Renin-angiotensin-aldosterone System Inhibitor Treatment Research Articles

#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.

#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.

Impact of early administration of beta-blocker and RAS inhibitor during VA-ECMO treatment for cardiogenic shock; the post-hoc study of the EARLY-UNLOAD trial

Abstract Funding Acknowledgements None. Background/introduction No data about timing and impact of beta-blocker (BB) or renin-angiotensin-aldosterone system inhibitor (RASi) administration for cardiogenic shock (CS) treated with venoatrial extracorporeal membrane oxygenation (VA-ECMO). Purpose To analyze an impact of early administration of BB or RASi during VA-ECMO treatment. Methods This study is a post-hoc analysis of the EARLY-UNLOAD trial (NCT04775472), the trial evaluated an impact of an early prophylactic unloading strategy using left atrial cannulation (LAC) performed within 12 hours from the initiation of VA-ECMO treatment for CS. Among total population (N=116), patients whose lactate was normalized during VA-ECMO and survived more than 2 days were included in this analysis (N=103). Patients were classified whether each medication (BB, RASi or one of BB or RASi) was administered during VA-ECMO or not. The primary endpoint was all-cause mortality. Survival analysis for a primary outcome and landmark analysis for all-cause mortality during different periods (<10 days, 10 to 30 days) were performed. Results BB, RASi, and BB or RASi were administered in 71.8%, 72.8%, and 83.5% of patients, respectively, during VA-ECMO treatment. In early treatment groups, Both BB and RASi were initiated on day 1 (as median). Duration of VA-ECMO treatment was longer in a group who treated with BB during VA-ECMO (8.5 days, vs 5.0 days as median, P = 0.003), and for RASi, it was comparable (8.0 days vs 7.0 days, P = 0.609). Incidence of 30-day all-cause mortality at were statistically comparable between groups (figure 1). The results of survival analysis are described in the figure 2. In Kaplan-Meier analysis, BB, RASi, and BB or RASi during VA-ECMO treatment was not associated with lower probability of 30-day all-cause mortality. Landmark analysis, however, showed lower probability of 10-day mortality in the group treated with BB (P by log-rank test = 0.045), RASi (P = 0.008) and BB or RASi (P=0.005) during VA-ECMO. Multivariate Cox proportional modellings also provided lower risk of 10-day all-cause mortality in groups with BB treatment (Hazard ratio [HR] = 0.26, 95% confidence interval [CI]=0.10-0.69, P = 0.007), RASi treatment (HR = 0.22, 95% CI = 0.08-0.56, P = 0.001) or BB or RASi (HR = 0.15, 95% CI = 0.05-0.41, P < 0.001) during VA-ECMO. RASi (HR = 0.47, 95% CI = 0.22-0.97, P = 0.041) or BB or RASi (HR = 0.37, 95% CI = 0.15-0.93, P = 0.038) treatment during VA-ECMO was also associated with lower risk of 30-day all-cause mortality. Conclusions In this post-hoc analysis of the EARLY-UNLOAD trial, administration of BB or RASi during VA-ECMO treatment for CS was associated with lower risk of short-term mortality.

Impact of Angiotensin Blockade on Development of Chronic Lung Allograft Dysfunction.

Background: The renin-angiotensin-aldosterone system (RAAS) is responsible for a multitude of physiological functions, including immunological effects such as promotion of TGF-β and upregulation of IL-6 and IL-8 which are also implicated in the development of chronic lung allograft dysfunction (CLAD). Blockade of the RAAS pathway in pre-clinical models has demonstrated a decrease in these cytokines and pulmonary neutrophil recruitment. Objective: This study sought to evaluate whether use of RAAS inhibitor (RAASi) in lung transplant recipients impacted CLAD-free survival. Methods: In this retrospective, single-center study, 35 lung transplant recipients who received a RAASi post-transplant were compared to 70 lung transplant recipients not exposed to a RAASi and were followed for up to 5years post-transplant. Results: The incidence of CLAD did not differ based on RAASi treatment (34.3% in RAASi vs 38.6%, P-value .668). This was confirmed with a multivariable Cox proportional hazards model with RAASi initiation as a time-varying covariate (RAASi hazard ratio of 1.01, P-value .986). Incidence of hyperkalemia and acute kidney injury were low in the RAASi group. Conclusions: This study demonstrated no association between post-transplant RAASi use and decreased risk of CLAD development. RAASi were also well tolerated in this patient population.

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.

MO151: A Randomized Controlled Trial of Sodium Zirconium Cyclosilicate Versus Standard of Care for Hyperkalaemia in Chronic Kidney Disease: Phase 4 Continuity Study Design and Rationale

Abstract BACKGROUND AND AIMS Individuals hospitalized with hyperkalaemia (HK) and chronic kidney disease (CKD) are at very high risk of HK recurrence, which often requires hospital re-admission [1]. Recurrent HK events have a significant impact on healthcare resource utilization (HCRU) and costs [2]. Several approaches, such as reduction in dietary potassium (K+), reduction or discontinuation of diuretic and renin-angiotensin-aldosterone system inhibitor (RAASi), or oral K+ binders may be used to manage HK in the outpatient setting. Sodium zirconium cyclosilicate (SZC) is an orally administered, non-absorbed, highly selective K+ binder approved for the treatment of HK in adults. In phase 3 trials, after achieving normokalaemia (NK), individualized once-daily SZC therapy maintained normal range serum K+ levels for up to 1 year in adult outpatients [3]. However, it is unknown if SZC prevents HK recurrence compared with standard of care (SoC). Here, we present the rationale and design of the phase 4 CONTINUITY study (D9480C00023), which will compare the efficacy of continued SZC treatment, as part of the post-discharge medication regimen, with SoC, in maintaining NK and reducing HK-related hospital admissions and emergency department (ED) visits. METHOD CONTINUITY is a randomized controlled, open-label, parallel-group, multicentre study in participants with CKD treated for HK while in hospital, to be conducted in 30–50 study sites across four to seven European countries. The study will comprise both an in-hospital and an outpatient (post-discharge) phase (Figure). During the in-hospital phase, all participants will be treated with SZC to correct HK (SZC 10 g three times daily, up to 72 h) and maintain NK (SZC from 5 g every other day to 10 g once daily) as per local label for 2–14 days. At discharge, participants with NK established on an SZC maintenance dose will be randomised (1:1) to either SZC per local label (Arm A) or SoC per local practice (Arm B); participants intended to be discharged with a K+ binder will not be randomized and will be discontinued from the study. Following randomization, participants enter the outpatient phase and will be monitored for 180 days post-discharge via seven planned follow-up visits or phone calls, followed by a site visit at 7 days after end of treatment (Figure). Participants will be screened to yield 506 entering the in-hospital phase, resulting in 430 participants discharged and randomized (215 per arm) and 344 evaluable participants. Adults (≥18 years) with stage 3b–5 CKD or eGFR &amp;lt;45 mL/min/1.73 m2 at or within 3 months prior to study screening, who are admitted to hospital with a serum K+ of 5.5–6.5 mmol/L, will be eligible. The primary endpoint is the occurrence of NK (serum K+ 3.5–5.0 mmol/L) at 180 days post-discharge. Secondary and exploratory outcomes assessed within 180 days post-discharge include a composite endpoint of any HK-related hospital admission or ED visit, use of rescue therapy for HK and all-cause death, as well as RAASi treatment status and dose, and K+ level. Safety and tolerability will also be evaluated. CONCLUSION CONTINUITY is the first study to examine the efficacy of extended use of a novel K+ binder post-discharge compared with SoC, on the maintenance of NK and reduced HCRU among patients with HK, with CKD stage 3b–5. This study will address the importance of maintaining NK after discharge in routine clinical practice, and the impact of improved management of patients with CKD and HK.

747 Long-term effects of pharmacological treatment in patients with takotsubo syndrome with or without hypertension: a report from the takotsubo Italian network

Abstract Aims Hypertension (HT) is one of the most frequent comorbidities reported in patients with Takotsubo syndrome (TTS). However, the clinical outcome as well as the effect of pharmacological treatment on long-term follow-up have never been investigated in this cohort. To investigate the impact of the pharmacological treatment with beta-blocker (BB) and/or renin–angiotensin–aldosterone system inhibitor (RAASi) on long-term outcome of TTS patients with and without HT. Methods and results This study included TTS patients prospectively included in the Takotsubo Italian Network register from January 2007 to December 2018. The study population was divided in two groups according to the presence or not of HT. The effect of BB and RAASi at discharge was evaluated in these groups. The primary outcome was the composite of all-cause death and TTS recurrence; secondary outcomes were the single components of the primary outcome. The propensity score weighting technique was employed to account for potential selection bias in treatment assignment at discharge. The study population included 825 patients [median age 72 (63–78) years; 8.1% were males]; 525 (63.6%) patients had history of HT and 300 (36.4%) patients did not. At median follow-up of 24.0 months (11.0–38.0), the primary outcome occurred in 102 patients (12.4%); all-cause death and TTS recurrence were reported in 76 (9.2%) and 33 (4.0%), respectively. There were no differences in terms of the primary outcome (adjusted HR: 1.082; 95% CI: 0.689–1.700; P = 0.733), all-cause death (adjusted HR: 1.214; 95% CI: 0.706–2.089; P = 0.483) and TTS recurrence (adjusted HR: 0.795; 95% CI: 0.373–1.694; P = 0.552) between patients with vs. without HT. Among patients with HT, those receiving BB at discharge showed a significantly lower risk of the primary outcome (adjusted HR: 0.375; 95% CI: 0.228–0.617; P &amp;lt; 0.001) compared with patients not receiving BB. There was also a significantly lower risk of all-cause death (adjusted HR: 0.381; 95% CI: 0.217–0.666; P &amp;lt; 0.001) and TTS recurrence (adjusted HR: 0.393; 95% CI: 0.155–0.998; P = 0.049) in patients treated with BB. Among patients without HT, there was no significant association of BB treatment with any of the study outcomes. RAASi treatment showed no significant effect on the primary and secondary outcomes. These results were consistent between patients with and without HT. Conclusions TTS patients with HT patients experienced a survival benefit from BB treatment in terms of both all-cause death and TTS recurrence; this effect was not confirmed in patients without HT. Conversely, RAASi did not affect long-term outcome, independently from the coexistence of HT. Albeit hypothesis-generating, a such evidence supports a tailored pharmacological therapy after discharge in TTS patients taking into account the coexistence of HT.

A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons.

Parkinson's disease (PD) is a common neurodegenerative disorder without effective disease-modifying therapeutics. Here, we establish a chemogenetic dopamine (DA) neuron ablation model in larval zebrafish with mitochondrial dysfunction and robustness suitable for high-content screening. We use this system to conduct an in vivo DA neuron imaging-based chemical screen and identify the Renin-Angiotensin-Aldosterone System (RAAS) inhibitors as significantly neuroprotective. Knockdown of the angiotensin receptor 1 (agtr1) in DA neurons reveals a cell-autonomous mechanism of neuroprotection. DA neuron-specific RNA-seq identifies mitochondrial pathway gene expression that is significantly restored by RAAS inhibitor treatment. The neuroprotective effect of RAAS inhibitors is further observed in a zebrafish Gaucher disease model and Drosophila pink1-deficient PD model. Finally, examination of clinical data reveals a significant effect of RAAS inhibitors in delaying PD progression. Our findings reveal the therapeutic potential and mechanisms of targeting the RAAS pathway for neuroprotection and demonstrate a salient approach that bridges basic science to translational medicine.

Renin Feedback Is an Independent Predictor of Outcome in HFpEF.

Drugs which interact with the renin angiotensin aldosterone system (RAAS) aim to reduce the negative effects of angiotensin (Ang) II. Treatment with these drugs anticipate a compensatory up-regulation of renin; however, it has been shown that there is a large variability in circulating plasma renin (PRA), even in patients with optimal medical therapy in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Our aim was to measure plasma renin activity (PRA-S), its response to RAAS inhibitor (RAASi) therapies and its effects on outcome in patients with HF with preserved ejection fraction (HFpEF). For this purpose, 150 HFpEF patients were included into a prospective single-center registry. Equilibrium (eq) angiotensin metabolites were measured from serum samples using mass spectroscopy. PRA-S (eqAng I + eqAng II) was calculated and compared in respect to the primary endpoint defined as all-cause death. PRA-S in patients with RAASi therapy was not significantly higher than in patients without RAASi (p = 0.262). Even after adjusting for confounding factors, PRA-S remained predictive for all-cause death in the multivariable model with a hazard ratio of 2.14 (95%CI 1.20–3.82, p = 0.010). We conclude that high PRA-S is associated with poor prognosis in patients with HFpEF, regardless of RAASi treatment, which could ultimately result in hyperactivated RAAS and consecutive negative effects on the cardiovascular and renal system, leading to poor outcome in patients with HFpEF.

Effect of renin-angiotensin-aldosterone system inhibitors on Covid-19 patients in Korea.

The effect of renin-angiotensin-aldosterone system (RAAS) inhibitors in coronavirus disease 19 (Covid-19) patients has not been fully investigated. We evaluated the association between RAAS inhibitor use and outcomes of Covid-19. This study was a retrospective observational cohort study that used data based on insurance benefit claims sent to the Health Insurance Review and Assessment Service of Korea by May 15, 2020. These claims comprised all Covid-19 tested cases and the history of medical service use in these patients for the past five years. The primary outcome was all-cause mortality, and the rate of ventilator care was compared between the groups. From a total of 7,590 patients diagnosed with Covid-19, two distinct cohorts were generated based on RAAS inhibitors prescribed within 6 months before Covid-19 diagnosis. A total of 1,111 patients was prescribed RAAS inhibitors, and 794 patients were prescribed antihypertensive drugs, excluding RAAS inhibitors. In propensity-score matched analysis, 666 pairs of data set were generated, and all-cause mortality of the RAAS inhibitor group showed no significant difference compared with the non-RAAS inhibitor group (14.6% vs. 11.1%; hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.54-1.15; p = 0.22). The rate of ventilator care was not significantly different between the two groups (4.4% vs. 4.1%; HR, 1.04; 95%CI, 0.60-1.79; p = 0.89). RAAS inhibitor treatment did not appear to increase the mortality of Covid-19 patients compared with other antihypertensive drugs, suggesting that they may be safely continued in Covid-19 patients.

Frequency and clinical impact of hyperkalaemia within a large, modern, real-world heart failure population.

AimsThis analysis qualitatively describes the impact of hyperkalaemia (HK) and renin‐angiotensin‐aldosterone system inhibitor (RAASi) use on clinical outcomes in patients with heart failure (HF).Methods and resultsPatients were included if they were ≥18 years old; had a serum potassium result between 1 January 2003 and 3 December 2018; had ≥2 separate, non‐urgent care or emergency department encounters; and had an HF diagnosis. Criteria were met by 52 253 patients; 48 333 had sufficient follow‐up for analysis. Patients were stratified by the presence/absence of HK (serum potassium >5.0 mmol/L) (n = 31 619 and n = 20 634, respectively) and by baseline left ventricular ejection fraction (LVEF) ≤40% or >40%. Compared with patients without HK (no‐HK), those with HK had significantly higher rates of baseline cardiovascular risk factors, prior diagnoses, and greater RAASi use in both baseline and follow‐up periods. Assessed outcomes included RAASi use, rate of 3 year major adverse cardiovascular events (MACE), and individual component rates. Between baseline and follow‐up analyses, the proportion of patients on RAASi decreased by 5% in patients with HK but increased by 20% in no‐HK patients. Overall, MACE and death were consistently highest in the presence of HK without RAASi treatment (63% and 62%, respectively) and lowest in no‐HK but on RAASi (25% and 21%, respectively). After complete multivariable adjustment, these trends were consistent regardless of baseline LVEF.ConclusionsIn this large, real‐world HF population, HK was common and linked to baseline clinical risk factors, declining use of RAASi treatment, and an increase in future MACE, regardless of baseline LVEF. Both HK and reduced RAASi use were independent predictors of future MACE.

Association between renin–angiotensin–aldosterone system inhibitor treatment, neutrophil–lymphocyte ratio, D-Dimer and clinical severity of COVID-19 in hospitalized patients: a multicenter, observational study

The aim of this study was to investigate the possible relationship between worse clinical outcomes and the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in hospitalized COVID-19 patients. A total of 247 adult patients (154 males, 93 females; mean age: 51.3 ± 14.2 years) hospitalized for COVID-19 as confirmed by polymerase chain reaction (PCR) were retrospectively reviewed. Demographic and clinical characteristics and laboratory parameters were analyzed using various statistical modeling. Primary outcomes were defined as the need for intensive care unit (ICU), mechanical ventilation, or occurrence of death. Of the patients, 48 were treated in the ICU with a high flow oxygen/noninvasive mechanical ventilation (NIMV, n = 12) or mechanical ventilation (n = 36). Median length of ICU stay was 13 (range, 7–18) days. Mortality was seen in four of the ICU patients. Other patients were followed in the COVID-19 services for a median of 7 days. There was no significant correlation between the primary outcomes and use of ACEIs/ARBs (frequentist OR = 0.82, 95% confidence interval (CI) 0.29–2.34, p = 0.715 and Bayesian posterior median OR = 0.80, 95% CI 0.31–2.02) and presence of hypertension (frequentist OR = 1.23, 95% CI 0.52–2.92, p = 0.631 and Bayesian posterior median OR = 1.25, 95% CI 0.58–2.60). Neutrophil-to-lymphocyte ratio (NLR) and D-dimer levels were strongly associated with primary outcomes. In conclusion, the presence of hypertension and use of ACEIs/ARBs were not significantly associated with poor primary clinical outcomes; however, NLR and D-dimer levels were strong predictors of clinical worsening.

Renin-angiotensin-aldosterone system inhibition decreased contrast-associated acute kidney injury in chronic kidney disease patients

Chronic kidney disease (CKD) is a risk factor for contrast associated acute kidney injury (CA-AKI). The risk of renin-angiotensin-aldosterone system inhibitor (RASi) use in patients with CKD before the administration of contrast is not clear. In this nested case-control study, 8668 patients received contrast computed tomography (CT) from 2013 to 2018 during index administration in a multicenter hospital cohort. The identification of AKI is based on the Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria within 48h after contrast medium used. Finally, 986 patients (age, 63.36±12.22; men, 72.92%) with CKD (estimated glomerular filtration rate (eGFR)=35.0±19.8mL/min/1.73m2) were eligible for analysis. After the index date, RASi users (n=315) were less likely to develop CA-AKI (13.65% vs 30.4%, p<0.001), and had a lower hospital mortality (8.25% vs 19.23%, p<0.001) compared with non-users. The pre-contrast use of RASi decrease the risk of AKI (OR, 0.342, p<0.001) and hospital mortality (OR, 0.602, p=0.045). Even a few defined daily doses (DDDs) of RASi treatment, more than 0.02 prior to contrast CT could attenuate CA-AKI. The hospital mortality was higher in RASi non-users if their eGFR value was more than 17.9mL/min/1.73m2. RASi use in patients with CKD prior to contrast CT has the potential to mitigate the incidence of AKI and hospital mortality. Even a low dose of RASi will noticeably decrease the risk of AKI and will not increase the risk of hyperkalemia.

Hypertension, renin–angiotensin–aldosterone system inhibition, and COVID-19

Hypertension, renin–angiotensin–aldosterone system inhibition, and COVID-19

Effect of Renin-Angiotensin-Aldosterone System Inhibitors on Short-Term Mortality After Sepsis: A Population-Based Cohort Study.

Antagonists of the renin-angiotensin-aldosterone system (RAAS), including ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers), may prevent organ failure. We, therefore, investigated whether specific RAAS inhibitors are associated with reduced mortality in patients with sepsis.We conducted a population-based retrospective cohort study using multivariable propensity score-based regression to control for differences among patients using different RAAS inhibitors. A multivariable-adjusted Cox proportional-hazards regression model was used to determine the association between RAAS inhibitors and sepsis outcomes. To directly compare ACEI users, ARB users, and nonusers, a 3-way propensity score matching approach was performed. Results were pooled with previous evidence via a random-effects meta-analysis. A total of 52 727 patients were hospitalized with sepsis, of whom 7642 were prescribed an ACEI and 4237 were prescribed an ARB. Using propensity score-matched analyses, prior ACEI use was associated with decreased 30-day mortality (hazard ratio, 0.84 [95% CI, 0.75-0.94]) and 90-day mortality (hazard ratio, 0.83 [95% CI, 0.75-0.92]) compared with nonuse. Prior ARB use was associated with an improved 90-day survival (hazard ratio, 0.88 [95% CI, 0.83-0.94]). These results persisted in sensitivity analyses focusing on patients without cancer and patients with hypertension. By contrast, no beneficial effect was found for antecedent β-blockers exposure (hazard ratio, 0.99 [95% CI, 0.94-1.05]). The pooled estimates obtained from the meta-analysis was 0.71 (95% CI, 0.58-0.87) for prior use of ACEI/ARB.The short-term mortality after sepsis was substantially lower among those who were already established on RAAS inhibitor treatment when sepsis occurred.

Development of a health economic model to evaluate the potential benefits of optimal serum potassium management in patients with heart failure

Aims: Patients with heart failure are at increased risk of hyperkalemia, particularly when treated with renin-angiotensin-aldosterone system inhibitor (RAASi) agents. This study developed a model to quantify the potential health and economic value associated with sustained potassium management and optimal RAASi therapy in heart failure patients.Materials and methods: A patient-level, fixed-time increment stochastic simulation model was designed to characterize the progression of heart failure through New York Heart Association functional classes, and predict associations between serum potassium levels, RAASi use, and consequent long-term outcomes. Following internal and external validation exercises, model analyses sought to quantify the health and economic benefits of optimizing both serum potassium levels and RAASi therapy in heart failure patients. Analyses were conducted using a UK payer perspective, independent of costs and utilities related to pharmacological potassium management.Results: Validation against multiple datasets demonstrated the predictive capability of the model. Compared to those who discontinued RAASi to manage serum potassium, patients with normokalemia and ongoing RAASi therapy benefited from longer life expectancy (+1.38 years), per-patient quality-adjusted life year gains (+0.53 QALYs), cost savings (£110), and associated net monetary benefit (£10,679 at £20,000 per QALY gained) over a lifetime horizon. The predicted value of sustained potassium management and ongoing RAASi treatment was largely driven by reduced mortality and hospitalization risks associated with optimal RAASi therapy.Limitations: Several modeling assumptions were made to account for a current paucity of published literature; however, ongoing refinement and validation of the model will ensure its continued accuracy as the clinical landscape of hyperkalemia evolves.Conclusions: Predictions generated by this novel modeling approach highlight the value of sustained potassium management to avoid hyperkalemia, enable RAASi therapy, and improve long-term health economic outcomes in patients with heart failure.