia-related and all-cause hospitalisations or emergency department visits between matched patients treated with long- or short-term sodium zirconium cyclosilicate (SZC), using real-world data. This analysis evaluated outcomes in patients with a history of hyperkalaemia. Method A large US insurance claims database (from HealthVerity) was used to identify adults who initiated SZC (index date) in the outpatient setting between 1 January 2019 and 30 June 2022, with a diagnosis of hyperkalaemia within 6 months prior to the index date. Exclusion criteria included patients without either 6 months of continuous insurance coverage prior to index, or 30 days of continuous insurance coverage post-index. Patients were followed to the earliest of 6 months post-index, loss of coverage, end of the study period or (re) initiation of a potassium binder. Patients with short-term SZC use (≤30 days) were exact and propensity score–matched to patients with long-term SZC use (&amp;gt;90 days). Hyperkalaemia-related hospitalisations and emergency department visits were identified by the International Classification of Diseases (tenth revision) diagnosis code for hyperkalaemia. Rates of the composite outcomes of the number of hyperkalaemia-related hospitalisations or emergency department visits (primary endpoint) and all-cause hospitalisations or emergency department visits (exploratory endpoint) per person-year (PPY) were compared during follow-up using generalised estimating equations. Results Among 2088 eligible matched pairs with a history of hyperkalaemia, the mean age was 63.8 years and 41.4% of the population was female. Most patients (94.9%) had a diagnosis of chronic kidney disease, which mostly included stage 3 (27.3%), stage 4 (25.4%) and stage 5/end-stage (38.7%) kidney disease, while one-third (34.4%) had a diagnosis of heart failure irrespective of ejection fraction. The median (interquartile range) duration of follow-up was 183 (183, 183) days for long-term SZC and 169 (82, 183) days for short-term SZC. During follow-up, in patients with a history of hyperkalaemia, those with long-term SZC use had a 43% lower rate of hyperkalaemia-related hospitalisations or emergency department visits than matched patients with short-term SZC use (rate [95% confidence interval] PPY: 0.89 [0.79–0.98] vs 1.56 [1.35–1.76]; P&amp;lt;0.001) (Fig. 1). Similarly, patients with long-term SZC use had a 35% lower rate of all-cause hospitalisations or emergency department visits than those with short-term SZC use (2.63 [2.44–2.82] vs 4.05 [3.71–4.40]; P&amp;lt;0.001]) (Fig. 2). Conclusion In this real-world study of patients with hyperkalaemia, individuals treated with long-term SZC experienced significantly lower rates of hyperkalaemia-related and all-cause hospitalisations or emergency department visits compared with matched patients with short-term SZC use.