System Inhibitor Therapy Research Articles

Hyperkalemia and maintenance of renin-angiotensin system inhibitor therapy after initiating SGLT-2 or DPP-4 inhibitors.

Post-hoc analyses of clinical trials suggest that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) lower the risk of hyperkalemia and facilitate the use of renin-angiotensin system inhibitors (RASi) in people with type 2 diabetes. Whether this is also observed in routine care is unclear. We investigated whether SGLT-2i lowered the risk of hyperkalemia and RASi discontinuation as compared to dipeptidyl peptidase 4 inhibitors (DPP-4i). Using the target trial emulation framework, we studied adults with type 2 diabetes (T2D) who started SGLT-2i or DPP-4i in Stockholm, Sweden (2014-2021). The outcomes were incident hyperkalaemia (potassium>5.0 mmol/L), mild hyperkalemia (potassium>5-≤5.5mmol/L) and moderate to severe hyperkalemia (potassium>5.5mmol/L). Among RASi users, we studied time to RASi discontinuation through evaluation of pharmacy fills. Cox regression with inverse probability of treatment weighting was used to estimate per-protocol hazard ratios (HRs). 29 849 individuals (15 326 SGLT-2i and 14 523 DPP-4i initiators) were included (mean age 66 years, 37% women). About one third of participants in each arm discontinued treatment within a year. Compared with DPP-4i, SGLT-2i use was associated with a lower rate of hyperkalemia (HR 0.77; 95% CI: 0.64-0.93), including both mild (0.76; 0.62-0.93) and moderate/severe (0.53; 0.40-0.69) hyperkalemia events. Of 19.116 participants that used RASi at baseline, 7% discontinued therapy. Initiation of SGLT-2i vs. DPP-4i was not associated with the rate of RASi discontinuation (0.97; 0.83-1.14). Results were consistent in intention-to-treat analyses and across strata of age, sex, cardiovascular comorbidity, and baseline kidney function. In patients with diabetes managed in routine clinical care, the use of SGLT-2i was associated with lower rates of hyperkalemia compared with DPP-4i. Possibly because of a relatively high rate of treatment discontinuations, this was not accompanied by higher persistence on RASi therapy.

Cystatin C vs creatinine eGFR in advanced CKD: an analysis of the STOP-ACEi trial

ABSTRACT Background In this secondary analysis of the STOP-ACEi trial, we explored the impact of discontinuing or continuing renin–angiotensin system inhibitor therapy in people with advanced chronic kidney disease on cystatin C estimated glomerular filtration rate (eGFR). Methods Cystatin C eGFRs were calculated at baseline, 12, 24 and 36 months using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin 2012, European Kidney Function Consortium and CKD-EPI Combined 2021 equations. We excluded samples obtained after the initiation of kidney replacement therapy. Primary analysis used complete case analysis and mixed-effects linear regression model, adjusting for minimization variables, baseline value, time-point and treatment by time interaction. Sensitivity analysis was conducted using a pattern mixture model to account for missing data that was not at random. To model the longitudinal cystatin C data with time-to-event data, a joint model was utilized which incorporated the cystatin C measurements at various time points and accounted for the occurrence of kidney replacement therapy. Results The mean cystatin C eGFRs (CKD-EPI 2012) at baseline were 17.8 mg/L [standard deviation (SD 6.3)] and 17.9 mL/min/1.73 m2 (SD 6.3) in the STOP and CONTINUE arms, respectively. The estimated least squares mean difference at 12 months between STOP and CONTINUE arm was –1.46 [95% confidence interval (CI) –2.39 to –0.52, P = .002]. The estimated least squares mean difference at 24 months was –2.27 (95% CI –3.48 to –1.06, P < .001). The estimated least squares mean difference at 36 months was –1.72 (95% CI –3.48 to 0.03, P = .05). Conclusion Our results are consistent with the primary study's analysis and sensitivity analyses support these findings and provide additional insights. Our findings demonstrate the similarity of creatinine and cystatin eGFR results and therefore support the use of cystatin C as an alternative marker of eGFR in advanced CKD, particularly in those in whom creatinine is likely to be less accurate.

Hyperkalemia-Related RAASi Reduction and Estimated Number Needed to Treat to Avoid a First Hospitalization by Maintaining RAASi.

Renin-angiotensin-aldosterone system inhibitor (RAASi) therapy provides cardiorenal protection but is often down-titrated or discontinued following a hyperkalemia episode. This observational study describes the extent of hyperkalemia-related RAASi reduction in patients with chronic kidney disease (CKD) and/or heart failure (HF), and estimates the number needed to treat (NNT) to avoid a first hospitalization if RAASi had been maintained at the prior dose. Healthcare registers and claims data from Germany, Spain, Sweden, and the UK were used to identify non-dialysis patients with CKD and/or HF who had a hyperkalemia episode while on RAASi. Patients whose RAASi therapy was reduced (down-titrated/discontinued) after the hyperkalemia episode were propensity score (PS)-matched to those with maintained RAASi, and their risks of a hospitalization within 6 months were estimated using the Kaplan-Meier method. Based on the absolute difference in this 6-month risk, the NNT framework was applied to estimate the number of patients who needed to have maintained instead of reduced their RAASi to avoid a first hospitalization during this period. Overall, 40,059 patients from Germany, Spain, Sweden, and the UK were included. Presence of CKD at baseline was similar across countries (72%-92%), while HF was less common in Spain (18%) versus other countries (32%-71%). After the hyperkalemia episode, RAASi was reduced in 25%-57% of patients. Following PS matching, the 6-month risk of hospitalization was consistently higher in those with reduced versus maintained RAASi; the absolute risk difference ranged from 2.7% to 7.3%. Applying the NNT framework, these data suggest that a first hospitalization within 6 months could potentially have been avoided if 25 patients had maintained instead of reduced their RAASi. Our findings suggest a potential for avoiding a first hospitalization, even within a short time frame, by increasing adherence to guidelines to maintain instead of reduce RAASi after a hyperkalemia 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 >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.

#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.

#1021 A phase 3 randomized controlled trial of ravulizumab in adult patients with IgA nephropathy

Abstract Background and Aims The pathogenesis of IgA nephropathy (IgAN) includes the deposition of immune complexes in the kidney and activation of the complement system. Complement components, including C5a (anaphylatoxin) and C5b-9 (membrane attack complex), are generated leading to mesangial inflammation and glomerular injury [1]. Ravulizumab, a humanized monoclonal antibody, is a long-acting complement C5 inhibitor that provides immediate, complete, and sustained inhibition of the terminal complement pathway, thereby targeting a key component of the pathophysiology of IgAN. A phase 2 study of ravulizumab (NCT04564339) demonstrated a rapid effect and significant reduction in proteinuria compared with placebo at week 26 (change from baseline in 24-hour urine protein to creatinine ratio [UPCR] –40.3% vs –10.9%), and treatment was well-tolerated [2]. This abstract describes the study design of the planned phase 3 trial of ravulizumab in adult patients with IgAN. Method This phase 3, randomized, double-blind, placebo-controlled trial (I CAN) will evaluate the efficacy and safety of ravulizumab (IV; weight-based dosing Q8W) in adults with IgAN. Eligibility criteria include a diagnosis of primary IgAN based on kidney biopsy at any point, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 at screening, and UPCR ≥0.75 g/g or urine protein ≥1.0 g/day (Table 1). The study consists of a 6-week screening period, followed by randomization (1:1) of participants to ravulizumab or placebo and a 2-year blinded treatment period (Fig. 1); all patients receive a stable and maximally tolerated dose of renin-angiotensin system inhibitor therapy. Approximately 450 patients will be randomized, stratified by proteinuria (<2 g/g vs ≥2 g/g), eGFR (<45 vs ≥45 mL/min/1.73 m2), and SGLT2i use (yes/no). The co-primary endpoints are change from baseline to week 34 in 24-hour UPCR evaluated on the log scale and the annualized total eGFR slope over 106 weeks. The sample size for the proteinuria endpoint of n = 204 will provide ∼90% power to detect a 35% relative treatment effect in UPCR at week 34 at a one-sided significance level of 0.005. The total sample size of n = 450 for the eGFR endpoint will provide ∼90% power to detect a difference in total annualized eGFR slope of 2.2 mL/min/1.73 m2 at week 106 at a one-sided significance level of 0.025. An open-label exploratory cohort (n = 20) with eGFR 20-29 mL/min/1.73 m2 and with kidney biopsy within 6 months of or during screening will be enrolled and analyzed separately from the main cohort. At completion of the blinded treatment period, all study participants will have the option to enter an open-label ravulizumab access period for up to 2 years. Results The co-primary endpoints are the change in 24-hour UPCR at week 34 and the annualized total eGFR slope over 106 wks. Secondary and exploratory endpoints include change in 24-hour UPCR at weeks 10, 26, 50, and 106, a composite kidney failure endpoint over 106 weeks, reduction in 24-hour UPCR ≥50% from baseline, time to UPCR <1 g/g and <0.3 g/g, and patient reported outcomes on fatigue, quality of life, and work-related productivity. Safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics will be evaluated. Conclusion Through immediate, complete, and sustained inhibition of C5, ravulizumab targets the pathophysiology of IgAN and has the potential to provide a disease modifying treatment option. This pivotal phase 3 study (I CAN) will evaluate the efficacy of ravulizumab in patients with IgAN who are at high risk of disease progression. The trial will evaluate effects on proteinuria and eGFR that may translate to long term kidney function preservation and provide a rapidly acting treatment option for patients living with IgAN.

Hyperkalemia Recurrence Following Medical Nutrition Therapy in Patients with Stage3-4 Chronic Kidney Disease: The REVOLUTIONIZEI Real-World Study.

The REVOLUTIONIZEI study aimed to characterize the relationships between medical nutrition therapy (MNT) and hyperkalemia recurrence in patients with stage3-4 chronic kidney disease (CKD) and hyperkalemia who received MNT in real-world clinical practice. This observational cohort study used de-identified electronic health record data from patients aged ≥18years with stage3-4 CKD who received MNT between January 2019 and October 2022 and had hyperkalemia (serum potassium >5.0mmol/L) within 30days before MNT. Patients were followed for 6months or until the first censoring event (death, prescription of outpatient potassium binder, or study end). The primary outcome was the percentage of patients with ≥1hyperkalemia recurrence during follow-up. Secondary outcomes included the number of hyperkalemia recurrences per patient, time to each recurrence, and hyperkalemia-related healthcare resource utilization. Exploratory outcomes included all-cause healthcare resource utilization and mortality. The final cohort comprised 2048 patients; 1503 (73.4%) patients remained uncensored after 6months. During the 6-month follow-up period, 56.0% of patients had ≥1hyperkalemia recurrence and 37.4% had ≥1 recurrence within the first month. Patients with ≥1hyperkalemia recurrence during follow-up had a mean ± standard deviation (SD) of 2.6 ± 2.2 recurrences. The mean ± SD time to first hyperkalemia recurrence was 45 ± 46days; the time between recurrences decreased with subsequent episodes. Hyperkalemia-related hospitalizations and emergency department visits were recorded for 13.7% and 1.5% of patients, respectively. Sensitivity analyses showed that results were consistent across patient subgroups, including those with comorbid heart failure and patients receiving renin-angiotensin-aldosterone system inhibitor therapy at baseline. Most patients with stage3-4 CKD had hyperkalemia recurrence, and MNT alone was inadequate to prevent recurrence. These patients may require additional long-term treatment, such as novel potassium binders, to maintain normokalemia and prevent hyperkalemia recurrence following MNT. Infographic available for this article. INFOGRAPHIC.

Maintained renin-angiotensin-aldosterone system inhibitor therapy with sodium zirconium cyclosilicate following a hyperkalaemia episode: a multicountry cohort study.

This observational cohort study compared the likelihood of maintained (stabilized/up-titrated) renin-angiotensin-aldosterone system inhibitor (RAASi) therapy at 6months following hyperkalaemia in patients with chronic kidney disease (CKD) and/or heart failure (HF) from the USA, Japan and Spain who received sodium zirconium cyclosilicate (SZC) for at least 120days, relative to those with no prescription for a potassium (K+) binder. Using health registers and hospital medical records, patients with CKD and/or HF receiving RAASi therapy who experienced a hyperkalaemia episode were identified. Propensity score (PS) matching (1:4) was applied to balance the SZC cohort to the no K+ binder cohort on baseline characteristics. Logistic regression analysis was performed to compare the odds of maintained RAASi therapy at 6months in the SZC versus no K+ binder cohorts. The PS-matched SZC cohort included 565 (USA), 776 (Japan) and 56 (Spain) patients; the no K+ binder cohort included 2068, 2629 and 203 patients, respectively. At 6months, 68.9% (USA), 79.9% (Japan) and 69.6% (Spain) in the SZC cohorts versus 53.1% (USA), 56.0% (Japan) and 48.3% (Spain) in the no K+ binder cohorts had maintained RAASi therapy. Meta-analysed across countries, the odds ratio of maintained RAASi therapy in the SZC cohort versus no K+ binder cohort was 2.56 (95% confidence interval 1.92-3.41; P<.0001). In routine clinical practice across three countries, patients treated with SZC were substantially more likely to maintain guideline-concordant RAASi therapy at 6months following hyperkalaemia relative to patients with no K+ binder treatment.

Maintaining Renin-Angiotensin-Aldosterone System Inhibitor Treatment with Patiromer in Hyperkalaemic Chronic Kidney Disease Patients: Comparison of a Propensity-Matched Real-World Population with AMETHYST-DN

Introduction: Guideline-directed renin-angiotensin-aldosterone system inhibitor (RAASi) therapy is rarely achieved in clinical settings, often due to hyperkalaemia. We assessed the potassium binder, patiromer, on continuation of RAASi therapy in hyperkalaemic patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) in the AMETHYST-DN trial, propensity score-matched to a real-world cohort not receiving patiromer (Salford Kidney Study). Methods: The phase 2, open-label AMETHYST-DN trial (NCT01371747) randomized 304 adults with CKD on RAASi, T2DM, hyperkalaemia (serum potassium [sK⁺] >5.0 mEq/L), and hypertension to receive patiromer, 8.4–33.6 g/day for 12 months. Patients underwent propensity score matching for systolic blood pressure (BP), heart failure status, and estimated glomerular filtration rate (eGFR), with 321 patients with CKD, T2DM, hyperkalaemia, and on RAASi from a prospective CKD cohort (Salford Kidney Study). Changes in RAASi utilization, sK⁺, BP, proteinuria, and eGFR during 12-month follow-up were assessed by Mann-Whitney U or χ² tests. Results: Matching produced 135:135 patients with no significant differences in age, sex, systolic BP, sK⁺, eGFR, or heart failure status, although differences in diastolic BP remained (p < 0.001). After 12 months, 100% of AMETHYST-DN patients receiving patiromer remained on RAASi therapy, whereas 38.5% of the Salford Kidney Cohort discontinued RAASi (p < 0.001); hyperkalaemia contributed in 16% of patients (42% of RAASi discontinuations). Significantly greater reductions in sK⁺ and BP, but not proteinuria or eGFR, were observed in AMETHYST-DN, compared with Salford Kidney Study patients (p < 0.05). Conclusions: These results demonstrate the benefit of patiromer for sK⁺ management to enable RAASi use while revealing beneficial effects on BP.

Hyperkalemia in CKD: an overview of available therapeutic strategies.

Hyperkalemia (HK) is a life-threatening condition that often occurs in patients with chronic kidney disease (CKD). High serum potassium (sKsK) is responsible for a higher risk of end-stage renal disease, arrhythmias and mortality. This risk increases in patients that discontinue cardio-nephroprotective renin-angiotensin-aldosterone system inhibitor (RAASi) therapy after developing HK. Hence, the management of HK deserves the attention of the clinician in order to optimize the therapeutic strategies of chronic treatment of HK in the CKD patient. The adoption in clinical practice of the new hypokalaemic agents patiromer and sodium zirconium cyclosilicate (SZC) for the prevention and chronic treatment of HK could allow patients, suffering from heart failure and chronic renal failure, to continue to benefit from RAASi therapy. We have updated a narrative review of the clear variables, correct definition, epidemiology, pathogenesis, etiology and classifications for HK among non-dialysis CKD (ND CKD) patients. Furthermore, by describing the prognostic impact on mortality and on the progression of renal damage, we want to outline the strategies currently available for the control of potassium (K+) plasma levels.

#4406 INCREASE IN HOSPITALIZED DAYS AFTER HYPERKALEMIA-RELATED REDUCTION IN RAASI USE: AN OBSERVATIONAL STUDY ON CARDIORENAL PATIENTS IN SWEDEN AND JAPAN

Abstract Background and Aims Guidelines recommend renin-angiotensin-aldosterone system inhibitor (RAASi) therapy at the maximum tolerated dose to achieve optimal treatment benefits in chronic kidney disease (CKD) and heart failure (HF). However, hyperkalemia (HK) is a barrier to achieving guideline-directed target dosing, with RAASi treatment often down-titrated or discontinued in patients who experience HK. Current international guidelines recommend novel oral anti-HK treatments to manage HK and facilitate optimization of RAASi therapy. The aim of this study was to describe the extent of RAASi reduction (down-titration or discontinuation) following an HK episode, and the associated change in inpatient days, in patients with cardiorenal disease in Sweden and Japan. Methods This observational study used data from health registers and hospital records in Sweden (national registers linked with health records from two large regions) and Japan (Medical Data Vision). Patients with an index HK episode, defined as ICD-10 code E87.5 (Japan and Sweden) or potassium &amp;gt;5.0 mmol/L (Sweden only), during March 2018 to July 2020 (Sweden) or May 2020 to February 2022 (Japan), with a prior diagnosis of CKD and/or HF, and RAASi use at index were included. RAASi classes included angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), mineralocorticoid receptor antagonists (MRA), and an angiotensin receptor-neprilysin inhibitor (ARNi). Patients were defined as having reduced or maintained their pre-HK RAASi treatment based on filled prescriptions, or lack thereof, within 90 (Japan) or 120 (Sweden) days before versus after the index HK episode. Propensity score matching (1:1) was applied to balance the cohorts who reduced versus maintained their pre-HK RAASi treatment on demographics, comorbidities, baseline medications (including RAASi), and inpatient days prior to index. The change in number of all-cause, CKD-, and HF-related inpatient days (per person-years of follow-up) was described from 6 months before to 6 months after the index HK episode. Results In total, 20,824 patients from Sweden and 7789 from Japan were included. The mean age was 76 (Sweden) and 74 (Japan) years; 57% and 65%, respectively, were male. In Sweden, 86% had CKD and 57% had HF; in Japan, 49% had CKD and 75% had HF. The most common RAASi classes in Sweden were ACEi (used by 49%), ARB (44%), and MRA (30%). In Japan, ARB was the most common class (73%), followed by MRA (28%), and ACEi (17%). Overall, 42% (n = 8716) of patients in Sweden and 38% (n = 2976) in Japan reduced their RAASi treatment after the HK episode. In the propensity score matched cohorts, the increase in number of all-cause inpatient days following an HK episode in those with reduced RAASi treatment was 18.2 days in Sweden (n = 6998) and 17.9 days in Japan (n = 2092) (Figure A and B). For reference, the increase in those who maintained their RAASi treatment was 9.4 and 8.5 days in Sweden and Japan, respectively. Similar patterns were observed for CKD- and HF-related inpatient days. Conclusion In clinical practice, an episode of hyperkalemia was often followed by reduced RAASi treatment. Reduced RAASi treatment was associated with a greater increase in the number of inpatient days, compared with maintained RAASi treatment. A better understanding of how guideline adherence can be increased to maintain RAASi treatment in patients experiencing HK is needed to achieve optimal treatment benefits in chronic kidney disease (CKD) and heart failure (HF).

#3303 SUBOPTIMAL EXTENT OF RAASI RE-INITIATION AFTER DISCONTINUATION FOLLOWING HYPERKALEMIA: AN OBSERVATIONAL STUDY OF CARDIORENAL PATIENTS IN THE US AND JAPAN

Abstract Background and Aims Guidelines recommend renin-angiotensin-aldosterone system inhibitor (RAASi) therapy at the maximal tolerated dose to achieve optimal treatment benefits in chronic kidney disease (CKD) and heart failure (HF). However, hyperkalemia (HK) is a barrier to achieving guideline-directed target dosing and RAASi treatment is often compromised in patients who experience HK. Current international guidelines recommend novel oral anti-HK treatments to manage HK and facilitate RAASi therapy. This study assessed the extent of both temporary and longer-term discontinuation of RAASi following an HK episode, and the magnitude of RAASi re-initiation, in cardiorenal patients in the US and Japan. Method This observational study used data from hospital records and claims from the US (Optum's de-identified Market Clarity Data) and Japan (Medical Data Vision). Patients with an index HK event (ICD-10 code E87.5) during July 2019–September 2021 (US) or May 2020–February 2022 (Japan) with a prior diagnosis of CKD and/or HF and use of RAASi in the preceding 6 months were included. RAASi classes included angiotensin-converting enzyme inhibitors (ACEi), angiotensin-receptor blockers (ARB), mineralocorticoid receptor antagonists (MRA), and angiotensin receptor neprilysin inhibitors (ARNi). In patients who discontinued RAASi treatment following their index HK episode, duration of discontinuation was described within a time frame of 6 months from the date of discontinuation (those with &amp;lt;6 months follow-up time were excluded). The RAASi dose prior to discontinuation versus at re-initiation was also assessed. Results In total, 25,963 patients from the US and 8,722 from Japan were included. The mean age was 68.3 (US) and 74.8 (Japan) years; 53% and 65% were male; and 30% and 12% of patients had a recorded history of HK prior to their index event. In the US, 85% filled a RAASi prescription in the 3 months prior to HK episode; the most common RAASi classes were ACEi (used by 46% of the overall cohort), ARB (27%), and MRA (19%). In Japan, 91% filled a RAASi prescription in the 3 months prior to HK episode; ARB was the most common (67%), followed by MRA (25%), and ACEi (16%). ARNi was used by &amp;lt;5% of patients in the US and &amp;lt;2% in Japan; it was not assessed further due to low patient numbers. Following the HK episode, ACEi/ARB were discontinued in 23–26% of patients, while MRA was discontinued in 33–46% (Table 1). In those who discontinued, re-initiation within 6 months occurred among 10–15% of patients in the US and among 6–8% of patients in Japan. In those who re-initiated, 17–37% of patients in the US and Japan had their dose reduced by &amp;gt;25%. Conclusion In clinical practice, HK leads to discontinuation of RAASi treatment despite guidelines recommending maintained treatment. Re-challenge of RAASi treatment is uncommon and, when re-introduced, the dose is commonly reduced. These findings emphasize the need for improved guideline adherence in managing HK to facilitate continued RAASi therapy.

RAASi Therapy Attenuates the Association between 24-h Urinary Potassium Excretion and Dietary Potassium Intake in CKD Patients.

The aim of this study was to evaluate urinary potassium (K) excretion as a reliable marker of dietary K intake, in a cohort of CKD patients with or without Renin-Angiotensin-Aldosterone System (RAAS) inhibitor therapy. One hundred and thirty-eight consecutive out-patients (51 f and 87 m) aged 60 ± 13 years and affected by CKD stage 3-4, who were metabolically and nutritionally stable, entered the study between November 2021 and October 2022. No difference was observed between patients with (n = 85) or without (n = 53) RAAS inhibitor therapy, regarding dietary intakes, blood biochemistry, and 24-h urine excretion parameters. Considering all patients, urinary K showed a weak relationship with eGFR (r = 0.243, p < 0.01), and with dietary K intake (r = 0.184, p < 0.05). Serum K was not associated with dietary K intake, but an inverse relationship was observed with eGFR (r = -0.269, p < 0.01). When patients were examined depending on whether they were receiving RAAS inhibitor therapy, the weak inverse relationship between serum K and eGFR was maintained in both groups. Conversely, urinary K excretion remained positively associated with dietary K intake only in the no RAAS inhibitor group. In conclusion, 24-h urine K excretion may be used as a surrogate of K intake, but RAAS inhibitor therapy reduces the association between 24-h urine K excretion and dietary K intake in CKD patients.

A cost-effectiveness analysis of patiromer in the UK: evaluation of hyperkalaemia treatment and lifelong RAASi maintenance in chronic kidney disease patients with and without heart failure

BackgroundChronic kidney disease (CKD) patients with and without heart failure (HF) often present with hyperkalaemia (HK) leading to increased risk of hospitalisations, cardiovascular related events and cardiovascular-related mortality. Renin–angiotensin–aldosterone system inhibitor (RAASi) therapy, the mainstay treatment in CKD management, provides significant cardiovascular and renal protection. Nevertheless, its use in the clinic is often suboptimal and treatment is frequently discontinued due to its association with HK. We evaluated the cost-effectiveness of patiromer, a treatment known to reduce potassium levels and increase cardiorenal protection in patients receiving RAASi, in the UK healthcare setting.MethodsA Markov cohort model was generated to assess the pharmacoeconomic impact of patiromer treatment in regulating HK in patients with advanced CKD with and without HF. The model was generated to predict the natural history of both CKD and HF and quantify the costs and clinical benefits associated with the use of patiromer for HK management from a healthcare payer’s perspective in the UK.ResultsEconomic evaluation of patiromer use compared to standard of care (SoC) resulted in increased discounted life years (8.93 versus 8.67) and increased discounted quality-adjusted life years (QALYs) (6.36 versus 6.16). Furthermore, patiromer use resulted in incremental discounted cost of £2,973 per patient and an incremental cost-effectiveness ratio (ICER) of £14,816 per QALY gained. On average, patients remained on patiromer therapy for 7.7 months, and treatment associated with a decrease in overall clinical event incidence and delayed CKD progression. Compared to SoC, patiromer use resulted in 218 fewer HK events per 1,000 patients, when evaluating potassium levels at the 5.5–6 mmol/l; 165 fewer RAASi discontinuation episodes; and 64 fewer RAASi down-titration episodes. In the UK, patiromer treatment was predicted to have a 94.5% and 100% chance of cost-effectiveness at willingness-to-pay thresholds (WTP) of £20,000/QALY and £30,000/QALY, respectively.ConclusionThis study highlights the value of both HK normalisation and RAASi maintenance in CKD patients with and without HF. Results support the guidelines which recommend HK treatment, e.g., patiromer, as a strategy to enable the continuation of RAASi therapy and improve clinical outcomes in CKD patients with and without HF.

The use of the drug Elizaria – a biosimilar of the original eculizumab in atypical hemolytic-uremic syndrome due to mutation of the С3 gene in children: clinical observation and literature review

This article presents the features of atypical haemolytic-uremic syndrome (ORPHA 544472) in children. Atypical haemolytic-uremic syndrome (aHUS) is defined by a triad: haemolytic anaemia, thrombocytopenia and acute kidney injury in pediatric and adult patients. The OMIM catalogue presents the phenotypic series of aHUS with mutations of the C3, CFB, CFH, CFHR1, CFHR3, DGKE, MCP, THBD genes. Atypical haemolytic-uremic syndrome is often associated with gene mutations in proteins and activators that regulate complement. We report the case of a girl who had a manifestation of aHUS at 8 years 5 months of age and a severe relapse at 8 years 10 months of age. The relapse was characterised by manifestations of haemolytic anaemia, thrombocytopenia, acute renal damage, severe arterial hypertension, high lactate dehydrogenase and membrane attack complex levels and low C3 component. After 5 courses of haemodialysis, 3 haemodiafiltration, diuresis increased and biochemical parameters improved. We presented with ASUS in a child associated with a p.Cys1101Tyr C3 gene mutation. We used a complement inhibitor, Elizaria®, a biosimilar to the original drug eculizumab, to treat a child with atypical haemolytic-uremic syndrome due to the C3 gene mutation. The complement system inhibitor therapy with Elizaria preserved the health and life of a sick girl with a severe relapse of aHUS.

Clinical impact of suboptimal RAASi therapy following an episode of hyperkalemia

BackgroundHyperkalemia (HK) is a barrier to optimization of renin-angiotensin-aldosterone system inhibitor (RAASi) therapy in heart failure (HF) and chronic kidney disease (CKD). We investigated cardiorenal risk associated with changes in RAASi regimen after an episode of HK in patients with HF and/or CKD.MethodsThis observational study utilized data from hospital records, claims, and health registers from the US (Optum’s de-identified Market Clarity Data) and Japan (Medical Data Vision). Included patients had an index episode of HK between July 2019 and September 2021 (US), or May 2020 and September 2021 (Japan), with prior diagnosis of HF or CKD (stage 3 or 4), and RAASi use. Risk of a cardiorenal composite outcome (HF emergency visit, HF hospitalization, or progression to end-stage kidney disease) was determined in patients who discontinued RAASi, down-titrated their dose by > 25%, or maintained or up-titrated their dose following the HK episode.ResultsA total of 15,488 and 6020 patients were included from the US and Japan, respectively. Prior to the episode of HK, 59% (US) and 27% (Japan) of patients had achieved > 50% target RAASi dose. Following the episode of HK, 33% (US) and 32% (Japan) of patients did not fill a new RAASi prescription. Risk of the cardiorenal outcome at 6 months was higher in patients who discontinued or down-titrated versus maintained or up-titrated RAASi treatment both in the US (17.5, 18.3, and 10.6%; p < 0.001) and in Japan (19.7, 20.0, and 15.1%; p < 0.001).ConclusionHK-related RAASi discontinuation or down-titration was associated with higher risk of cardiorenal events versus maintained or up-titrated RAASi.

Outcomes in patients with cardiometabolic disease who develop hyperkalemia while treated with a renin-angiotensin-aldosterone system inhibitor

Many patients with indications for renin-angiotensin-aldosterone system inhibitor (RAASi) therapy are not receiving these medications. Concern about hyperkalemia is thought to contribute to this lack of evidence-based therapy. A retrospective cohort study included adult patients in primary care practices affiliated with an integrated health care delivery system treated with RAASi between 2000 and 2019 for any of the following indications: (a) coronary artery disease (CAD); (b) heart failure (HF) with a left ventricle ejection fraction ≤ 40%; (c) diabetes mellitus (DM) with proteinuria; or (d) chronic kidney disease (CKD) with proteinuria. Relationship between hyperkalemia (K > 5.0 mEg/L) over the first 12 months of follow-up and a composite end point of cardiovascular events, renal dysfunction, and all-cause mortality was evaluated. Among 82,732 study patients, 7,727 (9.34%) developed hyperkalemia. Patients with hyperkalemia were older (69.0 vs 64.6) and more likely to have CAD (57.8 vs 53.7%), CKD (57.3 vs 51.1%), HF (19.3 vs 9.7%), and DM (45.3 vs 33.3%) (P < .001 for all). Five-year cumulative risk of the primary outcome was higher in patients who did (63.9%; 95% CI: 62.8%-65.1%) versus did not (37.2%; 95% CI: 36.8%-37.6%) develop hyperkalemia. Five-year cumulative risk of ED visit or hospitalization for hyperkalemia was 15.6% (14.7%-16.6%) for patients with versus 2.7% (95% CI: 2.6-2.9) for patients without hyperkalemia, rising to 25.9% (95% CI: 22.4-29.9) for patients with severe (K > 6.0 mEq/dL) hyperkalemia. Patients who experienced hyperkalemia were more likely (34.4%) than patients who did not (29.2%) to deintensify RAASi therapy (P < .001). Five-year cumulative risk of the primary outcome was higher in patients who lowered RAASi dose (50.4%; 95% CI: 48.5%-52.4%) or stopped RAASi therapy completely (49.3%; 95% CI: 48.5%-50.1%), compared to patients who continued RAASi therapy (36.1%; 95% CI: 25.7-36.5). Similar findings were observed in multivariable analyses and for individual components of the primary outcome. Hyperkalemia is a common complication of RAASi therapy and is associated with an increased risk of multiple adverse outcomes. Patients who have their RAASi medications deintensified after a hyperkalemic event have higher incidence of cardiovascular events, renal dysfunction and death.

EE17 Economic Evaluation of Patiromer for the Treatment of Hyperkalaemia in CKD Patients With and Without HF in Italy

Chronic kidney disease (CKD) patients with and without Heart failure (HF) are at risk of developing hyperkalaemia (HK), which is further heightened with the necessary use of renin–angiotensin–aldosterone system inhibitor (RAASi) therapy. Current standard of care (SoC) for HK is limited and often necessitates RAASi down-titration/discontinuation, resulting in detrimental outcomes. This study assessed the cost-effectiveness of patiromer for HK treatment in CKD patients with and without HF in an Italian setting.

Medical therapy for secondary prevention in patients with myocardial infarction with non-obstructive coronary artery disease: long-term outcome of a Portuguese centre

Abstract Background The outcomes of dual anti-platelet therapy (DAPT), β-blocker, renin-angiotensin-aldosterone system (RAAS) inhibitor and statin therapy are unknown in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA). The aim of this study was to examine the effects of secondary prevention therapy at discharge on long-term outcomes in MINOCA. Methods Patients with MINOCA undergoing early coronary angiography between 2009 and 2016 were extracted from a clinical database. Patients were followed until 2018 for outcome events. All patients with a MINOCA diagnosis and without history of atrial fibrillation were included. A total of 646 consecutive patients were enrolled. The primary end point was major adverse cardiac events (MACE) defined as all-cause mortality, myocardial infarction (MI), stroke, and heart failure (HF). Secondary endpoints comprised all individual endpoints for the composite end-point. The relationship between treatments and outcomes was evaluated by using Kaplan-Meier survival analysis and Cox regression models. Results Mean age was 67.9±13.4 years and 31.6% were women. No patient was lost to follow-up. Mean left ventricular ejection fraction was 47.8±13.1%. At discharge, 87.2%, 82.5% and 79.5% of the patients were on statins, RAAS inhibitors and β-blockers, respectively. The majority (72.8%) were discharged on DAPT. During follow-up (Mdn 59 months), 303 (46.9%) patients experienced a MACE and 208 (33.4%) died. MI occurred in 98 patients (17.8%) and stroke in 31 patients (5.6%). HF admissions were also common (82, 14.9%). The hazard ratio (HR) for major adverse cardiac events was 0.31 (0.23–0.41) in patients on statins, RAAS inhibitors and β-blockers. For patients on DAPT the HR was 0.61 (0.48–0.78). In univariate Cox regression analyses, a reduced risk of MACE was found in patients using combined secondary prevention therapies (HR 0.58, 0.46–0.74). Regarding the individual endpoints, combined secondary prevention therapy reduced the risk of stroke (HR 0.45, 0.22–0.99, P=0.04) but not risk of future MI nor HF admissions. Patients in the combined therapy group had a higher median survival (66 months, IQR 27–82 months) than the group without secondary prevention (34.5 months, IQR 6.8–74 months; P&amp;lt;0.001 of Log Rank test for equality of survivor functions). In a multiple Cox regression analysis including RAAS inhibitors, statins, DAPT and β-blockers in the model, none of these drugs was associated with lower MACE, except for RAAS inhibitors. Conclusions The results indicate long-term beneficial effects of treatment with secondary prevention medical therapies in patients with MINOCA. Properly powered randomized clinical trials are warranted. Funding Acknowledgement Type of funding sources: None.