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Background: The guidelines recommend the initiation or up-titration of heart failure (HF) treatments following an HF hospitalization; however, concerns about adverse events may limit the use of mineralocorticoid receptor antagonists (MRAs). Patient profiles or disease severity might impact adverse events associated with MRA therapy in acute HF., Methods: The EARLIER trial included patients with acute HF who were randomized to eplerenone or placebo over 6 months. Adverse events (i.e., worsening renal function [WRF], hyperkalemia, hypotension, and volume depletion/dehydration) were assessed. HF-related outcome included a composite of all-cause mortality, HF re-hospitalization, investigator-reported worsening HF and out-of-hospital diuretic intensification., Results: In 297 patients (mean age: 67 ± 13 years; 73% males), adverse events were observed: 44.4% experienced WRF (>20% drop in estimated glomerular filtration rate[eGFR] and/or investigator-reported WRF), 8.4% had hyperkalemia (potassium >5.5 mmol/L and/or investigator-reported hyperkalemia), 27.9% experienced hypotension (systolic blood pressure[SBP] <90 mmHg and/or investigator-reported hypotension), and 16.8% had investigator-reported volume depletion/dehydration. Eplerenone vs. placebo did not elevate the incidence of these events (all-p-values>0.0 5). Multivariable analyses revealed that, irrespective of treatment allocation, older age (>7 5 years), prevalent diabetes, symptomatic congestion, and microalbuminuria were associated with increased risk of WRF. Baseline eGFR<60 ml/min/1.73m 2 and SBP < 90 mmHg predicted hyperkalemia and hypotension, respectively, while older patients were more likely to experience volume depletion/dehydration. However, these patient profiles did not alter the benefit of eplerenone on outcomes (HR [9 5%CI] = 0.53 [0.29 to 0.97], P = 0.04; all-p-for-interaction>0.10)., Conclusion: Eplerenone did not increase adverse events compared with placebo in acute HF. Importantly, disease severity and comorbidity burden greatly influence adverse events, but not benefit from eplerenone., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Spironolactone (SPL) is an effective treatment for women acne, but other effects on skin biophysical properties remain to be investigated., Objectives: The aim of the current study was to explore the effects of oral SPL used to treat women acne on skin biophysical properties, including hydration, transepidermal water loss (TEWL), skin surface lipid (SSL) levels, mechanical properties, color, pH, and pore size., Materials and Methods: Twenty-five Thai women with acne treated with oral SPL were followed for 6 months. Skin hydration, TEWL, SSL levels, mechanical properties, color, pH, and pore size of the forehead, chest, and inner arm were evaluated at baseline and 2, 4, and 6 months after treatment with oral SPL. Facial and upper back pore size were also assessed. Clinical outcomes were changes in these skin biophysical properties at each visit compared with baseline., Results: Skin hydration, TEWL, SSL levels, color, pH, and pore size remained stable throughout the study. Facial skin parameters at 6 months demonstrated the following changes: hydration levels, 7.60 (95% confidence interval [CI], -59.74 to 74.94); TEWL, -2.36 (95% CI, -5.77 to 1.06); L* value, 0.51 (95% CI, -0.70 to 1.72); individual typology angle, 1.65 (95% CI -2.27 to 5.57); pH, 0.01 (95% CI -0.43 to 0.46); pore size, -0.24 (95% CI, -1.21 to 0.73); and SSL levels, 7.60 (95% CI -59.74 to 74.94). Improvement of facial mechanical properties was observed. R0 (indicating skin tightness) and R1 (indicating elasticity) showed significant decreases (-0.076 [95% CI, -0.141 to -0.010] and -0.016 [95% CI, -0.033 to -0.001]). R3 and R4 (representing tiring effects) were also improved (-0.091 [95% CI, -0.158 to -0.025] and -0.022 [95% CI, -0.044 to -0.001]). Parameters in the truncal and inner arm areas remained stable, except for skin elasticity and tiring effects, which exhibited a similar trend of improvement as the facial area. The changes were notable as early as 4 months., Conclusion: Oral SPL used for acne did not impair the skin barrier. Moreover, the skin mechanical properties were improved at 4 to 6 months., (© 2024 Japanese Dermatological Association.)

The concept of quadruple therapy as a "one-size-fit-all" approach is effective among all eligible patients with heart failure with reduced ejection fraction, with consistent and significant clinical benefits including reduced mortality across various subgroups. However, with exception of sodium-glucose cotransporter 2 inhibitors, the consistency of benefit with therapies does not extend to patients with heart failure with preserved ejection fraction. The clinical benefits of other promising medical therapies, such as angiotensin receptor-neprilysin inhibitors, mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists, have been demonstrated only in certain phenotypes of the highly heterogenous heart failure with preserved ejection fraction population. This variability can confuse frontline practicing cardiologists, potentially leading to the under-implementation of these medications. Therefore, we propose a simple approach: "targeted" combination therapy. This strategy aims to optimize evidence-based medications in heart failure with preserved ejection fraction by tailoring treatments to specific subgroups within the heart failure with preserved ejection fraction population where significant benefits are most evident., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Steroidal mineralocorticoid receptor antagonists reduce morbidity and mortality among patients with heart failure and reduced ejection fraction, but their efficacy in those with heart failure and mildly reduced or preserved ejection fraction has not been established. Data regarding the efficacy and safety of the nonsteroidal mineralocorticoid receptor antagonist finerenone in patients with heart failure and mildly reduced or preserved ejection fraction are needed., Methods: In this international, double-blind trial, we randomly assigned patients with heart failure and a left ventricular ejection fraction of 40% or greater, in a 1:1 ratio, to receive finerenone (at a maximum dose of 20 mg or 40 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of total worsening heart failure events (with an event defined as a first or recurrent unplanned hospitalization or urgent visit for heart failure) and death from cardiovascular causes. The components of the primary outcome and safety were also assessed., Results: Over a median follow-up of 32 months, 1083 primary-outcome events occurred in 624 of 3003 patients in the finerenone group, and 1283 primary-outcome events occurred in 719 of 2998 patients in the placebo group (rate ratio, 0.84; 95% confidence interval [CI], 0.74 to 0.95; P = 0.007). The total number of worsening heart failure events was 842 in the finerenone group and 1024 in the placebo group (rate ratio, 0.82; 95% CI, 0.71 to 0.94; P = 0.006). The percentage of patients who died from cardiovascular causes was 8.1% and 8.7%, respectively (hazard ratio, 0.93; 95% CI, 0.78 to 1.11). Finerenone was associated with an increased risk of hyperkalemia and a reduced risk of hypokalemia., Conclusions: In patients with heart failure and mildly reduced or preserved ejection fraction, finerenone resulted in a significantly lower rate of a composite of total worsening heart failure events and death from cardiovascular causes than placebo. (Funded by Bayer; FINEARTS-HF ClinicalTrials.gov number, NCT04435626.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Mineralocorticoid receptor antagonists (MRAs) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF). However, MRAs are often underused because of hyperkalemia concerns., Objectives: The purpose of this study was to assess whether sodium zirconium cyclosilicate (SZC), a nonabsorbed crystal that traps and rapidly lowers potassium, enables MRA use in patients with HFrEF and prevalent hyperkalemia (or at high risk)., Methods: REALIZE-K is a prospective, double-blind, placebo-controlled trial in patients with HFrEF (NYHA functional class II-IV; left ventricular ejection fraction ≤40%), optimal therapy (except MRA), and prevalent hyperkalemia (or at high risk). During the open-label run-in, all participants underwent protocol-mandated spironolactone titration (target: 50 mg daily); those with prevalent (cohort 1) or incident (cohort 2) hyperkalemia during titration started SZC. Participants achieving normokalemia while on spironolactone ≥25 mg daily were randomized to continuing SZC or matching placebo for 6 months. The primary composite endpoint was proportion of participants with optimal response (normokalemia, on spironolactone ≥25 mg daily, no rescue for hyperkalemia [months 1-6])., Results: Of 365 patients (run-in), 202 were randomized. Baseline characteristics included mean age 70 years, prevalent comorbidities (78% estimated glomerular filtration rate <60 mL/min/1.73 m 2 , 38% atrial fibrillation/flutter), high N-terminal pro B-type natriuretic peptide (median 1,136 pg/mL), and high HFrEF therapy use (64% sacubitril/valsartan, 96% beta-blocker, 42% sodium glucose co-transporter 2 inhibitor). At randomization, 78% were receiving spironolactone 50 mg daily., Conclusions: REALIZE-K is the first trial to evaluate whether SZC can enable rapid and safe MRA optimization and long-term continuation in patients with HFrEF and prevalent/high risk of hyperkalemia. (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients with Symptomatic HFrEF Receiving Spironolactone [REALIZE-K]; NCT04676646)., Competing Interests: Funding Support and Author Disclosures The REALIZE-K trial was funded by AstraZeneca. Drs Kosiborod, Cherney, Connelly, Desai, Guimarães, Kuthi, Lala, Madrini, Merkely, Villota, Squire, Testani, Vaclavik, Verma, Wranicz, and Petrie have received research funding in the form of grants to institutions from AstraZeneca and/or consulting for AstraZeneca. Mr Dahl, Mr Eudicone, and Ms Friberg are employees of, and hold or may hold stock in, AstraZeneca., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Both mineralocorticoid receptor antagonists (MRAs) and sodium-glucose co-transporter type 2 inhibitors (SGLT2is) have demonstrated beneficial reductions in cardiovascular outcomes. However, the risk of precipitating hyperkalemia with their concomitant usage remains unclear., Methods: MEDLINE and Cochrane were searched from inception through March 2022. Randomized controlled trials on patients with heart failure (HF) evaluating the effect of SGLT2is on clinical outcomes between MRA users and non-users were considered for inclusion. Outcomes of interest were mild and moderate/severe hyperkalemia, for which hazard ratios (HR) were pooled using a random effects model., Results: From the 972 articles retrieved from the initial search, three RCTs (n = 14,462 patients) were included in our meta-analysis. Pooled analysis demonstrated no significant difference in the incidence of mild hyperkalemia between MRA users (HR 0.82 [0.70-0.97]) and non-users (HR 0.95 [0.77-1.17]) (P-interaction = 0.28). The risk of severe hyperkalemia was significantly decreased in MRA users (HR 0.59 [0.44-0.78]; p = 0.0002; I 2 = 0%) but not in non-users (HR 0.76 [0.56-1.02]; p = 0.07; I 2 = 0%) (P-interaction = 0.22). Sensitivity analysis including patients with HF with reduced ejection fraction (HFrEF) revealed similar results across all subgroups, but no significant reduction in the incidence of mild hyperkalemia (HR 0.89 [0.76-1.04] was noted in MRA users with HFrEF., Conclusion: MRAs reduced the risk of mild or moderate/severe hyperkalemia, when added to SGLT2is. Future clinical trials should target scrupulous assessment of the risk of mild and moderate/severe hyperkalemia when used concomitantly with MRAs., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: This first-in-human study evaluated HRS-1780, an oral selective non-steroidal mineralocorticoid receptor antagonist, in healthy men., Research Design and Methods: In single ascending dose (SAD) part, 10 participants for each dose cohort (5, 10, 20, 40, 60, and 80 mg) were randomized (8:2) to HRS-1780 or placebo. In multiple ascending dose part, 12 participants for each dose (10, 20, and 40 mg) were randomized (9:3) to HRS-1780 or placebo once daily for 7 days. The primary endpoint was safety and tolerability., Results: HRS-1780 was well tolerated with all adverse events being mild. In the steady state, the median time to maximum concentration (T max ) was 0.750 h and mean half-life was 1.76-1.96 h. High-fat/high-calorie meal prolonged T max but did not affect exposure. Multiple dosing of HRS-1780 at 40 mg showed a decreasing trend in systolic blood pressure compared with placebo. Changes in plasma aldosterone and norepinephrine with HRS-1780 were higher compared to placebo. Upper bounds of two-sided 90% confidence interval of placebo-adjusted change-from-baseline QTcF were below 10 msec at the maximum concentration in SAD. The trial had limited sample size and short study duration., Conclusions: HRS-1780 had favorable safety and pharmacokinetic profiles and did not cause clinically meaningful QTcF prolongation., Trial Registration: ClinicalTrials.gov (NCT05638126).

Aim: To perform a comparative analysis of the efficacy of antihypertensive therapy (AHT) containing spironolactone or eplerenone in patients with essential arterial hypertension (AH) and atrial fibrillation (AF)., Material and Methods: The study included 99 male and female patients with essential AH complicated by permanent AF, who were receiving the outpatient treatment at the National Specialized Scientific and Practical Medical Center of Cardiology (Tashkent). The patients aged 61.3±9.5 years, the mean duration of AH was 12.9±8.3 years. All patients were divided into two groups: Group 1, patients who completed a 6-month combination AHT containing spironolactone (n=51); Group 2, patients who completed a 6-month combination AHT containing eplerenone (n=48). AF was diagnosed by electrocardiogram (ECG) and/or 24-hour ECG monitoring according to standard diagnostic criteria. The ECG study was performed in compliance with the American Society of Echocardiography Guidelines in M- and B-modes. The degree of structural vascular alterations was determined by the intima-media thickness of the common carotid artery by duplex scanning and microalbuminuria in morning urine. The concentrations of sex hormones were measured by the enzyme immunoassay. The serum concentrations of lipids, glucose, creatinine, and uric acid were measured by the enzymatic method. The glomerular filtration rate (GFR) was calculated with the EPI formula. Results of all studies were considered statistically significant at p&lt;0.05., Results: The proportion of patients who achieved the target diastolic blood pressure (BP) values was significantly greater in the eplerenone-containing treatment group than in the spironolactone-containing treatment group: 87.8% vs. 67.5% (p=0.043). The proportion of patients who simultaneously achieved the target systolic and diastolic BP values was slightly greater in the eplerenone-containing treatment group than in the spironolactone-containing group (100% vs. 92.1%, p=0.060). The best cardioprotective efficacy was observed in the group of combination AHT containing eplerenone. Specifically, in Group 2, the left ventricular ejection fraction (LVEF) was significantly improved compared to Group 1: from 55.4±10.6% at baseline to 52.6±9.1% in Group 1 (p&gt;0.05) and from 54.8±8.8% at baseline to 58.2±6.4% in Group 2 (p&lt;0.02). Only in Group 2, the left atrial volume index (LAVI) was significantly decreased compared to Group 1. Thus, in Group 1, the LAVI changed from 42.2±15.1 ml/m2 at baseline to 40.4±12.2 ml/m2 (p&gt;0.05) and in Group 2, from 41.2±15.3 ml/m2 at baseline to 37.3±13.5 ml/m2 after the treatment (p&lt;0.05); the ∆% LAVI in the eplerenone group was -5.9% vs. -0.36% in the spironolactone group. In men of Group 1, estradiol significantly increased from 13.9±12.6 pmol/l at baseline to 22.7±12.4 pmol/l (p&lt;0.001)., Conclusion: The good antihypertensive efficacy of the 6-month combination therapy containing eplerenone was significantly superior to spironolactone in achieving the target BP values. The eplerenone-containing treatment significantly improved LVEF and decreased LAVI compared to the spironolactone-containing treatment. A trend towards a beneficial effect of the AHT containing eplerenone on concentrations of sex hormones was noted in both women and men.

The combination of torsemide and spironolactone presents a promising approach to managing conditions such as edema and hypertension. Torsemide, a loop diuretic, enhances diuresis by inhibiting sodium reabsorption in the kidneys, while spironolactone, a potassium-sparing diuretic and mineralocorticoid receptor antagonist (MRA), complements this effect by preventing potassium loss and offering additional cardiovascular benefits. This review examines clinical evidence supporting their combined effectiveness in treating fluid retention and improving outcomes in conditions like heart failure (HF). Given the limited research available, it is essential to carefully evaluate patient-specific factors. However, several side effects necessitate careful patient selection and monitoring. Moreover, optimizing dosing regimens is crucial to ensure the safety and efficacy of torsemide and MRAs in clinical settings., (© Journal of the Association of Physicians of India 2024.)

Introduction: The 2021 European Society of Cardiology (ESC) Guidelines recommend the use of four different classes of drugs for heart failure with reduced ejection fraction (HFrEF): beta blockers (BB), sodium-glucose cotransporter-2 inhibitors (SGLT2i), angiotensin receptor/neprilysin inhibitor (ARNI), and mineralocorticoid receptor antagonists (MRAs). Moreover, the 2023 ESC updated Guidelines suggest an intensive strategy of initiation and rapid up-titration of evidence-based treatment before discharge, based on trials not using the four-pillars. We hypothesized that an early concomitantly administration and up-titration of four-pillars, compared with a conventional stepwise approach, may impact the vulnerable phase after hospitalization owing to HF., Methods: This prospective, single center, observational study included consecutive in-hospital patients with HFrEF. After performing propensity score matching, they were divided according to treatment strategy into group 1 (G1), with predischarge start of all four-pillars, with their up-titration within 1 month, and group 2 (G2) with the pre Guidelines update stepwise four-pillars introduction. HF hospitalization, cardiovascular (CV) death, and the composite of both were evaluated between the two groups at 6-month follow-up., Results: The study included a total of 278 patients who completed 6-month follow-up (139 for both groups). There were no differences in terms of baseline features between the two groups. At survival analysis, HF hospitalization risk was significantly lower in G1 compared with G2 (p < 0.001), while no significant differences were observed regarding CV death (p = 0.642) or the composite of CV death and HF hospitalization (p = 0.135)., Conclusions: In our real-world population, patients with HF treated with a predischarge and simultaneous use of four-pillars showed a reduced risk of HF hospitalization during the vulnerable phase after discharge, compared with  a conventional stepwise approach., (© 2024. The Author(s).)

Background: Patients experiencing myocardial infarction (MI) remain at high risk of future major adverse cardiovascular events (MACE). While low-dose colchicine and spironolactone have been shown to decrease post-MI MACE, more data are required to confirm their safety and efficacy in an unselected post-MI population. Therefore, we initiated the CLEAR SYNERGY (OASIS 9) trial to address these uncertainties., Methods: The CLEAR SYNERGY trial is a 2 × 2 factorial randomized controlled trial of low-dose colchicine 0.5 mg daily versus placebo and spironolactone 25 mg daily versus placebo in 7,062 post-MI participants who were within 72 hours of the index percutaneous coronary intervention (PCI). We blinded participants, healthcare providers, research personnel, and outcome adjudicators to treatment allocation. The primary outcome for colchicine is the first occurrence of the composite of cardiovascular death, recurrent MI, stroke, or unplanned ischemia-driven revascularization. The coprimary outcomes for spironolactone are (1) the composite of the total numbers of cardiovascular death or new or worsening heart failure and (2) the first occurrence of the composite of cardiovascular death, new or worsening heart failure, recurrent MI or stroke. We finished recruitment with 7,062 participants from 104 centers in 14 countries on November 8, 2022, and plan to present the results in the fall of 2024., Conclusions: CLEAR SYNERGY is a large international randomized controlled trial that will inform the effects of low-dose colchicine and spironolactone in largely unselected post-MI patients who undergo PCI. (ClinicalTrials.gov Identifier: NCT03048825)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: Many patients with heart failure (HF) have chronic kidney disease (CKD) and may not tolerate mineralocorticoid receptor antagonists. We investigated the efficacy and safety of the novel mineralocorticoid receptor modulator balcinrenone in combination with dapagliflozin in a phase 2b study., Methods and Results: From January 2021 to October 2023, we randomized 133 adults with symptomatic HF, ejection fraction <60%, estimated glomerular filtration rate (eGFR) ≥30 to ≤60 ml/min/1.73 m 2 and urinary albumin-to-creatinine ratio (UACR) ≥30 to <3000 mg/g, to receive balcinrenone 15, 50 or 150 mg/day plus dapagliflozin 10 mg/day, or dapagliflozin 10 mg/day plus placebo, for 12 weeks. Enrolment was stopped early because of slow recruitment. Relative reductions in UACR from baseline to week 12 (primary endpoint) were not significantly different between the balcinrenone plus dapagliflozin groups versus dapagliflozin plus placebo. There was no clear balcinrenone dose-response relationship. There were possible dose-dependent increases in serum potassium levels, reduced eGFR in the highest dose group, and non-significant trends towards reduced N-terminal pro-B-type natriuretic peptide levels. Hyperkalaemia adverse events led to discontinuation in two participants receiving balcinrenone plus dapagliflozin and none in those receiving dapagliflozin plus placebo., Conclusion: While the smaller than planned sample size limits interpretation, we did not see significant reduction in UACR in patients treated with balcinrenone plus dapagliflozin compared with dapagliflozin plus placebo., (© 2024 AstraZeneca and The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Purpose: To compare the efficacy and safety of subthreshold micropulse laser (SML) and spironolactone therapy for treating chronic central serous chorioretinopathy (CSC)., Methods: This was a quasi-randomized controlled trial. Eligible patients were quasi-randomized at a 1:1 ratio to receive SML or oral spironolactone and were assessed at 3 months after treatment., Results: A total of 84 patients (90 eyes) were randomly assigned to receive SML (n = 45) or spironolactone (n = 39) initially. At last follow-up, 59.5% of patients in the SML group had complete resolution of subretinal fluid (SRF) compared to 43.6% in spironolactone group (P = 0.362). The mean visual acuity did not significantly improve between the two groups (0.38 ± 0.44 vs. 0.43 ± 0.43 logMAR). The central retinal thickness was decreased from 335.06 ± 120.25 µm to 222.15 ± 94.90 µm in the SML group and from 308.02 ± 90.69 µm to 257.27 ± 102.28 µm in the spironolactone group. After treatment, subfoveal choroidal thickness, total choroidal area, and stromal and luminal choroidal area were significantly lower in the spironolactone group as compared to the SML group. During the entire visit, the recurrence rate of SRF was 9.1% in the SML group compared to 35.3% in the spironolactone group. Slight adverse events occurred more frequently in the spironolactone group (0% vs. 16%)., Conclusions: Both SML and oral spironolactone were effective and safe treatments to ameliorate retinal anatomical structures for chronic CSC. A lower recurrence rate and fewer adverse effects were observed in the SML group, and better choroidal structure recovery was seen in the spironolactone group., Translational Relevance: The investigation of SML and oral spironolactone may inform evidence-based clinical decisions for chronic CSC patients.

Aims: Cardiac resynchronization therapy (CRT) is an established treatment for drug-refractory heart failure (HF) in patients with left bundle branch block (LBBB). Acute haemodynamic improvement after CRT implantation may enable the intensification of HF medication soon thereafter. Immediate pharmacotherapy intensification (IPI) after CRT implantation achieves a synergetic effect, possibly leading to a better prognosis. This study aimed to explore the incidence, characteristics, and impact of IPI on real-world outcomes among CRT recipients with a history of hospitalization for acute HF., Methods and Results: This multicentre retrospective study enrolled CRT recipients with LBBB morphology, a QRS width ≥120 ms, a left ventricular ejection fraction ≤35%, and New York Heart Association II-IV HF symptoms. All patients had previous HF hospitalizations within the previous year and received guideline-directed medical therapy before CRT implantation. Patient baseline characteristics, including HF medication, were collected. IPI was defined as the intensification of beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists within 30 days of CRT implantation. The primary endpoint was all-cause death or first hospitalization for HF; the secondary endpoint was all-cause death. We enrolled 194 patients (75% male; mean age, 65 ± 13 years; 78% with non-ischaemic cardiomyopathy). One hundred five (54%) patients received IPI. Patients who received IPI exhibited a significantly shorter QRS duration (159 ± 26 vs. 171 ± 32 ms; P = 0.004), higher estimated glomerular filtration rate (55.2 ± 20.0 vs. 47.8 ± 24.7 mL/min/1.73 m 2 ; P = 0.022), and more dilated cardiomyopathy. During a median follow-up period of 29 months, 70 (36%) patients reached the primary endpoint and 42 (22%) patients died. Patients with IPI showed significantly better outcomes for the primary and secondary endpoints than patients without IPI. The volumetric responder ratio at 6 months after implantation was not significantly different between patients with and without IPI; however, patients who received IPI had reduced mortality even at 6 months after implantation. In the multivariate analysis, IPI was an independent predictor of the primary endpoint (hazard ratio, 0.51; 95% confidence interval, 0.27-0.97; P = 0.043)., Conclusions: Immediate intensification of HF medication was achieved in 54% of CRT recipients and was significantly higher in patients without excessive QRS prolongation, preserved renal function, and dilated cardiomyopathy than others. In patients with LBBB morphology and QRS ≥ 120 ms, IPI was associated with a significantly better prognosis and fewer HF hospitalizations after CRT implantation than others., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Vericiguat, a soluble guanylate cyclase stimulator known for augmenting cyclic guanosine monophosphate production, has garnered substantial clinical attention in patients with systolic heart failure. Despite its proven efficacy, discerning the specific subset of individuals who can enjoy clinical advantages from vericiguat therapy in contemporary real-world clinical practice, particularly among the individuals undergoing "quadruple medical therapy" comprising administration of a beta-blocker, angiotensin receptor neprilysin inhibitor, mineralocorticoid receptor antagonist, and sodium-glucose co-transporter 2 inhibitor, remains an unresolved query. This study involved patients undergoing 3-month vericiguat therapy alongside complete quadruple medical therapy in a contemporary real-world clinical practice. Baseline characteristics associated with the primary outcome, defined as a reduction in serum NT pro-B-type natriuretic peptide (BNP) levels over the 3-month therapeutic duration, were scrutinized. A cohort of 24 patients (median age: 66 years; 20 males) were included. All participants diligently adhered to the 3-month vericiguat therapy in conjunction with the quadruple medical regimen. A higher baseline systolic blood pressure emerged as an independent factor linked to the primary outcome, yielding an adjusted odds ratio of 1.31 (95% confidence interval: 1.03-1.65, P = 0.026) at a threshold of 105 mmHg. This threshold notably stratified the trajectories of serum NT pro-BNP levels during the 3-month vericiguat therapy. In conclusion, preservation of baseline systolic blood pressure emerged as a pivotal determinant for reaping the clinical benefits from mid-term vericiguat therapy among patients with systolic heart failure receiving quadruple medical therapy.

Background: It has been postulated that cancer hampers the delivery of guideline-directed medical therapy (GDMT) for heart failure (HF). However, few data are available in this regard., Methods: We performed a retrospective analysis from the HF Outpatient Clinic of the IRCCS Ospedale Policlinico San Martino in Genova, Italy. All HF patients evaluated between 2010 and 2019, with a left ventricular ejection fraction <50% and at least two visits ≥3 months apart with complete information about GDMT were included in the study. We assessed the prescription of GDMT-in particular, beta-blockers (BB), renin-angiotensin system inhibitors (RASi), and mineralocorticoid antagonists (MRA)-at the time of the last HF evaluation and compared it between patients with and without incidental cancer. For those with incidental cancer, we also evaluated modifications of GDMT comparing the HF evaluations before and after cancer diagnosis., Results: Of 464 HF patients, 39 (8%) had incidental cancer. There were no statistical differences in GDMT between patients with and without incidental cancer at last evaluation. In the year following cancer diagnosis, of 33 patients with incidental cancer on BB, none stopped therapy, but two had a down-titration to a dosage <50%; of 27 patients on RASi, two patients stopped therapy and three had a down-titration to a dosage <50%; of 19 patients on MRA, four stopped therapy., Conclusions: Although HF patients with incidental cancer may need to have GDMT down-titrated at the time of cancer diagnosis, this does not appear to significantly hinder the delivery of HF therapies during follow-up., Competing Interests: Conflicts of Interest PA received speaker and/or advisor fees from AstraZeneca, Boehringer Ingelheim, Bayer, Daiichi-Sankyo, Janssen, Merck Sharp & Dohme, all outside the submitted work. The other authors have no conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Chronic kidney disease (CKD) is a prevalent complication of Type II diabetes (T2D). The coexistence of CKD with T2D is comparable to cardiovascular disease (CVD) when the estimated glomerular filtration rate declines below 60 ml/min/1.73 m 2 . Screening and early detection of people with high risk for CKD would be beneficial in managing CKD progress and the associated complications such as CV complications. Renin-angiotensin-aldosterone system inhibitors (RAASi) have demonstrated beneficial effects in delaying CKD progression, but they carry the risk of hyperkalemia. Nonsteroidal mineralocorticoid antagonists (nsMRA), such as finerenone, exhibit considerable efficacy in their anti-inflammatory, antifibrotic, and renal protective effects with demonstrable reductions in CV complications. In addition, nsMRAs do not cause significant changes in serum potassium levels compared to traditional steroidal MRA. Ongoing research explores the capacity of the sodium-glucose transport protein 2 inhibitors (SGLT-2i), combined with nsMRA, to produce synergistic renal protective effects and reduce the risk of hyperkalemia. Also, a dedicated renal outcomes study (FLOW study) involving a once-weekly injectable Glucagon-like peptide-1 receptor agonist, semaglutide, was halted early by the data monitoring committee due to having achieved the predefined efficacy endpoint and considerations related to renal disease. In CKD patients with T2D on nsMRA, hyperkalemia management requires a comprehensive approach involving lifestyle adjustments, dietary modifications, regular serum potassium level monitoring, and potassium binders, if necessary. Withholding or down-titration of nsMRAs with close monitoring of serum potassium levels may be required in patients with concerning potassium levels. In light of the current state of knowledge, this review article explores the perspectives and approaches that HCPs may consider when monitoring and managing hyperkalemia in CKD patients with T2D.

Background: Excess aldosterone accelerates chronic kidney disease progression. This phase 2 clinical trial assessed BI 690517, an aldosterone synthase inhibitor, for efficacy, safety, and dose selection., Methods: This was a multinational, randomised, controlled, phase 2 trial. People aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 30 to less than 90 mL/min/1·73 m 2 , a urine albumin to creatinine ratio (UACR) of 200 to less than 5000 mg/g, and serum potassium of 4·8 mmol/L or less, taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, were enrolled. Participants were randomly assigned (1:1) to 8 weeks of empagliflozin or placebo run-in, followed by a second randomisation (1:1:1:1) to 14 weeks of treatment with once per day BI 690517 at doses of 3 mg, 10 mg, or 20 mg, or placebo. Study participants, research coordinators, investigators, and the data coordinating centre were masked to treatment assignment. The primary endpoint was the change in UACR measured in first morning void urine from baseline (second randomisation) to the end of treatment. This study is registered with ClinicalTrials.gov (NCT05182840) and is completed., Findings: Between Feb 18 and Dec 30, 2022, of the 714 run-in participants, 586 were randomly assigned to receive BI 690517 or placebo. At baseline, 33% (n=196) were women, 67% (n=390) were men, 42% (n=244) had a racial identity other than White, and mean participant age was 63·8 years (SD 11·3). Mean baseline eGFR was 51·9 mL/min/1·73 m 2 (17·7) and median UACR was 426 mg/g (IQR 205 to 889). Percentage change in first morning void UACR from baseline to the end of treatment at week 14 was -3% (95% CI -19 to 17) with placebo, -22% (-36 to -7) with BI 690517 3 mg, -39% (-50 to -26) with BI 690517 10 mg, and -37% (-49 to -22) with BI 690517 20 mg monotherapy. BI 690517 produced similar UACR reductions when added to empagliflozin. Investigator-reported hyperkalaemia occurred in 10% (14/146) of those in the BI 690517 3 mg group, 15% (22/144) in the BI 690517 10 mg group, and 18% (26/146) in the BI 690517 20 mg group, and in 6% (nine of 147) of those receiving placebo, with or without empagliflozin. Most participants with hyperkalaemia did not require intervention (86% [72/84]). Adrenal insufficiency was an adverse event of special interest reported in seven of 436 study participants (2%) receiving BI 690517 and one of 147 participants (1%) receiving matched placebo. No treatment-related deaths occurred during the study., Interpretation: BI 690517 dose-dependently reduced albuminuria with concurrent renin-angiotensin system inhibition and empagliflozin, suggesting an additive efficacy for chronic kidney disease treatment without unexpected safety signals., Funding: Boehringer Ingelheim., Competing Interests: Declaration of interests KRT reports grants for investigator-initiated research from NIDDK, NHLBI, NCATS, NIMHD, NIH Data Science office, Travere, Bayer, and Goldfinch Bio; contracts from CDC; consulting fees from Boehringer Ingelheim, Janssen, Novo Nordisk, AstraZeneca, Bayer, Eli Lilly, Gilead, and Merck Sharp & Dohme; payment for manuscript writing for Boehringer Ingelheim, Novo Nordisk, Bayer, Eli Lilly, and Gilead; payment of honoraria for Novo Nordisk, AstraZeneca, Bayer, Eli Lilly, and Gilead; payment for travel for Novo Nordisk; travel to meetings from Novo Nordisk; chair and member of a data safety monitoring committee for NIDDK and George Clinical; and leadership role for the American Society of Nephrology. MEC reports grants for investigator-initiated research and research funding from Baxter and Fresenius; and payment of honoraria for lectures, presentations, and education events from AstraZeneca, Fresenius, Bayer, Pfizer, and Bracepharma. MLC reports research grant support from NIH and NIDDK (all to the University of Minnesota and Cleveland Clinic) and research grant support sponsored by Bayer Pharmaceuticals (all to the University of Minnesota); consulting fees from Bayer Pharmaceuticals, Novo Nordisk, and AstraZeneca; payment for speaker bureaus and educational events from Bayer Pharmaceuticals; payment of honoraria for lectures and educational events from Cardiorenal Connections, Heart in Diabetes, Translational Medicine Academy, and the American College of Cardiology; support to attend investigator meetings for Kidney Precision Medicine Project from the NIH and NIDDK, American Diabetes Association meetings from NIH and NIDDK, and University of Minnesota and American Society of Nephrology meetings from NIH and NIDDK and Cleveland Clinic Foundation (all to the University of Minnesota); participation on and site principle investigator for the Data Safety Monitoring Board for Preventing Early Renal Loss in Diabetes Study for NIH and NIDDK (all to the University of Minnesota); and attendee of Kidney Disease Improving Global Outcomes writing group meetings. DC reports research grants from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL Behring, and Novo Nordisk; consulting fees from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi Tanabe, AbbVie, Janssen, Bayer, Prometic, Bristol Myers Squibb, Maze, Gilead, CSL Behring, Otsuka, Novartis, Youngene, Lexicon, Inversago, GSK, and Novo Nordisk; payment of honoraria for lectures and advisory boards from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi Tanabe, Janssen, Bayer, and Novo Nordisk; support for traveling to and attending meetings from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Janssen, Bayer, and Novo Nordisk; and receipt of a drug for research from AstraZeneca. HJLH reports funding to conduct clinical trials from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and Novo Nordisk (all to the University of Groningen); consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Behring, DImerix, Eli Lilly, Fresenius, Gilead, Janssen, Novo Nordisk, Novartis, and Travere Therapeutics; payment of honoraria for lectures from AstraZeneca, Novo Nordisk, and Bayer; support for traveling to and attending the American Diabetes Association meeting and American Society of Nephrology meeting from AstraZeneca and Eli Lilly (to HJLH and the University of Groningen); and receipt of the study drug from AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and Novo Nordisk. MN reports donations for research through Shogaku Kifu practice from KyowaKiirin, Mitsubishi Tanabe, Chugai, Boehringer Ingelheim, Torii, Takeda, Daiichi Sankyo, and JT; consulting fees from KyowaKiirin and Mitsubishi Tanabe; and payment of honoraria for lectures from KyowaKiirin, Mitsubishi Tanabe, Bayer, Astellas, JT, and AstraZeneca. RCR reports participation as a trial investigator for Novo Nordisk and AstraZeneca; consulting fees from Boehringer Ingelheim, Bayer, AstraZeneca, Chinook, and Novo Nordisk; payment of honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Amgen, and Bayer; and voluntary membership of the steering committee for World Kidney Day and of the Diabetes Committee. AS reports research contracts from Boehringer Ingelheim, Mineralysis, ProKidney, Reata, and Novartis; consulting fees from Boehringer Ingelheim, Ardelyx, and Pro Kidney; payment of honoraria for presentations from ProKidney, Boehringer Ingelheim, AstraZeneca, and Bayer; and participation on an Advisory Board for Travere, Boehringer Ingelheim, and Reata. DdZ reports consulting fees from Bayer, Fresenius, and Travere. PR reports grants and payment of honoraria for lectures, educational events, and steering group participation from AstraZeneca, Bayer, and Novo Nordisk (all to the Steno Diabetes Center Copenhagen); payment of honoraria for lectures and participation in advisory boards from Boehringer Ingelheim, Sanofi, Abbott, and Astellas (all to the Steno Diabetes Center Copenhagen). SJH, LC, SVS, and ZS are employees of Boehringer Ingelheim. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: The current study evaluated menstrual bleeding profiles, compliance and tolerability in women using a drospirenone (DRSP)-only pill., Patients and Methods: This is a non-interventional, retrospective, multi-center study on healthy female adults [n=276, aged between 18 and 53 years and premenopausal using a DRSP-only pill for at least six months with a mean duration of 10.4 months (+/-SD 4.0) months]. 75.6% used other contraceptives than POP before starting with the DRSP-only pill. A questionnaire was used to evaluate the bleeding profile. 56.5% of the women had associated cardiovascular risk factors., Results: Two hundred and sixty-two (262) women (mean age of 32.5 ± 9.1 years; mean BMI of 23.1 ± 3.8 kg/m²) were eligible for analysis. 42.6% of the users had a scheduled bleeding, 33,3% unscheduled bleeding and 48% no bleeding during the last evaluable cycle. 75.4% evaluated the bleeding profile in the last cycle as very good or good, 13.8% said there was no change since starting the medication, 8.4% declared the profile was bad and 2.3% as very bad. 87.8% of the users evaluated the general satisfaction of the contraception as very good or good, whereas only 8.8% and 3.4% said there was no change or that it was bad. No women evaluated the general satisfaction as very bad., Conclusions: These data demonstrate that the DRSP-only pill is associated with a very high satisfaction as a contraceptive in general and in the individual bleeding profile. These aspects reaffirm the acceptability not only in women with cardiovascular risk factors.

Objective: Long-term outcomes (especially mortality and/or major cardiovascular events (MACE)) of the unilateral primary aldosteronism (uPA) patients who underwent medical or surgery-targeted treatment, relative to those with essential hypertension (EH), have been scarcely reported., Design and Settings: Using the prospectively designed observational Taiwan Primary Aldosteronism Investigation cohort, we identified 858 uPA cases among 1220 primary aldosteronism patients and another 1210 EH controls., Exposures: Operated uPA patients were grouped via their 1-year post-therapy statuses., Results: Primary Aldosteronism Surgical Outcome clinical complete success (hypertension remission) was achieved in 272 (49.9%) of 545 surgically treated uPA patients. After follow-up for 6.3 ± 4.0 years, both hypertension-remissive (hazard ratio (HR): 0.54; P < 0.001) and not-cured (HR: 0.61; P < 0.001) uPA patients showed a lower risk of all-cause mortality than that of EH controls; whereas the not-cured group had a higher risk of incident MACE (sub-hazard ratio (sHR), 1.41; P = 0.037) but similar atrial fibrillation (Af) and congestive heart failure (CHF). Mineralocorticoid receptor antagonist (MRA)-treated uPA patients had higher risks of MACE (sHR: 1.38; P = 0.033), Af (sHR:1.62, P = 0.049), and CHF (sHR: 1.44; P = 0.048) than those of EH controls, with mortality as a competing risk. Using inverse probability of treatment-weighted matching and counting adrenalectomy as a time-varying factor, treatment with adrenalectomy was associated with lower risks of all-cause mortality (HR: 0.57; P = 0.035), MACE (HR: 0.67; P = 0.037), and CHF (HR: 0.49; P = 0.005) compared to those of MRA therapy., Conclusions: Adrenalectomy, independent of post-surgical hypertension remission, was associated with lower all-cause mortality of uPA patients, compared to that of EH patients. We further documented a more beneficial effect of adrenalectomy over MRA treatment on long-term mortality, MACE, and CHF in uPA patients.

Purpose: Eplerenone (EPL) is a selective mineralocorticoid receptor antagonist used for treatment of chronic central serous chorioretinopathy which characterized by accumulation of subretinal fluid causing a localized area of retinal detachment. unfortunately, EPL suffers from poor oral bioavailability due to poor aqueous solubility in addition to high hepatic first pass metabolism., Method: Aiming to improve its oral bioavailability, EPL-loaded nanostructured lipid carriers (NLCs) were prepared by the emulsification solvent evaporation method and in-vitro evaluated for particle size (PS), polydispersity index (PDI), zeta potential (ZP), and entrapment efficiency (EE%). A D-optimal design was used for study the effect of liquid lipid to solid lipid ratio, surfactant type and percentage on PS, PDI, EE%, and for data optimization. The optimized EPL-loaded NLCs system was further evaluated using in-vitro drug release and ex-vivo permeation studies through rabbit intestine in comparison to EPL aqueous suspension. The physicochemical properties of the drug in the optimized system were further examined using FT-IR and X-ray diffraction studies., Results: The resultant NLCs showed small PS (100.85-346.60 nm), homogenous distribution (0.173-0.624), negatively charged particles (ZP -20.20 to -36.75 mV), in addition to EE% (34.31-70.64%). The optimized EPL-loaded NLCs system with a desirability value of 0.905 was suggested through the Design expert ® software, containing liquid to solid lipid ratio (2:1) in presence of 0.43%w/v Pluronic ® F127 as a surfactant. The optimized EPL-loaded NLCs system showed a PS of 134 nm and PDI of 0.31, in addition to high EE% (76 ± 6.56%w/w), and ZP (-32.37 mV). The ex-vivo permeation study showed two-fold higher drug permeation through rabbit intestine compared to that from the aqueous drug suspension after 24 h, confirming the ability of optimized EPL-loaded NLCs system as successful oral targeting delivery carrier., Conclusion: Our results pave the way for a new oral nanotherapeutic approach toward CSCR treatment. In-vivo study is currently under investigation.

Objectives: Progestin-only pills do not increase the risk of venous thromboembolism, stroke, and myocardial infarction but are associated with poor cycle control. A novel estrogen-free pill containing only drospirenone (DRSP) to improve bleeding patterns and tolerability and reduce discontinuation rates has been introduced into the market. The present study aims to describe the improvement in the acceptability of this DRSP-only pill, e.g. regarding the bleeding profile and the reduction in discontinuation rates due to unacceptable bleeding compared to desogestrel (DSG)., Study Design: Double-blind, double-dummy prospective phase III study in healthy women aged 18-45 years evaluating a total of 858 women with 6691 DRSP and 332 women with 2487 DSG treatment cycles., Results: Overall, 82 (9.6%) women in the DRSP group and 44 (13.3%) women in the DSG group experienced treatment-emergent adverse events (TEAEs) leading to premature termination of the trial meaning that 32% more women in the DRSP group finished the trial in comparison to the DSG group (based on the AUC of Kaplan-Meier's curves). Discontinuation rates due to abnormal bleeding were 3.7% for DRSP and 7.3% for DSG users. This is a 55.7% lower discontinuation rate in the DRSP group compared to the DSG group., Conclusions: This report describes the improvement in acceptability and bleeding profile of women using the new DRSP-only oral contraceptive compared to DSG, providing a better quality of life and adherence to the contraceptive method as demonstrated by lower discontinuation rates of women using the estrogen-free DRSP-only pill.

Objective: Women with heart failure with reduced ejection fraction (HFrEF) may reach optimal treatment effect at half of the guideline-recommended medication dose. This study investigates prescription practice and its relation with survival of patients with HF in daily care., Methods: Electronic health record data from 13 Dutch outpatient cardiology clinics were extracted for HF receiving at least one guideline-recommended HF medication. Dose changes over consecutive prescriptions were modelled using natural cubic splines. Inverse probability-weighted Cox regression was used to assess the relationship between dose (reference≥50% target dose) and all-cause mortality., Results: The study population comprised 561 women (29% HFrEF (ejection fraction (EF)<40%), 49% heart failure with preserved ejection fraction (EF≥50%); HFpEF and 615 men (47% and 25%, respectively). During a median follow-up of 3.7 years, 252 patients died (48% women; 167 HFrEF, 84 HFpEF). Nine hundred thirty-four patients (46% women) received ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), 795 (48% women) beta blockers and 178 (42% women) mineralocorticoid receptor antagonists (MRAs). In both sexes, the mean target dose across prescriptions was 50% for ACEI/ARBs and beta blockers, and 100% for MRAs. ACEI/ARB dose of <50% was associated with lower mortality in women but not in men with HFrEF. This was not seen in patients with HFpEF. Beta-blocker dose was not associated with all-cause mortality., Conclusion: Patients with HF seen in outpatient cardiology clinics receive half of the guideline-recommended medication dose. Lower ACEI/ARB dose was associated with improved survival in women with HFrEF. These results underscore the importance of (re)defining optimal medical therapy for women with HFrEF., Competing Interests: Competing interests: GAS and IIT are employed by Cardiology Centers of the Netherlands. FWA is supported by UCL Hospitals NIHR Biomedical Research Centre., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Diabetic retinopathy remains a major cause of vision loss worldwide. Mineralocorticoid receptor (MR) pathway activation contributes to diabetic nephropathy, but its role in retinopathy is unknown. In this study, we show that MR is overexpressed in the retina of type 2 diabetic Goto-Kakizaki (GK) rats and humans and that cortisol is the MR ligand in human eyes. Lipocalin 2 and galectin 3, two biomarkers of diabetes complications regulated by MR, are increased in GK and human retina. The sustained intraocular delivery of spironolactone, a steroidal mineralocorticoid antagonist, decreased the early and late pathogenic features of retinopathy in GK rats, such as retinal inflammation, vascular leakage, and retinal edema, through the upregulation of genes encoding proteins known to intervene in vascular permeability such as Hey1 , Vldlr , Pten , Slc7a1 , Tjp1 , Dlg1 , and Sesn2 but did not decrease VEGF. Spironolactone also normalized the distribution of ion and water channels in macroglial cells. These results indicate that MR is activated in GK and human diabetic retina and that local MR antagonism could be a novel therapeutic option for diabetic retinopathy., (© 2021 by the American Diabetes Association.)

Aims: Impaired renal function is a major contributor to the low proportion of mineralocorticoid receptor antagonist (MRA) treatment in patients with heart failure with reduced ejection fraction (HFrEF). Our aims were to investigate the impact of MRA treatment on all-cause mortality and worsening renal function (WRF) in patients with HFrEF and moderately impaired renal function., Methods: Retrospective data between 2010-2018 on HFrEF patients from a single-centre hospital with estimated glomerular renal function (eGFR) < 60 ml/min/1.73 m2 were analysed. WRF was defined as a decline of by eGFR ≥ 20%., Results: 416 patients were included, 131 patients on MRA and 285 without MRA, mean age was 77 years (SD ± 9) and 82 years (SD ± 9), respectively. Median follow-up was 2 years. 128 patients (32%) experienced WRF, 25% in the MRA group and 30% in patients without MRA (p = 0.293). In multivariable analysis, hospitalization for heart failure and systolic blood pressure were associated with WRF (p = 0.015 and p = <0.001), but not use of MRA (p = 0.421). MRA treatment had no impact on the risk of adjusted all-cause mortality (HR 0.93; 95% CI, 0.66-1.32 p = 0.685). WRF was associated with increased adjusted risk of all-cause mortality (HR 1.43; 95% CI, 1.07-1.89 p = 0.014). Use of MRA did not increase the adjusted overall risk of mortality even when experiencing WRF (HR 1.15; 95% CI, 0.81-1.63 p = 0.422)., Conclusion: In this cohort of elderly HFrEF patients with moderately impaired renal function, MRA did not increase risk for WRF or all-cause mortality., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Resistant hypertension (RH) is more prevalent in the advanced stages of chronic kidney disease (CKD) and contributes to a greater likelihood of poor cardiovascular and renal outcomes. However, RH often goes untreated in this population as the currently available recommended add-on therapy, steroidal mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone, may lead to unacceptable side effects, mainly hyperkalemia in a cohort with reduced kidney function. KBP-5074 is a novel non-steroidal MRA that addresses the unmet need of treating RH in the CKD population without hyperkalemia., Areas Covered: We provide an overview of the current state of RH treatment in stage 3B/4 CKD as it relates to available steroidal MRAs and the current limitations of this treatment. We then explore the emerging data on nonsteroidal MRAs, particularly the novel agent KBP-5074 and its applicability to treatment in this context., Expert Opinion: In a randomized, double-blind, placebo-controlled phase 2b trial, the novel nonsteroidal MRA KBP-5074 demonstrated clinical efficacy and safety in treating RH in stage 3B/4 CKD and offers a potential new treatment option in this population at high risk for cardiovascular disease (CVD) and CKD progression.

Background and Objective: Esaxerenone showed the potential to inhibit and induce activity against cytochrome P450 (CYP) 3A in in vitro studies. We investigated whether repeated administration of 5 mg/day esaxerenone for 14 days influences the pharmacokinetics of midazolam, a sensitive CYP3A substrate, in healthy Japanese males., Methods: This single-centre, open-label, single-sequence study had two administration periods: period 1: single oral dose of 2 mg midazolam (day 0); period 2: repeated oral doses of 5 mg/day esaxerenone for 14 days, with a single oral dose of 2 mg midazolam on day 14. Full pharmacokinetic profiles of midazolam and 1-hydroxymidazolam on days 0 and 14 and safety data were obtained. Primary pharmacokinetic endpoints for midazolam were area under the plasma concentration-time curve (AUC) from zero to time of the last measurable concentration (AUC last ), AUC from zero to infinity (AUC inf ), and peak plasma concentration (C max )., Results: The study included 28 male subjects. One subject was withdrawn because of a mild adverse event (increased hepatic enzyme levels) that resolved without intervention. Repeated administration of esaxerenone increased midazolam AUC last , AUC inf , and C max by about 1.2-fold (1.201, 1.201, and 1.224, respectively) compared with administration of midazolam alone. However, repeated administration of esaxerenone did not affect the elimination half-life of midazolam (2.86 versus 2.63 h with and without esaxerenone). There were no safety concerns associated with concomitant administration of esaxerenone and midazolam., Conclusions: Esaxerenone 5 mg/day had no clinically significant effect on midazolam pharmacokinetics and was not associated with any safety issues. Esaxerenone can be concomitantly administered with drugs of CYP3A substrates without dose adjustments., Clinical Trial Registration: JapiCTI-152832., (© 2021. The Author(s).)

Despite significant advances in evidence-based treatments for heart failure with reduced ejection fraction (HFrEF), the use of guideline directed medical therapy (GDMT) at recommended doses remains suboptimal. We examine the usage and modification of inpatient GDMT and its effect on outcomes in patients hospitalized with a diagnosis of acute on chronic HFrEF between 2013 and 2018. Overall use and modification of GDMT, which included heart failure appropriate beta-blockers (BB), renin-angiotensin system inhibitors (RASi) and aldosterone blockers (MRA) during the hospitalization were collected. Target dosages were based on guideline recommendations. Primary endpoints included 30-day hospitalization-free survival and 1-year survival. Among 1,655 patients, discharge use of BB, RASi, and MRA was 73.4%, 55.9% and 13.8%, respectively. Upon discharge, ≥50% target dose of BB, RASi, and MRA was used in 25.3%, 15.6%, and 13.7%, respectively. In multivariable analyses, there was a statistically significant improvement in 1-year survival and 30-day hospitalization-free survival in patients discharged on increasing number of medication classes optimized at ≥50% target dose (per extra medication, HR 0.74, 0.64-0.86, p <0.001, and HR 0.73, 0.62-0.86, p = 0.0002), respectively. Initiation and/or uptitration of BB and RASi was associated with improved 30-day hospitalization-free survival and 1-year survival, (HR 0.73 (0.57-0.92), p = 0.0087; HR 0.62 (0.46-0.82), p <0.001) for BB and (HR 0.77 (0.62-0.95), p <0.001; HR 0.62 (0.48-0.80), p <0.001) for RASi, respectively. In conclusion, inpatient optimization of GDMT in acute HFrEF is feasible and associated with improved 30-day hospitalization-free survival and 1-year survival., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: CKD is common in heart failure (HF) and associated with morbidity and mortality, yet life-prolonging medications such as renin-angiotensin-aldosterone inhibitors (RAASi) are underused due to risk of hyperkalaemia. Sodium zirconium cyclosilicate (SZC) is a potassium-binding medication that has been shown to reduce incidence of hyperkalaemia in CKD, non-CKD, and HF populations, which we propose will support maximisation of RAASi therapy., Methods: We propose a 1:1 randomised, double-blind, placebo-controlled trial in which participants will receive either SZC or placebo. We will up-titrate participants' RAASi therapy while monitoring their serum potassium levels and adjusting their SZC dose if necessary. Participants with CKD and HF will be recruited from CKD and HF clinics at St George's Hospital. The total study period will be 18 months; 130 participants will be enrolled for approximately two months each following screening. Our primary outcome will be the proportion of participants who achieve maximum RAASi dose while maintaining normokalaemia. Secondary outcomes include participants reaching maximum RAASi dose without severe hyperkalaemia; time from randomisation to hyperkalaemia; time from randomisation to severe hyperkalaemia; number of RAASi dose escalations per participant; final doses of RAASi therapy; changes in quality of life score, eGFR, ACR, serum sodium, troponin T; number and duration of hospital admissions; and within-participant change in serum potassium compared to baseline., Discussion: This trial will be the first to examine the use of SZC for the maximisation of RAASi dosing in patients with advanced CKD and HF. We will assess the impact of achieving target RAASi dosing on hospital admission rates and duration of stay, with the hope that optimum RAASi treatment will translate into reduced morbidity and improved QoL. If clinical benefit is demonstrated, we hope that the joint multidisciplinary CKD-HF approach will be expanded., Trial Registration: EudraCT number 2020-002946-18. Registered on 08 June 2020. Online record pending.

Aim: As mineralocorticoid receptor antagonists (MRAs) may possess renoprotective effects in type 2 diabetes (T2D), it was decided to investigate the impact of high-dose MRA on prespecified secondary endpoints-namely, change in urinary albumin-creatinine ratio (UACR) and 24-h ambulatory blood pressure-in the MIRAD trial., Methods: This was a double-blind clinical trial in which T2D patients at high risk of or with established cardiovascular disease (CVD) were randomized to either high-dose (100-200 mg) eplerenone or a dose-matched placebo as an add-on to background antihypertensive treatment for 26 weeks. Safety was evaluated by the incidence of hyperkalaemia and kidney-related adverse events., Results: A total of 140 patients were enrolled (70 in each group). Baseline UACR was 17 mg/g (geometric mean; 95% CI: 13-22); this decreased by 34% in the eplerenone group compared with the placebo group at week 26 (95% CI: -51% to -12%; P =  0.005). There was no significant decrease in 24-h systolic blood pressure (SBP) due to treatment (-3 mmHg; 95% CI: -6 to 1; P = 0.150). However, the observed change in 24-h SBP correlated with the relative change in UACR in the eplerenone group (r = 0.568, P < 0.001). Mean baseline (± SD) estimated glomerular filtration rate (eGFR) was 85 (± 18.6) mL/min/1.73 m 2 , and 12 (± 9%) had an eGFR of 41-59 mL/min/1.73 m 2 . No significant differences in the incidence of mild hyperkalaemia (≥ 5.5 mmol/L; eplerenone vs placebo: 6 vs 2, respectively; P = 0.276) and no severe hyperkalaemia (≥ 6.0 mmol/L) were observed., Conclusion: The addition of high-dose eplerenone to T2D patients at high risk of CVD can markedly reduce UACR with an acceptable safety profile., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: Among patients with heart failure and reduced ejection fraction (HFrEF), angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEI/ARB), β-blockers (BB) and mineralocorticoid receptor antagonist (MRA) are known as guideline-directed medical therapy to improve prognosis. However, low blood pressure (BP) and renal dysfunction are often challenges prevent clinical implementation, so we investigated the association of different combinations of GDMT treatments with all-cause mortality in HFrEF population with low BP and renal dysfunction., Methods: This study initially included 51, 060 HF patients from the Swedish Heart Failure Registry, and finally 1464 HFrEF patients with low BP (systolic BP ≦ 100 mmHg) and renal dysfunction (estimated glomerular filtration rate (eGFR) ≦ 60 ml/min/1.73m 2 ) were ultimately enrolled. Patients were receiving oral medication for HF at study enrollment, and divided into four groups (group 1-4: ACEI/ARB + BB + MRA, ACEI/ARB + BB, ACEI/ARB + MRA or ACEI/ARB only, and other). The outcome is time to all-cause mortality., Results: Among the study patients, 485 (33.1%), 672 (45.9%), 109 (7.4%) and 198 (13.5%) patients were in group 1-4. Patients in group 1 were younger, had highest hemoglobin, and most with EF < 30%. During a median of 1.33 years follow-up, 937 (64%) patients died. After adjustment for age, gender, LVEF, eGFR, hemoglobin when compared with the group 1, the hazard ratio for all-cause mortality in group 2 was 1.04 (0.89-1.21) (p = 0.62), group 3 1.40 (1.09-1.79) (p = 0.009), and group 4 1.71 (1.39-2.09) (p < 0.001)., Conclusions: In real-world HFrEF patients with low BP and renal dysfunction, full medication of guideline-directed medical therapy is associated with improved survival. The benefit was larger close to the index date and decreased with follow-up time.

Objectives: In human studies and genetically altered mouse studies, variants in the striatin gene (STRN) are associated with increased blood pressure (BP) and aldosterone on a liberal salt diet. This clinical trial is based on the presumed mechanism for striatin-associated HTN - increased aldosterone. It is designed to determine if participants with the STRN risk alleles will have a greater BP reduction on a liberal salt diet with a specific, mechanism-based therapy - a mineralocorticoid receptor antagonist, eplerenone - as compared with a nonspecific anti-hypertensive therapy - amlodipine., Methods: One hundred five hypertensive adults with the STRN risk alleles (SNP rs2540923 carriers or rs888083 homozygotes) will be enrolled in a 12-week, double-blind, dose-escalation, clinical trial. After a minimum 2-week washout period and baseline assessment of BP on a liberal salt diet, participants will be randomized to either daily eplerenone or amlodipine. Participants will take daily at-home BP recordings as a safety check. After 4 and 8 weeks of drug therapy, BP will be measured by the study team and medication will be increased, if needed, to achieve a participant goal BP of <140/90 mmHg.Anticipated results We anticipate that STRN risk allele carriers will demonstrate a greater reduction in BP with eplerenone and will require a lower dose of eplerenone to reach goal BP as compared with amlodipine., Conclusion: This is a proof-of-concept clinical trial. Positive results support the feasibility of performing genetically-defined, mechanistically-driven trials in HTN. Clinically, it would suggest that genetic biomarkers can identify individuals highly responsive to specific treatment., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

A straightforward and rapid high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay allowing the sensitive and selective quantitation of finerenone (BAY 94-8862) in lithium heparin human plasma is described. Finerenone is a novel, selective, nonsteroidal mineralocorticoid receptor antagonist that is in phase III clinical trials for the treatment of chronic kidney disease. Finerenone quantitation is performed after addition of its stable isotope-labelled internal standard (ISTD) by protein precipitation with acidified acetonitrile followed by HPLC-MS/MS separation and detection. The determination of finerenone concentrations was validated for a plasma volume of 0.100 mL and subsequently also for a lower plasma volume of 0.010 mL, collected e.g. in paediatric studies. The analytical range was from 0.100 µg/L (lower limit of quantification) to 200 µg/L (upper limit of quantification). Inter-day accuracy was 99.7-105.0% for the plasma volume of 0.100 mL and 101.1-104.5% for the plasma volume of 0.010 mL. Inter-day precision was ≤ 7.0%, independent of the extracted plasma volume. A moderate, concentration-independent matrix effect on ionisation was observed for both finerenone and its ISTD of 0.535-0.617, which is fully compensated by the ISTD (ISTD-normalised matrix factors were 0.98-1.03). The assay was successfully applied with both validated plasma volumes to a clinical phase I study in which the pharmacokinetics of 20 mg finerenone were compared in capillary plasma (0.010 mL) and venous plasma (0.100 mL) in a concentration range from the lower limit of quantification to 310 µg/L (capillary plasma) and 252 µg/L (venous plasma). The area under the plasma concentration versus time curve was similar in both matrices, while maximum concentrations were 37% higher in capillary plasma. In conclusion, capillary sampling should not bias pharmacokinetic exposure estimates compared with venous plasma values, if limited to sampling times in the distribution and elimination phases of finerenone., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: There are limited data regarding the long-term outcomes of spironolactone use for women with acne and its effect on truncal acne., Objective: To comprehensively describe outcomes of patients treated with spironolactone in routine clinical practice, including long-term outcomes., Methods: We performed a retrospective case series of 403 adult women treated for acne with spironolactone at an academic medical center between 2008 and 2019. Rates of objective, as assessed by Comprehensive Acne Severity Scale scores, and subjective acne clearance were evaluated, as well as rates of treatment discontinuation, dosage changes, and drug survival. Logistic regression was used to assess for association between incidence of menstrual adverse effects and combined oral contraceptive use., Results: As evaluated by Comprehensive Acne Severity Scale scores, at the first follow-up, 75.5%, 84.0%, and 80.2% of patients with available data had reduction or complete clearance of acne on the face, chest, and back, respectively. The mean drug survival was 470.7 days. Menstrual adverse effects were less common among those using combined oral contraception (odds ratio, 0.23; 95% confidence interval, 0.11-0.50)., Limitations: This study was conducted at a single academic medical center., Conclusions: Spironolactone improves clinical outcomes and is well tolerated for many adult women with acne using it for an extended duration., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2021 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Apararenone is a long-acting, nonsteroidal mineralocorticoid receptor antagonist (MRA). The safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of single- and multiple-dose apararenone were assessed in 3 phase 1 randomized, double-blind studies in 223 healthy adults. Study 1 assessed the PK, safety/tolerability, and PD of single-dose apararenone (3.75-640 mg) and multiple-dose apararenone (10-40 mg/day on days 1-14, 320 mg loading dose on day 1 + 10 mg/day on days 2-14, or 40-320 mg loading dose on day 1 + 2.5-20 mg/day on days 2-14) in Caucasian and Black men and women. Study 2 assessed the PK and safety of single-dose apararenone (5-320 mg) in healthy Japanese men. Study 3 assessed the PK, PD, and safety/tolerability of single-dose apararenone (160 or 640 mg) or eplerenone (200 mg; only for 160 mg of apararenone), each after fludrocortisone challenge in Caucasian men. In studies 1 and 2, an approximately dose-proportional increase was observed in PK parameters over the apararenone dose range of 3.75-40 mg; at higher doses, a less than dose-proportional increase was observed. Food, sex, age, and race had no apparent effect on apararenone PK. A long half-life was seen for apararenone and its principal metabolite; in addition, the exposure of the metabolite was lower than that of apararenone. Apararenone suppressed the decrease in urinary sodium and potassium ion ratio that occurs after loading with fludrocortisone. These studies support the mechanism of action of apararenone as an MRA, and further clinical development is warranted., (© 2020 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

[Figure: see text].

Background: Mineralocorticoid receptor antagonists (MRAs) and sodium glucose co-transporter 2 inhibitors favorably influence the clinical course of patients with heart failure and reduced ejection fraction., Objectives: This study sought to study the mutual influence of empagliflozin and MRAs in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction)., Methods: Secondary analysis that compared the effects of empagliflozin versus placebo in 3,730 patients with heart failure and a reduced ejection fraction, of whom 71% used MRAs at randomization., Results: The effects of empagliflozin on the primary endpoint, on most efficacy endpoints, and on safety were similar in patients receiving or not receiving an MRA (interaction p > 0.20). For cardiovascular death, the hazard ratios for the effect of empagliflozin versus placebo were 0.82 (95% confidence interval [CI]: 0.65 to 1.05) in MRA users and 1.19 (95% CI: 0.82 to 1.71) in MRA nonusers (interaction p = 0.10); a similar pattern was seen for all-cause mortality (interaction p = 0.098). Among MRA nonusers at baseline, patients in the empagliflozin group were 35% less likely than those in the placebo group to initiate treatment with an MRA following randomization (hazard ratio: 0.65; 95% CI: 0.49 to 0.85). Among MRA users at baseline, patients in the empagliflozin group were 22% less likely than those in the placebo group to discontinue treatment with an MRA following randomization (hazard ratio: 0.78; 95% CI: 0.64 to 0.96). Severe hyperkalemia was less common in the empagliflozin group., Conclusions: In EMPEROR-Reduced, the use of MRAs did not influence the effect of empagliflozin to reduce adverse heart failure and renal outcomes. Treatment with empagliflozin was associated with less discontinuation of MRAs. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977)., Competing Interests: Funding Support and Author Disclosures EMPEROR-Reduced was funded by Boehringer Ingelheim and Eli Lilly. Dr. Ferreira has received consulting fees from Boehringer Ingelheim during the conduct of the study. Dr. Zannad has received personal fees from Boehringer Ingelheim during the conduct of the study; has received personal fees from Janssen, Novartis, Boston Scientific, Amgen, CVRx, AstraZeneca, Vifor Fresenius, Cardior, Cereno Pharmaceutical, Applied Therapeutics, Merck, Bayer, and Cellprothera outside the submitted work; and has received other support from CardioVascular Clinical Trialists and Cardiorenal, outside the submitted work. Dr. Pocock has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr. Anker has received grants from Vifor; has received personal fees from Vifor, Bayer, Boehringer Ingelheim, Novartis, Servier, Impulse Dynamics, Cardiac Dimensions, and Thermo Fisher Scientific; and has received grants and personal fees from Abbott Vascular, outside the submitted work. Dr. Butler has received consultancy fees from Boehringer Ingelheim during the conduct of the study; and has received consultancy fees from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, BerlinCures, Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, V-Wave, and Vifor, outside the submitted work. Dr. Filippatos has received payment for being a trial committee member from Boehringer Ingelheim during the conduct of the study; and has received payment for being a trial committee member from Medtronic, Vifor, Servier, and Novartis, outside the submitted work. Dr. Brueckmann has received personal fees from Boehringer Ingelheim during the conduct of the study; and has received personal fees from AbbVie, Akcea, Amarin, AstraZeneca, Amgen, Boehringer Ingelheim, Cardiorentis, Daiichi-Sankyo, Johnson & Johnson, Lilly, Novartis, Pfizer, Relypsa, Sanofi, Synthetic Biologics, Theravance, and Novo Nordisk, outside the submitted work. Drs. Brueckmann, Steubl, Jamal, and Steubl are employees of Boehringer Ingelheim. Dr. Schueler is an employee of mainanalytics, contracted by Boehringer Ingelheim. Dr. Packer has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Importance: Although recent studies and guideline recommendations indicate that potassium level monitoring is of low usefulness for healthy young women being treated for acne with spironolactone, little is known about whether these recommendations have been implemented in clinical practice., Objective: To evaluate trends in rates of potassium level monitoring among young women treated for acne with spironolactone and clinician variability in monitoring practices., Design, Setting, and Participants: This retrospective cohort study was conducted between January 1, 2008, and June 30, 2019, using data from the Optum deidentified Clinformatics Data Mart database. Participants comprised 108 547 healthy female patients aged 12 to 45 years who were treated for acne with spironolactone., Main Outcome and Measures: The primary outcome was the proportion of women who received a test for baseline potassium level and the proportion of women whose potassium levels were monitored in the first 180 days of being treated for acne with spironolactone. For clinicians who had prescribed at least 5 courses of spironolactone, the percentage of clinicians who ordered baseline potassium testing or monitoring and the percentage of clinicians who always monitored potassium were compared between 2008 and 2015 vs between 2016 and 2018., Results: For 108 547 women included in this cohort study, the mean (SD) age at the start of treatment was 30.7 (8.6) years, and the mean (SD) course duration was 159 (218) days. Between 2008 and 2018, the percentage of women whose potassium levels were monitored within 180 days of starting spironolactone by all clinicians decreased from 41.4% to 38.5%, with a decrease from 48.9% to 41.0% among dermatologists and from 39.7% to 37.7% among internists but with an increase from 71.4% to 75.4% among advanced practice clinicians (ie, nurse practitioners and physician assistants). The proportion of dermatologists who always monitored potassium decreased from 10.6% between 2008 and 2015 to 4.2% between 2016 and 2018. There was no significant difference in the proportion of internists who always monitored potassium from 2008 to 2015 (15.8%) vs from 2016 to 2018 (17.7%)., Conclusions and Relevance: Despite increasing evidence and guidelines supporting the elimination of potassium monitoring among healthy young women treated for acne with spironolactone, the present study findings suggest that potassium monitoring remains common, with substantial variability in clinician practices. There is a need for future implementation and dissemination research to understand underlying factors for this variation and to develop strategies to address this practice gap.

Androgens play an important role in the pathogenesis of acne. Being an anti-androgen drug with many side effects, spironolactone has recently been used in dermatology as a topical therapy for acne. Off-label drug use in dermatology is common, although those drugs are basically available as compounded formulations; the choice of a proper vehicle is often neglected in that case. Alkyl polyglucosides (APGs) are a FDA certified class of polyethylene glycol (PEG)-free surfactants produced from the renewable resources. Following the preformulation tests, two different APG emulsifiers were used in this study to stabilize emulsions as carriers for topical spironolactone. Assessment of the physical stability of emulsions per se and after incorporation of 5% of spironolactone was performed using polarization microscopy, electrical conductivity and pH measurements. The skin irritation profile and moisturizing potential was assessed in vivo on human volunteers. APG-based emulsions per se and with 5% of spironolactone showed acceptable skin irritation profiles and significant potential for skin hydration, which is important in acne treatment. Good physical stability and satisfying preliminary safety profile of all investigated samples were also obtained showing that moisturizing APG-based emulsions could be promoted as vehicles for off-label topical spironolactone.

Introduction: Our aim was to evaluate the safety and efficacy of low-dose mineralocorticoid receptor antagonists (MRAs) in dialysis patients., Methods: We systematically searched PubMed, EMBASE, and Cochrane libraries for clinical trials on the use of MRAs in dialysis patients. Review Manager 5.3 software was used to analyze relevant data and evaluate the quality of evidence., Results: We identified nine randomized controlled trials including 1128 chronic dialysis patients. In terms of safety, when hyperkalemia was defined as serum potassium level ≥5.5 mmol/L, low-dose MRAs were significantly associated with hyperkalemia (relative risk [RR] 1.76, 95% confidence intervals [CI] 1.07-2.89, P = .02); however, when hyperkalemia was defined as serum potassium level ≥6.0 mmol/L or serum potassium level ≥6.5 mmol/L, no significant association was observed between low-dose MRAs and hyperkalemia (RR 1.40, 95% CI 0.83-2.37, P = .20; RR 1.98, 95% CI 0.91-4.30, P = .09, respectively). Use of low-dose MRAs can reduce cardiovascular mortality by 54% compared with the control group (0.46, 95% CI 0.28-0.76, P = .003). Similarly, the RR of all-cause mortality for the low-dose MRAs group was 0.48 (95% CI 0.33-0.72, P = .0003)., Conclusion: Low-dose MRAs may benefit dialysis patients without significantly increasing moderate to severe hyperkalemia., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Intravenous mineralocorticoid receptor antagonists (MRAs) have been used in some centers for decades to reduce the risk of hypokalemia and boost diuresis in acutely decompensated heart failure (ADHF). We report the well-tolerated use of intravenous MRAs as a rescue procedure in 3 patients admitted for ADHF with important diuretic resistance. Undertaking trials evaluating the effect of this therapeutic strategy in ADHF could represent a promising avenue.

Polycystic ovarian syndrome (PCOS), is a multifactorial endocrine disorder in women of reproductive age. It usually associates with metabolic disorders (MDs), which aggravates the risk of infertility, cardiometabolic events and associated comorbidities in women with PCOS. Adiponectin, a circulating protein produced by adipocytes, which has been suggested to inversely correlate with MDs. Spironolactone, a non-selective mineralocorticoid receptor (MR) antagonist, has been in wide clinical use for several decades. Herein, we investigated the effects of low dose spironolactone (LDS) and the role of adiponectin in endocrine-metabolic disturbances in experimentally-induced PCOS rats. Eighteen female Wistar rats (160-180 g) were randomly allotted into 3 groups and treated with vehicle (p.o.), letrozole (LET; 1 mg/kg) and LET + LDS (0.25 mg/kg), once daily for 21 days, respectively. The results showed that LET-treated animals had features of PCOS, characterized by elevated plasma testosterone and prolactin, increased body weight gain and ovarian weight as well as disrupted ovarian cytoarchitecture and degenerated follicles. Additionally, elevated fasting blood glucose, 1 h-postload glucose and plasma insulin, impaired glucose tolerance, insulin resistance, reduced insulin sensitivity, increased plasma and ovarian lipid profile, plasma lipid peroxidation, TNF-α, IL-6 and decreased plasma glutathione peroxidase and glutathione content were observed. These alterations were associated with decreased circulating adiponectin and were reversed when treated with LDS. The present results suggest that LDS ameliorates endocrine-metabolic disturbances and inflammation-related comorbidities associated with LET-induced PCOS by modulating circulating androgen-adiponectin status., (Copyright © 2020 Elsevier Inc. All rights reserved.)