Renin-angiotensin-aldosterone System Inhibitor Therapy Research Articles

#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.

Hyperkalemia in chronic kidney disease patients with and without heart failure: an Italian economic modelling study

BackgroundHyperkalemia (HK) is frequently present in chronic kidney disease (CKD). Risk factors for HK among CKD patients include comorbidities and renin–angiotensin–aldosterone system inhibitor (RAASi) treatment. Current standard of care (SoC) often necessitates RAASi down-titration or discontinuation, resulting in poorer cardiorenal outcomes, hospitalization and mortality. This study evaluates the cost-effectiveness of patiromer for HK in CKD patients with and without heart failure (HF) in an Italian setting.MethodsA lifetime Markov cohort model was developed based on OPAL-HK to assess the health economic impact of patiromer therapy in comparison to SoC after accounting for the effects of HK and RAASi use on clinical events. Outcomes included accumulated clinical events, number needed to treat (NNT) and the incremental cost-effectiveness ratio (ICER). Subgroup analysis was conducted in CKD patients with and without HF.ResultsPatiromer was associated with an incremental discounted cost of €4,660 and 0.194 quality adjusted life years (QALYs), yielding an ICER of €24,004. Per 1000 patients, patiromer treatment prevented 275 moderate/severe HK events, 54 major adverse cardiovascular event, 246 RAASi discontinuation and 213 RAASi up-titration/restart. Subgroup analysis showed patiromer was more effective in preventing clinical events in CKD patients with HF compared to those without; QALY gains were greater in CKD patients without HF versus those with HF (0.267 versus 0.092, respectively). Scenario analysis and sensitivity analysis results support base-case conclusions.ConclusionPatiromer is associated with QALY gains in CKD patients with and without HF compared to SoC in Italy. Patiromer prevented HK events, enabled RAASi therapy maintenance and reduced cardiovascular event risk.

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.

Cost-effectiveness of sodium zirconium cyclosilicate for advanced chronic kidney patients in Singapore.

Hyperkalaemia (HK) is prevalent among patients with chronic kidney disease (CKD) and chronic heart failure, especially if they are treated with renin-angiotensin-aldosterone system inhibitors (RAASi). This study evaluated the cost-effectiveness of a newly developed anti-HK therapy, sodium zirconium cyclosilicate (SZC), to the current standard of care for treating HK in advanced CKD patients from the Singapore health system perspective. We adapted a global microsimulation model to simulate individual patients' potassium level trajectories with baseline potassium ≥5.5 mmol/L, CKD progression, changes in treatment, and other fatal and non-fatal events. Effectiveness data was derived from ZS-004 and ZS-005 trials. Model parameters were localised using CKD patients' administrative and medical records at the Singapore General Hospital Department of Renal Medicine. We estimated the lifetime cost and quality-adjusted life years (QALYs) of each HK treatment, and the incremental cost-effectiveness ratio of SZC. SZC demonstrated cost-effectiveness with an incremental cost-effectiveness ratsio of SGD 45 068 per QALY over a lifetime horizon, below the willingness-to-pay threshold of SGD 90 000 per QALY. Notably, SZC proved most cost-effective for patients with less severe CKD who were concurrently using RAASi. Sensitivity analyses confirmed the robustness of the findings, accounting for alternative parameter values and statistical uncertainty. This study establishes the cost-effectiveness of SZC as a treatment for HK, highlighting its potential to mitigate the risk of hyperkalaemia and optimise RAASi therapy. These findings emphasise the value of integrating SZC into the Singapore health system for improved patient outcomes and resource allocation.

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.

Novel potassium binders to optimize RAASi therapy in heart failure: A systematic review and meta-analysis

AimsHyperkalemia often occurs among heart failure (HF) patients, particularly when treated with renin-angiotensin-aldosterone system inhibitors (RAASi). Even modest potassium levels variations raise the risk of mortality and prompt patients to discontinue disease-modifying treatment, as RAASi. Novel potassium binders (NPB), patiromer and sodium zirconium cyclosilicate, are effective in reducing potassium levels and are approved for the treatment of hyperkalemia in HF, but whether their use results in a real optimization of HF treatment remains to be seen. The aim of the present meta-analysis was to assess the efficacy of NPB on the optimization of RAASi therapy in HF patients. Methods and resultsPubMed, Web of Science and Clinicaltrial.gov were searched without restrictions from inception to 06 August 2022 to identify valuable articles. The studies that met the inclusion criteria were analyzed. The prespecified primary outcome was the optimization of RAASi therapy in HF patients, defined as the proportion of patients on RAASi at the end of follow-up. Secondary outcomes were hyperkalemia events, reduction in potassium levels, and adverse drugs reactions. Six studies with a total of 1390 patients were included. NPB improved RAASi therapy optimization in HF by 14% (95% CI: 4–26%), decreased hyperkalemia events by 29% (95% CI: 55–92%), and reduced potassium levels by 0.31 mEq/L (95% CI: 0.18–0.44) compared to placebo, maintaining a good safety profile. ConclusionNPB are effective in allowing RAASi therapy optimization in patients affected by HF, in reducing hyperkalemia events and potassium levels. Systematic Review registrationCRD42022351811 URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=351811

Impact of Sodium Zirconium Cyclosilicate Plus Renin-Angiotensin-Aldosterone System Inhibitor Therapy on Short-Term Medical Costs in Hyperkalemia: OPTIMIZEII Real-World Study.

Patients receiving cardiorenal-protective renin-angiotensin-aldosterone system inhibitors (RAASis) are at increased risk of developing hyperkalemia, which is associated with increased medical costs. The aim of this study was to evaluate the impact of adding sodium zirconium cyclosilicate (SZC) therapy on 3-month medical costs in patients who experienced hyperkalemia while receiving RAASi therapy. The retrospective OPTIMIZEII study used medical and pharmacy claims data from IQVIA PharMetrics® Plus. Patients aged ≥ 18years who received SZC (≥ 60day supply over 3months' follow-up) and continued RAASi between July 2019 and December 2021 (Continue RAASi + SZC cohort) were 1:1 exact and propensity score matched with patients who discontinued RAASi after hyperkalemia diagnosis and did not receive SZC (Discontinue RAASi + no SZC cohort). The primary outcome was hyperkalemia-related medical costs to payers over 3months; all-cause medical and pharmacy costs were also analyzed. In the Continue RAASi + SZC (n = 467) versus Discontinue RAASi + no SZC (n = 467) cohort, there were significant reductions in mean per-patient hyperkalemia-related medical costs (reduction of $2216.07; p = 0.01) and all-cause medical costs (reduction of $6102.43; p < 0.001); mean hyperkalemia-related inpatient medical costs and all-cause inpatient and emergency department medical costs were significantly reduced. The reduction in all-cause medical cost in the Continue RAASi + SZC cohort offset an increase in the mean per-patient all-cause pharmacy cost (increase of $3117.71; p < 0.001). RAASi therapy has well-established cardiorenal benefits. In OPTIMIZEII, management of RAASi-induced hyperkalemia with SZC was associated with lower hyperkalemia-related and all-cause medical costs than RAASi discontinuation without SZC, demonstrating medical cost savings with maintaining RAASi therapy with SZC.

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.

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.

Real-World Modifications of Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Hyperkalemia Initiating Sodium Zirconium Cyclosilicate Therapy: The OPTIMIZE I Study.

Hyperkalemia (HK) may result in disruptions of guidelines-concordant renin-angiotensin-aldosterone system inhibitors (RAASi), a standard of care in persons with chronic kidney disease (CKD). Such disruptions-dose reduction or discontinuation-diminish the benefits of RAASi, placing patients at risk of serious events and renal dysfunction. This real-world study evaluated RAASi modifications among patients who initiated sodium zirconium cyclosilicate (SZC) for HK. Adults (≥ 18years) initiating outpatient SZC (index date) while on RAASi were identified from a large US claims database (January 2018-June 2020). RAASi optimization (maintain same or up-titration of RAASi dosage), non-optimization (down-titration of RAASi dosage or discontinuation), and persistence were descriptively summarized following index. Predictors of RAASi optimization were assessed using multivariable logistic regression models. Analyses were conducted by subgroups, including patients without end-stage kidney disease (ESKD), with CKD, and with CKD + diabetes. A total of 589 patients initiated SZC during RAASi therapy (mean age 61.0years, 65.2% male), and 82.7% patients (n = 487) kept RAASi after index (mean follow-up = 8.1months). Most patients (77.4%) optimized RAASi therapy after initiating SZC; 69.6% maintained the same dosage while 7.8% had up-titrations. A similar rate of RAASi optimization was observed among subgroups without ESKD (78.4%), with CKD (78.9%), and with CKD + diabetes (78.1%). At 1-year post-index, 73.9% of all patients who optimized RAASi were still on therapy, while only 17.9% of patients who did not optimize therapy were still on a RAASi. Among all patients, predictors of RAASi optimization included fewer prior hospitalizations (odds ratio = 0.79, 95% CI [0.63-1.00]; p < 0.05) and fewer prior emergency department (ED) visits (0.78 [0.63-0.96]; p < 0.05). Consistent with clinical trial findings, nearly 80% of patients who initiated SZC for HK optimized their RAASi therapy. Patients may require long-term SZC therapy to encourage continuation of RAASi therapy especially after inpatient and ED visits.

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.

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.

488 NOVEL POTASSIUM BINDERS IMPROVES RAASI THERAPY OPTIMIZATION IN HEART FAILURE: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background Hyperkalemia (HK) often occurs among patients with heart failure (HF), particularly when treated with renin-angiotensin-aldosterone system inhibitors (RAASi). Even modest variations from normal potassium levels raise the risk of mortality and prompt patients to limit or cease disease-modifying treatment. Novel potassium binders (NPB), patiromer and sodium zirconium cyclosilicate, are approved for treatment of HK, but whether this results in a real optimization of HF treatment remains to be seen. Objectives To assess the efficacy of NPB on the persistence of therapy with RAASi in HF patients. Methods PubMed and Web of Science were searched without restrictions from inception to 06 August 2022 to identify valuable articles. The studies that met the inclusion criteria were analyzed. The prespecified main outcome was the proportion of HF patients achieving target dose of RAASi. Secondary outcomes were the reduction in potassium levels, hyperkalemia events and persistence of therapy with RAASi in the overall population. Results Eight studies, with a total of 2247 patients were included. NPB improved optimization of RAASi therapy in HF compared to placebo by 21% (95% CI: 5% – 39%), decreased potassium levels by 0.48 mEq/L (95% CI: 0.28–0.67) and decreased hyperkalemia events by 53% (95% CI: 34% – 64%) and improved the proportion of the overall study population on RAASi therapy by 28% (95% CI: 7% – 52%). Conclusion The present meta-analysis suggests that NPB are favorable in improving the proportion of patients on RAASi therapy, whether they have HF or not, in reducing potassium levels and hyperkalemia events.

Safety and Efficacy of Patiromer in Hyperkalemic Patients with CKD: A Pooled Analysis of Three Randomized Trials.

Hyperkalemia is a common electrolyte abnormality in patients with CKD, which is associated with worse outcomes and limits use of renin-angiotensin-aldosterone system inhibitors (RAASi). This post hoc subgroup analysis of three clinical trials evaluated the efficacy and safety of the sodium-free, potassium-binding polymer, patiromer, for the treatment of hyperkalemia in adults with nondialysis CKD. Data from the 4-week treatment periods of AMETHYST-DN, OPAL-HK, and TOURMALINE studies were combined. Patients had baseline diagnosis of CKD, hyperkalemia (serum potassium >5.0 mEq/L), and received patiromer 8.4-33.6 g/day. Patients were stratified by baseline eGFR into two subgroups: severe/end-stage CKD (stage 3b-5; eGFR <45 ml/min per 1.73 m2) and mild/moderate CKD (stage 1-3a; eGFR ≥45 ml/min per 1.73 m2). Efficacy was assessed by the change in serum potassium (mean±SE) from baseline to week 4. Safety assessments included incidence and severity of adverse events (AEs). Efficacy analyses (n=626; 62% male, mean age 66 years) included 417 (67%) patients with severe/end-stage CKD and 209 (33%) with mild/moderate CKD. Most patients were receiving RAASi therapy at baseline (severe/end-stage CKD 92%; mild/moderate CKD 98%). The mean±SE change in serum potassium (baseline to week 4) was -0.84±0.03 in the severe/end-stage CKD subgroup, and -0.60±0.04 mEq/L in the mild/moderate CKD subgroup. AEs were reported for 40% and 27% patients in the severe/end-stage and mild/moderate CKD subgroups, respectively, with 16% and 12% reporting AEs considered related to patiromer. The most frequent AEs were mild-to-moderate constipation (8% and 3%) and diarrhea (4% and 2%). AEs leading to patiromer discontinuation occurred in 6% and 2% of patients with severe/end-stage CKD, and mild/moderate CKD, respectively. Patiromer was effective for treatment of hyperkalemia and well tolerated in patients across stages of CKD, most of whom were receiving guideline-recommended RAASi therapy.

A cost-effectiveness analysis of patiromer for the treatment of hyperkalemia in chronic kidney disease patients with and without heart failure in Spain

Aims Renin-angiotensin-aldosterone system inhibitors (RAASi) therapy is commonly used to reduce the risk of death and to slow down disease progression in patients with chronic kidney disease (CKD), heart failure (HF) and hypertension. However, the cardio-renal benefits of RAASi therapy are also associated with an increased risk of hyperkalemia (HK), which may lead to dose reduction or discontinuation of therapy. Patiromer has demonstrated to reduce the risk of HK, which enables to maintain optimal doses of RAASi therapy. This study aimed to assess the cost-effectiveness of patiromer for the management of HK in CKD patients with and without HF in Spain. Methods A Markov model was developed to evaluate the costs and benefits of patiromer for the management of HK in patients with CKD stages 3–4 with and without HF treated with RAASi over a lifetime horizon. The main outcomes included total direct costs (€2021), quality-adjusted life-years (QALYs), life-years gained (LYG) and incremental cost-effectiveness ratio (ICER). Deterministic one-way and probabilistic sensitivity analyses were performed to assess the robustness of the results. Results Patiromer was more effective compared to no patiromer (5.76 vs 5.57 QALYs; 7.73 vs 7.50 LYG), and resulted in an incremental cost of €3,574, yielding an ICER of €19,092/QALY gained and of €15,236/LYG. Sensitivity analyses suggested that the results were robust to changes in most input parameters. Conclusions Patiromer is a cost-effective intervention in maintaining normokalemia and enabling optimal RAASi therapy in patients with CKD stages 3–4 with and without HF in Spain.

Association of statin and/or renin-angiotensin-aldosterone system modulating therapy with mortality in adults with diabetes admitted to hospital with COVID-19: A retrospective multicentre European study

Background & aimsTo assess the impact of pre-admission renin-angiotensin-aldosterone system inhibitor (RAASi) and statin use on mortality following COVID-19 hospitalization in adults with pre-existing diabetes. MethodsRetrospective cohort study of adults with diabetes admitted to ninety-nine participating hospitals in the United Kingdom, France and Spain during the first wave of the COVID-19 pandemic. Logistic regression models adjusted for demographic factors and comorbidity were used to describe associations with mortality in hospital or within 28 days of admission and individual or combined RAASi and statin therapy prescription followed by a country level meta-analysis. ResultsComplete data were available for 3474 (42.6%) individuals. Prescribing patterns varied by country: 25–50% neither RAASi nor statin therapy, 14–36% both RAASi and statin therapy, 9–24% RAASi therapy alone, 12–36% statin alone. Overall, 20–37% of patients died within 28 days. Meta-analysis found no evidence of an association between mortality and prescription of RAASi therapy (OR 1.09, CI 0.78–1.52 (I2 22.2%)), statin (OR 0.97, CI 0.59–1.61 (I2 72.9%)) or both (OR 1.14, CI 0.67–1.92 (I2 78.3%)) compared to those prescribed neither drug class. ConclusionsThis large multicentre, multinational study found no evidence of an association between mortality from COVID-19 infection in people with diabetes and use of either RAASi, statin or combination therapy. This provides reassurance that clinicians should not change their RAASi and statin therapy prescribing practice in people with diabetes during the COVID-19 pandemic.

Prescription patterns of sodium and calcium polystyrene sulfonate in patients with hyperkalemia and chronic kidney disease receiving RAAS inhibitors.

ABSTRACTBackgroundSodium and calcium polystyrene sulfonate (SPS/CPS) cation-exchange resins have had long-standing clinical use for hyperkalemia in patients with chronic kidney disease (CKD). However, uncertainty exists regarding the real-world usage of SPS/CPS for acute and chronic management of hyperkalemia. We evaluated the prescription patterns of SPS/CPS and their impact on renin–angiotensin–aldosterone system inhibitor (RAASi) treatment in patients with CKD Stages G3–G5 after an episode of de novo hyperkalemia.MethodsWe conducted a retrospective cohort study using population-level administrative databases in Manitoba, Canada, which included adults with CKD and a RAASi prescription who had an episode of de novo hyperkalemia (≥5.5 mmol/L) between January 2007 and December 2017.ResultsA total of 10 009 individuals were included in our study cohort. Among the study population, 4% received an SPS/CPS prescription within 30 days of their hyperkalemia episode. Of those, 22% received a 1-day supply of SPS/CPS and 7% received a prescription for more than 30 days. There were 8145 patients using RAASi at baseline who survived 90 days after their first hyperkalemia episode. Of those, 1447 (18%) discontinued their RAAS inhibitor and 339 (5%) received a prescription of SPS/CPS. Also, the proportion of patients who discontinued their RAASi was similar among those who did and did not receive a prescription of SPS/CPS.ConclusionIn patients with CKD receiving RAASi therapy, there is a low frequency of SPS/CPS prescription after an episode of hyperkalemia. RAASi discontinuation or downtitration is the most used pharmacologic approach for the management of hyperkalemia, a strategy that deprives patients of the cardiac and renal protective benefits of RAASi. New options for the management of hyperkalemia in this population are needed.

Cost Consequence Analysis of the Management of Hyperkalemia by Patiromer and Optimization of Renin-Angiotensin-Aldosterone System Inhibitors Therapy in Chronic Kidney Disease Patients in Saudi Arabia

Renin-angiotensin-aldosterone system inhibitors (RAASi) have been shown to improve outcomes in chronic kidney disease (CKD) patients but are associated with an increased risk of hyperkalemia in this vulnerable population. Hyperkalemia often leads to patients' downtitrating or discontinuing RAASi which can result in sub-optimal health outcomes. The objective is to evaluate the cost and health benefits of maintaining normokalemia using patiromer, an oral potassium binder while optimizing RAASi therapy in CKD patients in the Kingdom of Saudi Arabia. The medium-to long-term costs and health outcomes of patients with CKD stage 3-4 and raised serum potassium levels (≥5.5 mmol/L) at baseline were estimated, from a Saudi Arabia payer perspective, using a Markov state-transition model simulating the natural progression of CKD depending on patients' serum potassium level and usage of RAASi at different dosages. The analysis demonstrated that appropriate management of hyperkalemia, enabling optimization of RAASi, leads to cost and health benefits. The cost of patiromer is offset by 68% due to a reduction in management costs associated with CKD progression, hyperkalemia-related hospitalization, and cardiovascular (CV) events. Over a 10-year time horizon, a pool of 300 patients treated with patiromer experience increased life-expectancy [+3.78 life-years (LYs)] and slower disease progression, with decreased time spent in end-stage renal disease (-9.59 LYs). Patiromer may deliver value to both CKD patients and payers in Saudi Arabia, leading to better health outcomes for the former and reduced cost of management of CKD progression and CV events at low additional costs for the latter.