Renin Angiotensin Aldosterone Inhibitors Research Articles

#1179 Early change of eGFR predicts long-term renal event in patients with hypertensive chronic kidney disease using a RAS blocker

Abstract Background and Aims The renin-angiotensin-aldosterone inhibitor (RASI) is one of the important medications for chronic kidney disease (CKD) with potential decrease of glomerular filtration rate (GFR) after initiation. There are few studies about the effect of GFR change by the RASI on variations of GFR and albuminuria. Method This observational cohort study was the extension of an open-label, case-controlled randomized clinical trial (NCT01552954) including adult hypertensive CKD patients with estimated GFR ≥30 ml/min/1.73 m2 and random urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g creatinine. In the trial phase, the angiotensin receptor blocker (ARB: Olmesartan 40 mg/day) was prescribed to participants after cessation of RASIs for 8 weeks of screening phase. (0-week). Participants had the second visit at 8 weeks after initiation of ARB (8-week) with randomization into the intensive education for low salt diet and the conventional education. Third visit was conducted at 16 weeks after 0-week (16-week). After 27 (19∼38) months later, we recruited participants for the cohort observation and finished at 38 (29∼48) months after 0-week visit. We grouped patients by tertiles of percent change of initial GFR during the first 8 weeks (from 0-week to 8-week) (pcGFRi) and compared the change of UACR from 24-hour urine and estimated GFR during trial and observational period. Results We analyzed data from 174 people finished 38-month observation among 235 participants enrolled for the trial phase. Initial GFR and 24-h urine UACR were 67 ± 24 ml/min/1.73 m2 and 829 ± 829 mg/g cr, respectively. There were −16.0 (−41.5∼−8.1) %, −2.8 (−7.3∼1.6) %, and 8.3 (1.8∼28.4) % pcGFRi in the first tertile group (group 1), the second tertile group (group 2), and the third tertile group (group 3), respectively. There were no differences in age, gender, GFR, 24-hour UACR, and 24-hour sodium excretion among the tertile groups at 0-week visit. The pcGFRi and the tertile group showed positive correlation with GFR change during 16 weeks of the trial, however, were not related to the percent change of 24-hour UACR during the trial phase. They were also positively correlated to the percent change of GFR during whole study period of 38 months (factor B = 8.180 and p-value< 0.001 for the group and factor B = 0.801 and p-value< 0.001 for pcGFRi), although, they did not show relationships with the percent change of 24-hour UACR during whole study period and UACR at last visit. The GFR slopes per year during 38 (29∼48) months were −2.9 (−4.0∼ −1.8), −1.3 (−2.4∼-0.3), and 0.1 (−1.0∼1.2) ml/min/1.73 m2/year in group 1, group 2, and group 3, respectively (p = 0.001 by the ANCOVA test). The relative risks to estimate GFR decrease ≥ 30% during whole study period were 0.237 (0.07∼0.798) (p = 0.020) and 0.035 (0.004∼0.302) (p = 0.035) in group 2 and group 3 compared to group 1, respectively. The AUC to estimate GFR decline ≥ 30% by the pcGFRi was 0.787 (0.685∼0.889, p< 0.001). The cut-off value 7.25% of pcGFRi estimates GFR decline ≥ 30% with 71.4% sensitivity and 70.9% specificity. Conclusion The decline of GFR by initiation of RASI predicts long-term renal event of GFR decline ≥ 30% in users of RASI, strongly. We need to compare the renal outcomes between RASI users with initial decrease of GFR and non-users to make guideline adjusting RASI usage according to initial change of GFR with RASI prescription.

#1609 Effect of dapagliflozin in proteinuria reduction and glomerular filtration rate in a group of Alport syndrome patients

Abstract Background and Aims Alport syndrome (AS) is the most common cause of inherited chronic kidney disease. This disorder is caused by deleterious variants on COL4A3, COL4A4 or COL4A5 genes. These genes codify the proteins that constitute collagen type IV of the glomerular basement membrane (GBM). Alterations in any of collagen type IV constituents cause disruption of the GMB structure, allowing the leakage of red blood cells and proteins, mainly albumin, into the urine resulting in kidney damage and loss of renal function. In AS progressive kidney impairment can be delayed or possibly prevented by timely initiation of renin angiotensin aldosterone inhibitors (RAAi): in males with X-linked AS and in autosomal recessive AS ARAS at diagnosis and in females with XLAS and autosomal dominant AS at the onset of microalbuminuria. Recently, it was showed that sodium-cotransporter-2 inhibitors (SGLT2i) reduce proteinuria and slow the progression of kidney disease in many glomerular diseases. Thus, also in AS, SGLT2i could be promising in renal disease progression control. The aim of this study was to determine the proteinuria reduction and the effect on the glomerular filtration rate (GFR) in a group of AS patients with persistent proteinuria besides the use of RAAi in maximum tolerated doses after adding SGLT2i to the treatment. Method This study was single-center, observational and prospective study evolving 8 AS adult patients, without a diagnosis of diabetes, with persistent proteinuria besides the use of RAAi in maximum tolerated doses. All patients were prescribed wit dapagliflozin 10 mg daily. We determine the changes from baseline of urinary protein/creatine (Up/cr) and glomerular filtration rate (based on epiGFR formula). Results Eight AS patients were included in this study. All were male patients. One patient has XLAS and the other 7 patients have ADAS. No patient was diabetic, and all were under RAAi in maximum tolerated doses. We determine de Up/cr and epiGFR at baseline and median time of 213.5 days (IQR 208.3-259) after SGLT2i initiation. At baseline, the median of Up/cr was 1.4 (IQR 0.8-2.1) and after SGLT2i Up/cr was 1.5 (0.8-2.6), p = 0.727. Up/cr, after SGLT2i treatment, reduced in 3 patients and worsened in 5. Median epiGFR at baseline was 80.3 ml/min (IQR 40.9-109.5) and after SGLT2i initiation was 74.7 ml/min (40.4-112.0), p = 0.727. Conclusion In this study, we did not observe an improvement in Up/cr of AS patients with SGLT2i treatment. A slight decrease in GFR was observed that may be due to the well know hemodynamic effects of SGLT2i. The small cohort and short time of the study are factors that can interfere in these results and should not discourage the treatment of AS patients with SGLT2i.

#325 Prescribing patterns in older people with advanced chronic kidney disease approaching the end of life

Abstract Background and Aims Advancing age and chronic kidney disease (CKD) are risk factors for polypharmacy—the regular daily intake of >5 medications. Polypharmacy is a key action area for the World Health Organization in its effort to reduce global medication-related harm. Deprescribing, the systematic review and rationalisation of potentially inappropriate medications, is a proposed way of addressing polypharmacy. Deprescribing is particularly relevant near the end of life, when preventative treatments provide less benefit. Prescribing practices for elderly people with advanced CKD in the last years of life are currently unknown. The aim of this study was to describe prescribing and deprescribing patterns in such a cohort. Method The EQUAL study [1] is an international, prospective cohort study of people ≥65 years with an incident estimated glomerular filtration rate (eGFR) of ≤20 ml/min/1.73 m2. We analysed data from participants who died during follow up, including 3-6 monthly study-visit-collected prescribed oral medications (POMs). Generalized additive models were used to explore trends leading up to death in the total number of POMs, and the proportion of participants taking specific medications. Data are presented for medications: a) identified as targets for deprescribing in the elderly with CKD (statins, proton-pump inhibitors (PPIs) and antihypertensives—alpha-blockers, beta-blockers, calcium-channel blockers (CCBs), diuretics and renin-angiotensin-aldosterone inhibitors (RAASis)); b) used for symptom control in kidney failure (opioids and gabapentinoids); and c) prescribed to >30% of the cohort (allopurinol, aspirin, vitamin D). Results Data from 563 participants were analysed, comprising 2793 study visits (median follow-up time 2.2 years (interquartile range (IQR) 1.1-3.8) pre-death), and 22,200 POMs. At baseline, mean age was 77.8 years (standard deviation (SD) 6.7), median eGFR 18.1 mls/min/1.73 m2 (IQR 15.0-21.2), and 87.2% were experiencing polypharmacy. The number of POMs increased over the time approaching death (Fig. 1)—7.3 (95% confidence interval (CI) 6.9-7.7) at 5 years pre-death, 8.3 (95% CI 8.0-8.6) at 2.5 years pre-death, and 8.7 (95% CI 8.4-9.1) at death. At their final study visit 90.1% were experiencing polypharmacy. Trends in the proportion of individuals prescribed specific medications differed by POM class (Fig. 2). Opioids, diuretics and PPIs increased in the last years of life; statins, RAASis, alpha-blockers and CCBs decreased; and allopurinol, beta-blockers and gabapentinoids remained stable. Aspirin and vitamin D showed phasic patterns, increasing then decreasing. Conclusion Elderly people with advanced CKD experience increasing levels of polypharmacy as they approach the end of life. Although there is evidence that certain medication classes are being deprescribed, this is outweighed by increased prescribing of other agents. Previous analyses of EQUAL decedents have shown that blood pressure decreases pre-death—we show this is despite reductions in most classes of antihypertensives. Our work suggests a high reliance upon pharmacological interventions (both symptom-directed and preventative) for older people with CKD who are approaching death. We cannot ascertain whether this reflects personalised prescribing, aligned with individuals’ preferences and prognoses; however, high levels of polypharmacy potentiate risks of side effects, medication burden and drug-drug interactions, and indicate a role for enhanced medication review in this setting.

Abstract WP187: Association of Renin Angiotensin Aldosterone Blockade and Hypotension After Carotid Artery Stenting

Background: Persistent hypotension after carotid artery stenting (CAS) can lead to adverse outcomes, prolong length of stay (LOS), and increase hospital costs. As catecholamine plays a critical role in blood pressure (BP) regulation, we aimed to determine the relationship between the use of renin-angiotensin-aldosterone inhibitor (RASI) drugs and post-CAS hypotension. Methods: A multicenter prospective study of patients with extracranial internal carotid artery stenosis and history of hypertension requiring CAS at two hospitals in China between January 2020 to May 2023. BP was recorded at frequent intervals for at least 24 hours post-CAS. Blood catecholamine concentrations were assessed in the morning of, and day immediately after, CAS in a subset of patients. Persistent hypotension was defined as systolic BP <90 mmHg or requiring vasopressor treatment for at least 6 hours. Logistic regression models assessed differences in the rates of post-CAS hypotension between RASI and non-RASI patients with adjustment for known confounding variables. Findings: There were 329 patients included: 160 in the RASI group and 169 in the non-RASI group. The RASI group had a higher rate of persistent hypotension (relative risk 1.52, P=0.031). The RASI group showed a greater decline in norepinephrine concentration after CAS compared with the non-RASI group (P=0.008). Patients with persistent post-CAS hypotension showed a similar decline in norepinephrine concentration (P=0.004) when compared with patients without persistent hypotension. Persistent hypotension prolonged LOS (P=0.014). Conclusion: Prior use of RASI for the treatment of hypertension is associated with persistent hypotension after CAS. A relation between decline of norepinephrine after stenting and persistent hypotension supports the role of catecholamine in BP control.

Hyperkalaemia in Cardiological Patients: New Solutions for an Old Problem.

Hyperkalaemia is one of the most common electrolyte disorders in patients with cardiovascular disease (CVD). The true burden of hyperkalaemia in the real-world setting can be difficult to assess, but in population-based cohort studies up to 4 in 10 patients developed hyperkalaemia. In addition to drugs interfering with potassium metabolism and food intake, several conditions can cause or worsen hyperkalaemia, such as advanced age, diabetes, and chronic kidney disease. Mortality, cardiovascular morbidity, and hospitalisation are higher in patients with hyperkalaemia. Hyperkalaemia represents a major contraindication or a withholding cause for disease-modifying therapies like renin-angiotensin-aldosterone inhibitors (RAASi), mainly mineralocorticoid receptor antagonists. Hyperkalaemia can be also classified as acute and chronic, according to the onset. Acute hyperkalaemia is often a life-threatening emergency requiring immediate treatment to avoid lethal arrhythmias. Therapy goal is cell membrane stabilisation by calcium administration, cellular intake, shift of extracellular potassium to the intracellular space (insulin, beta-adrenergic agents, sodium bicarbonate), and increased elimination with diuretics or dialysis. Chronic hyperkalaemia was often managed with dietary counselling to prevent potassium-rich food intake and tapering of potassium-increasing drugs, mostly RAASi. Sodium polystyrene sulphonate, a potassium binder, was the only therapeutic option. Recently, new drugs such as patiromer and sodium zirconium cyclosilicate give new opportunities for the treatment of hyperkalaemia, as they proved to be safe, well tolerated, and effective. Aim of this review is to describe the burden of hyperkalaemia in cardiovascular patients, its direct and indirect effects, and the therapeutic options now available in the acute and chronic setting.

Association and progression of multi-morbidity with Chronic Kidney Disease stage 3a secondary to Type 2 Diabetes Mellitus, grouped by albuminuria status in the multi-ethnic population of Northwest London: A real-world study.

The prevalence of Diabetic Kidney Disease (DKD) secondary to Type 2 Diabetes Mellitus (T2DM) is rising worldwide. However, real-world data linking glomerular function and albuminuria to the degree of multi-morbidity is lacking. We thus utilised the Discover dataset, to determine this association. Patients with T2DM diagnosed prior to 1st January 2015 with no available biochemical evidence of CKD were included. Patients subsequently diagnosed and coded for CKD3a in 2015, were grouped by the degree of albuminuria. Baseline and 5-year co-morbidity was determined, as were prescribing practices with regards to prognostically beneficial medication. We identified 56,261 patients with T2DM, of which 1082 had CKD stage 3a diagnosed in 2015 (224-CKD3aA1,154-CKD3aA2,93-CKD3aA1; 611 patients with CKD3a but no uACR available in 2015 were excluded from follow up). No statistically significant difference was observed in the degree of co-morbidities at baseline. A significant difference in the degree of hypertension, retinopathy, ischaemic heart disease and vascular disease from baseline compared to study end point was observed for all 3 study groups. Comparing co-morbidities developed at study end point, highlighted a statistical difference between CKD3aA1 Vs CKD3aA3 for retinopathy alone and for hypertension and heart failure between CKD3aA2 Vs CKD3aA3. 40.8% of patients with CKD3aA2 or A3 were prescribed Renin Angiotensin Aldosterone inhibitors (RAASi) therapy between June-December 2021. Survival analysis showed 15% of patients with CKD3aA3 developed CKD stage 5 within 5 years of diagnosis. CKD3a secondary to DKD is associated with significant multimorbidity at baseline and 5 years post diagnosis, with CKD3aA3 most strongly associated with CKD progression to CKD 5, heart failure, hypertension and retinopathy compared to CKD3aA1 or CKD3aA2 at 5 years post diagnosis. The lack of uACR testing upon diagnosis and poor prescribing of RAASi, in those with CKD3aA2/A3, raises significant cause for concern. DKD is associated with significant multimorbidity. Significant work is needed to be done to ensure patients undergo testing for uACR, to allow for future risk stratification and ability to be started on prognostically beneficial medication.

Probiotics and Fecal Transplant: An Intervention in Delaying Chronic Kidney Disease Progression?

Chronic kidney disease (CKD) is a global health challenge affecting nearly 700 million people worldwide. In the United States alone, the Medicare costs for CKD management has reached nearly USD 80 billion per year. While reversing CKD may be possible in the future, current strategies aim to slow its progression. For the most part, current management strategies have focused on employing Renin Angiotensin Aldosterone (RAS) inhibitors and optimizing blood pressure and diabetes mellitus control. Emerging data are showing that a disruption of the gut-kidney axis has a significant impact on delaying CKD progression. Recent investigations have documented promising results in using microbiota-based interventions to better manage CKD. This review will summarize the current evidence and explore future possibilities on the use of probiotics, prebiotics, synbiotics, and fecal microbial transplant to reduce CKD progression.

Characteristics, management and outcomes in patients with CKD in a healthcare region in Sweden: a population-based, observational study

ObjectivesTo describe chronic kidney disease (CKD) regarding treatment rates, comorbidities, usage of CKD International Classification of Diseases (ICD) diagnosis, mortality, hospitalisation, evaluate healthcare utilisation and screening for CKD in relation...

Comparing clinical outcomes of ARB and ACEi in patients hospitalized for acute COVID-19

Continued receipt of Renin–Angiotensin–Aldosterone inhibitors in patients with COVID-19 has shown potential in producing better clinical outcomes. However, superiority between ACEi (angiotensin-converting enzyme inhibitors) and ARB (angiotensin II receptor blockers) regarding clinical outcomes in this setting remains unknown. We retrospectively collected data on patients hospitalized for acute COVID-19 using the nationwide administrative database (Diagnosis and Procedure Combinations, DPC). The DPC data covered around 25% of all acute care hospitals in Japan. Patient outcomes, with focus on inpatient mortality, were compared between patients previously prescribed ACEi and those prescribed ARB. Comparisons based on crude, multivariate and propensity-score adjusted analysis were conducted. We examined a total of 7613 patients (ARB group, 6903; ACEi group 710). The ARB group showed lower crude in-hospital mortality, compared to the ACEi group (5% vs 8%; odds ratio, 0.65; 95% CI 0.48–0.87), however not in the multivariate-adjusted model (odds ratio, 0.95; 95% CI 0.69–1.3) or propensity-score adjusted models (odds ratio, 0.86; 95% CI 0.63–1.2). ARB shows potential in reducing hospital stay duration over ACEi in patients admitted for COVID-19, but does not significantly reduce in-hospital mortality. Further prospective studies are needed to draw a definitive conclusion, but continuation of either of these medications is warranted to improve clinical outcomes.

#2697 ASSOCIATION OF CARDIOMETABOLIC PROTEINS WITH EGFR DECLINE IN OLDER ADULTS WITH ADVANCED CHRONIC KIDNEY DISEASE

Abstract Background and Aims Cardiovascular disease and advanced chronic kidney disease often coexist and share risk factors in older individuals. We investigated the association of cardiometabolic and cardiovascular proteins and pathways with decline in estimated glomerular filtration rate (eGFR). Method Two plasma protein panels (Olink® cardiometabolic T96 and cardiovascular II T96, Uppsala, Sweden) were analysed at the baseline visit of individuals enrolled in the prospective observational European QUALity (EQUAL) study of older people > 65 years with advanced CKD (incident eGFR < 20 ml/min/1.73m2). Generalised linear mixed effects models with a log link and random intercept and slope were used to determine annualised eGFR slope (CKD-EPI 2009 equation) using a complete case model. The model was executed in a “discovery” sample (Germany, United Kingdom and Poland) and positive results (< false discovery rate [FDR] of 5%) were tested in a Swedish “validation” sample using the same FDR criterion. The primary analysis was adjusted for baseline age, sex, country, diabetes mellitus status, primary renal disease, systolic blood pressure, urine albumin to creatinine ratio (ACR), and the use of renin-angiotensin aldosterone inhibitors and β-blockers. A sensitivity analysis was conducted to determine the effect of informative censoring on eGFR slope using a joint model. Results The discovery and validation samples had 254 subjects (median age 67 years, 41% female, median baseline eGFR 18 ml/min/1.73m2) and 247 (median age 75 years, 28% female and median baseline eGFR 18 ml/min/1.73m2) respectively with longer follow-up time for the validation sample (median 3.6 versus 2.6 years) primarily due to less kidney replacement therapy initiation (33% versus 37%) and fewer losses to follow up (5% versus 12%). Two of the 175 proteins showed more rapid eGFR annual decline per doubling in protein levels (Figure 1): Receptor-type tyrosine-protein phosphatase S [PTPRS] (-15%; 95% confidence interval [CI] –24 to –7%, pFDR = 0.01) and Insulin-like growth factor-binding protein 6 [IGFBP6] (–8%; 95% CI –12 to –3%, pFDR = 0.03) (Figure 2). Predicted slopes were similar across both samples and for the sensitivity analyses. Conclusion Receptor-type tyrosine-protein phosphatase S and Insulin-like growth factor-binding protein 6 were associated with more rapid CKD progression. Further research is needed to determine if these proteins are pathophysiologically linked to accelerated progression of CKD in older people or a secondary consequence of disturbances in protein sequestration or excretion.

Correction: Kohsaka et al. Risk–Benefit Balance of Renin–Angiotensin–Aldosterone Inhibitor Cessation in Heart Failure Patients with Hyperkalemia. J. Clin. Med. 2022, 11, 5828

In the original publication [...].

Sex disparities in medication prescribing amongst patients with type 2 diabetes mellitus managed in primary care.

Sex differences in clinical outcomes have been observed for patients with type 2 diabetes mellitus (T2DM). These could be related to sex disparities in treatment. To determine whether there are sex disparities in medication prescribing amongst patients with T2DM. A cohort study was conducted using the Groningen Initiative to ANalyze Type 2 diabetes Treatment (GIANTT) database, which includes data from primary care patients with T2DM from the north of the Netherlands. Data on demographics, physical examinations, laboratory measurements and prescribing were extracted. A set of validated prescribing quality indicators assessing the prevalence, start, intensification and safety of glucose-, lipid-, blood pressure- and albuminuria-lowering medication was applied for the calendar year 2019. Univariate logistic regression analyses were conducted. We included 10,456 patients (47% females). Females were less often treated with metformin (81.7% vs. 86.5%; OR 0.70, 95% CI 0.61-0.80), and were less often prescribed a renin-angiotensin-aldosterone inhibitor (RAAS-i) when treated with multiple blood pressure-lowering medicines (81.9% vs. 89.3%; OR 0.55, 95% CI 0.46-0.64) or when having albuminuria (74.7% vs. 82.1%; OR 0.64, 95% CI 0.49-0.85) than males. Statin treatment was less frequently started (19.7% vs. 24.7%; OR 0.75, 95% CI 0.58-0.96) and prescribed (58.7% vs. 63.9%; OR 0.80, 95% CI 0.73-0.89) in females. There were no differences in starting and intensifying glucose-, blood pressure- and albuminuria-lowering medication. Sex disparities in medication prescribing amongst T2DM patients were seen, including less starting with statins and potential undertreatment with RAAS-i in females. Such disparities may partly explain higher excess risks for cardiovascular and renal complications associated with diabetes observed in females.

Machine Learning Models Predicting Cardiovascular and Renal Outcomes and Mortality in Patients with Hyperkalemia.

Hyperkalemia is associated with increased risks of mortality and adverse clinical outcomes. The treatment of hyperkalemia often leads to the discontinuation or restriction of beneficial but potassium-increasing therapy such as renin-angiotensin-aldosterone inhibitors (RAASi) and high-potassium diet including fruits and vegetables. To date, limited evidence is available for personalized risk evaluation in this heterogeneous and multifactorial pathophysiological condition. We developed risk prediction models using extreme gradient boosting (XGB), multiple logistic regression (LR), and deep neural network. Models were derived from a retrospective cohort of hyperkalemic patients with either heart failure or chronic kidney disease stage ≥3a from a Japanese nationwide database (1 April 2008-30 September 2018). Studied outcomes included all-cause death, renal replacement therapy introduction (RRT), hospitalization for heart failure (HHF), and cardiovascular events within three years after hyperkalemic episodes. The best performing model was further validated using an external cohort. A total of 24,949 adult hyperkalemic patients were selected for model derivation and internal validation. A total of 1452 deaths (16.6%), 887 RRT (10.1%), 1,345 HHF (15.4%), and 621 cardiovascular events (7.1%) were observed. XGB outperformed other models. The area under receiver operator characteristic curves (AUROCs) of XGB vs. LR (95% CIs) for death, RRT, HHF, and cardiovascular events were 0.823 (0.805-0.841) vs. 0.809 (0.791-0.828), 0.957 (0.947-0.967) vs. 0.947 (0.936-0.959), 0.863 (0.846-0.880) vs. 0.838 (0.820-0.856), and 0.809 (0.784-0.834) vs. 0.798 (0.772-0.823), respectively. In the external dataset including 86,279 patients, AUROCs (95% CIs) for XGB were: death, 0.747 (0.742-0.753); RRT, 0.888 (0.882-0.894); HHF, 0.673 (0.666-0.679); and cardiovascular events, 0.585 (0.578-0.591). Kaplan-Meier curves of the high-risk predicted group showed a statistically significant difference from that of the low-risk predicted groups for all outcomes (p < 0.005; log-rank test). These findings suggest possible use of machine learning models for real-world risk assessment as a guide for observation and/or treatment decision making that may potentially lead to improved outcomes in hyperkalemic patients while retaining the benefit of life-saving therapies.

Risk-Benefit Balance of Renin-Angiotensin-Aldosterone Inhibitor Cessation in Heart Failure Patients with Hyperkalemia.

Background: Whether to continue renin–angiotensin–aldosterone system inhibitor (RAASi) therapy in patients with hyperkalemia remains a clinical challenge, particularly in patients with heart failure (HF), where RAASis remain the cornerstone of treatment. We investigated the incidence of dose reduction or the cessation of RAASis and evaluated the threshold of serum potassium at which cessation alters the risk–benefit balance. Methods: This retrospective analysis of a Japanese nationwide claims database investigated treatment patterns of RAASis over 12 months after the initial hyperkalemic episode. The incidences of the clinical outcomes of patients with RAASi (all ACEi/ARB/MRA) or MRA-only cessation (vs. non-cessation) were compared via propensity score-matched patients. A cubic spline regression analysis assessed the hazard of death resulting from treatment cessation vs. no cessation at each potassium level. Results: A total of 5059 hyperkalemic HF patients were identified; most received low to moderate doses of ACEis and ARBs (86.9% and 71.5%, respectively) and low doses of MRAs (76.2%). The RAASi and MRA cessation rates were 34.7% and 52.8% at 1 year post-diagnosis, while the dose reduction rates were 8.4% and 6.5%, respectively. During the mean follow-up of 2.8 years, patients who ceased RAASi or MRA therapies were at higher risk for adverse outcomes; cubic spline analysis found that serum potassium levels of <5.9 and <5.7 mmol/L conferred an increased mortality risk for RAASi and MRA cessation, respectively. Conclusions: Treatment cessation/dose reduction of RAASis are common among HF patients. The risks of RAASi/MRA cessation may outweigh the benefits in patients with mild to moderate hyperkalemia.

Management of Heart Failure in Patients with Chronic Kidney Disease.

Chronic kidney disease (CKD) is increasingly prevalent in patients with heart failure (HF) and HF is one of the leading causes of hospitalisation, morbidity and mortality in patients with impaired renal function. Currently, there is strong evidence to support the symptomatic and prognostic benefits of β-blockers, renin–angiotensin–aldosterone inhibitors (RAASis), angiotensin receptor-neprilysin inhibitors (ARNIs) and mineralocorticoid receptor antagonists (MRA) in patients with HF and CKD stages 1–3. However, ARNIs, RAASis and MRAs are often suboptimally prescribed for patients with CKD owing to concerns about hyperkalaemia and worsening renal function. There is growing evidence for the use of sodium–glucose co-transporter 2 inhibitors and IV iron therapy in the management of HF in patients with CKD. However, few studies have included patients with CKD stages 4–5 and patients receiving dialysis, limiting the assessment of the safety and efficacy of these therapies in advanced CKD. Interdisciplinary input from HF and renal specialists is required to provide integrated care for the growing number of patients with HF and CKD.

THE RENIN-ANGIOTENSIN SYSTEM INHIBITORS IN HAEMODIALYSIS: CARDIOPROTECTIVE? TO WHAT EXTENT?

Objective: The renin-angiotensin-aldosterone (RAAS) system is one of the most important systems in the pathogenesis of coronary heart disease. Its blockage constitutes a central pillar of cardiovascular therapeutics. Patients in end-stage renal disease or on dialysis are almost invariably excluded from trials evaluating antihypertensive treatments. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) are more cardioprotective than other antihypertensive agents in patients with chronic renal disease but whether this applies also to patients on dialysis is unknown. This study followed a cohort of haemodialysis patients over a median of three years, we analysed all-cause mortality and cardio-vascular admissions for patients under RAAS inhibitors. Design and method: Twenty-seven HD patients were cross-sectionally analysed in the following groups: G1: patients with hypertension under ACE or ARB treatment (n = 10), G2: patients with hypertension under another class (n = 7), G3: non-hypertensive patients (n = 10). Associations with all-cause and cardiovascular mortality were assessed over a median of 3 years of follow-up. Results: Overall we had three homogeneous groups, there was no significant difference between median ages (46,3 vs52,7 vs49,9), initial nephropathy or dialysis vintage (5,9 years vs 5,1 vs 11,4). In G1: 4 patients experienced cardiovascular events (40%), but none of them died of cardiovascular causes/complications. In G2: 4 patients had cardiovascular events (57%) amongst whom two died of its complications. In G3: two patients had cardiovascular events (20%) amongst whom one died. There was statistically no significant difference between our groups in terms of cardiovascular morbidity or mortality and in all-causes mortality. Nevertheless, patients under SRA inhibitors presented the lowest number of cardiovascular mortalities. Conclusions: In the study, we observed that patients with SRA inhibitors experienced less cardio-vascular related death, although it is not enough to conclude its cardioprotective status. Larger studies need to be carried to unveil its utility among haemodialysis patients.

Hypertension and Arrhythmias: A Clinical Overview of the Pathophysiology-Driven Management of Cardiac Arrhythmias in Hypertensive Patients.

Because of demographic aging, the prevalence of arterial hypertension (HTN) and cardiac arrhythmias, namely atrial fibrillation (AF), is progressively increasing. Not only are these clinical entities strongly connected, but, acting with a synergistic effect, their association may cause a worse clinical outcome in patients already at risk of ischemic and/or haemorrhagic stroke and, consequently, disability and death. Despite the well-known association between HTN and AF, several pathogenetic mechanisms underlying the higher risk of AF in hypertensive patients are still incompletely known. Although several trials reported the overall clinical benefit of renin–angiotensin–aldosterone inhibitors in reducing incident AF in HTN, the role of this class of drugs is greatly reduced when AF diagnosis is already established, thus hinting at the urgent need for primary prevention measures to reduce AF occurrence in these patients. Through a thorough review of the available literature in the field, we investigated the basic mechanisms through which HTN is believed to promote AF, summarising the evidence supporting a pathophysiology-driven approach to prevent this arrhythmia in hypertensive patients, including those suffering from primary aldosteronism, a non-negligible and under-recognised cause of secondary HTN. Finally, in the hazy scenario of AF screening in hypertensive patients, we reviewed which patients should be screened, by which modality, and who should be offered oral anticoagulation for stroke prevention.

Chronic use of renin–angiotensin–aldosterone inhibitors in hypertensive COVID-19 patients: Results from a Spanish registry and meta-analysis

BackgroundHypertension is a prevalent condition among SARS-CoV-2 infected patients. Whether renin–angiotensin–aldosterone system (RAAS) inhibitors are beneficial or harmful is controversial. MethodsWe have performed a national retrospective, nonexperimental comparative study from two tertiary hospitals to evaluate the impact of chronic use of RAAS inhibitors in hypertensive COVID-19 patients. A meta-analysis was performed to strengthen our findings. ResultsOf 849 patients, 422 (49.7%) patients were hypertensive and 310 (73.5%) were taking RAAS inhibitors at baseline. Hypertensive patients were older, had more comorbidities, and a greater incidence of respiratory failure (−0.151 [95% CI −0.218, −0.084]). Overall mortality in hypertensive patients was 28.4%, but smaller among those with prescribed RAAS inhibitors before (−0.167 [95% CI −0.220, −0.114]) and during hospitalization (0.090 [−0.008,0.188]). Similar findings were observed after two propensity score matches that evaluated the benefit of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers among hypertensive patients. Multivariate logistic regression analysis of hypertensive patients found that age, diabetes mellitus, C-reactive protein, and renal failure were independently associated with all-cause mortality. On the contrary, ACEIs decreased the risk of death (OR 0.444 [95% CI 0.224–0.881]). Meta-analysis suggested a protective benefit of RAAS inhibitors (OR 0.6 [95% CI 0.42–0.8]) among hypertensive COVID-19. ConclusionOur data suggest that RAAS inhibitors may play a protective role in hypertensive COVID-19 patients. This finding was supported by a meta-analysis of the current evidence. Maintaining these medications during hospital stay may not negatively affect COVID-19 outcomes.

M15. The potential benefits of renin-angiotensin-aldosterone and beta-adrenergic inhibitions for lowering trastuzumab-associated cardiotoxicity risks among breast cancer patients: meta-analysis of randomized controlled trials

Abstract Background and Aims Trastuzumab is one of the principal treatments for HER2-positive breast cancer patients and related to high cardiotoxicity risk. This study aims to compare the efficacies among Renin-Angiotensin-Aldosterone inhibitors (RAASi) and beta-blockers (BB) to lower trastuzumab-associated cardiotoxicity risks. Method and Results Comprehensive literature searching was conducted through online databases then followed the PRISMA guideline. Studies included were all randomized controlled trials (RCTs) that compared the changes of left ventricular ejection fraction (LVEF) and brain natriuretic peptides (BNP) among RAASi, BB, and placebo (PCB) in HER2-positive breast cancer patients who received trastuzumab. Bias risk was accessed by using the Cochrane Risk-of-bias (RoB 2) instrument. Analysis was performed to provide pooled risk ratio (RR) and standard mean difference (SMD) with 95% confidence interval (CI) using fixed-effect heterogeneity test. The RAASi group shows significant LVEF improvement compared with PCB (SMD=0.63, 95%CI 0.27 to 0.99, p = 0.0006, I2=0%), while the BB group also shows LVEF improvement compared with PCB although not statistically significant (SMD=0.04, 95%CI -0.32 to 0.39, p = 0.84, I2=0%). Both RAASi (SMD=0.18, 95%CI 0.00 to 0.37, p = 0.05, I2=0%) and BB (SMD=0.23, 95%CI 0.05 to 0.42, p = 0.01, I2=0%) groups have significant BNP improvement. Patients received RAASi have significant reduction of 2-year cardiac risk development (RR = 0.42, 95%CI 0.27-0.67, p = 0.0002, I2=42%) and non-significance LVEF &amp;lt;50% reduction risk (RR = 0.49, 95%CI 0.23-1.08, p = 0.08, I2=50%). Conclusion Both RAASi and BB show potential benefits in lowering the trastuzumab-associated cardiotoxicity risks. However, further studies are needed to establish the efficacies.

Monoamine oxidase contributes to the valvular oxidative stress in patients with mitral valve regurgitation

Abstract Background Oxidative stress plays a central role in the pathogenesis of cardiovascular diseases but the role of enzymatic sources of reactive oxygen species (ROS) remains elusive. There is scarce information in the literature regarding valvular oxidative stress. Monoamine oxidases (MAOs), with 2 isoforms, A and B, have emerged as important sources of oxidative stress in the cardiovascular system. Purpose To assess whether MAOs-related oxidative stress occurs in the pathological valves in patients with severe mitral regurgitation (due to valve degeneration and chordae rupture) and surgical indication and its interference with the activation of the renin-angiotensin aldosterone (RAAS) system. Material and methods Samples of mitral valve (n=17) were harvested during the valvular replacement procedure and used for reactive oxygen species (ROS) assessment (immune-fluorescence, spectrophotometry) and MAO mRNA and protein expression (qPCR and immune-fluorescence) measurement. Inflammatory markers, biochemical parameters and echocardiography (GE, Vivid 9, Vivid E95) data were also collected. Results Both MAO isoforms are expressed in the diseased mitral valves, with a predominance of MAO-A isoform. Ex vivo incubation with angiotensin 2 (12 h, 100 nM) of samples obtained from patients without RAAS medication lead to MAO upregulation and high ROS production. MAO-related oxidative stress was mitigated by MAO inhibition with clorgyline (MAO-A inhibitor, 10 microM) and selegyline (MAO-B inhibitor, 10 microM) and also by the angiotensin II receptor type 1 (AT1) antagonist, irbersartan (10 microM). Conclusions Monoamine oxidase is expressed in the pathological mitral valves, regardless the etiology. Its expression and the related-oxidative stress are modulated by angiotensin 2, irbesartan. Whether the latter effect is present in valvular patients treated with RAAS inhibitors is currently under investigation. Funding Acknowledgement Type of funding sources: None.