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Patients with heart failure (HF), particularly those with impaired renal function receiving renin–angiotensin–aldosterone system inhibitors (RAASis), are at risk of hyperkalaemia; when hyperkalaemia is severe, this can have serious clinical consequences. The incidence, prevalence, and risk factors for hyperkalaemia reported in randomized trials of RAASis may not reflect clinical practice due to exclusion of patients with elevated serum potassium (sK+) or severe renal impairment: information on patients managed in routine clinical care is important to understanding the actual burden of hyperkalaemia. This paper reviews the available clinical epidemiology data on hyperkalaemia in HF and considers areas requiring further research. Observational studies published since 2017 that focused on hyperkalaemia, included patients with HF, and had ≥1000 participants were considered. Hyperkalaemia occurrence in HF varied widely from 7% to 39% depending on the setting, HF severity, follow‐up length, and concomitant medications. Rates were lowest in patients with newly diagnosed HF and highest in patients with greater disease severity; comorbidities, such as chronic kidney disease and diabetes, and RAASi use, reflected commonly identified risk factors for hyperkalaemia in patients with HF. Hyperkalaemia was most often mild; however, from the limited data available, persistence of mild hyperkalaemia was associated with an increased risk of mortality and major adverse cardiovascular events. There were also limited data available on the progression of hyperkalaemia. Recurrence was common, occurring in one‐quarter to two‐fifths of hyperkalaemia cases. Despite HF guidelines recommending close monitoring of sK+, 55–93% of patients did not receive appropriate testing before or after initiation of RAASi or in follow‐up to moderate/severe hyperkalaemia detection. Many of the observational studies were retrospective and from a single country. There is a need for international, prospective, longitudinal, observational studies, such as the CARE‐HK in HF study (NCT04864795), to understand hyperkalaemia's prevalence, incidence, and severity; to identify and characterize cases that persist, progress, and recur; to highlight the importance of sK+ monitoring when using RAASi; and to assess the impact of newer HF therapies and potassium binders in clinical practice. Data from both clinical trials and observational studies with adjustments for confounding variables will be needed to assess the contribution of hyperkalaemia to clinical outcomes. [ABSTRACT FROM AUTHOR]

Despite the progress in the care of individuals with heart failure (HF), important sex disparities in knowledge and management remain, covering all the aspects of the syndrome, from aetiology and pathophysiology to treatment. Important distinctions in phenotypic presentation are widely known, but the mechanisms behind these differences are only partially defined. The impact of sex‐specific conditions in the predisposition to HF has gained progressive interest in the HF community. Under‐recruitment of women in large randomized clinical trials has continued in the more recent studies despite epidemiological data no longer reporting any substantial difference in the lifetime risk and prognosis between sexes. Target dose of medications and criteria for device eligibility are derived from studies with a large predominance of men, whereas specific information in women is lacking. The present scientific statement encompasses the whole scenario of available evidence on sex‐disparities in HF and aims to define the most challenging and urgent residual gaps in the evidence for the scientific and clinical HF communities. [ABSTRACT FROM AUTHOR]

Aim: To assess the effect of empagliflozin on patients with comorbid heart failure (HF) and diabetes with or without baseline insulin, and to study the impact of empagliflozin on insulin requirements over time. Materials and Methods: We performed a post‐hoc analysis of pooled patient‐level data from two cardiovascular outcomes trials of empagliflozin in HF (EMPEROR‐Reduced and EMPEROR‐Preserved trials). We undertook a subgroup analysis stratified by baseline insulin use, including all patients with diabetes. The studied endpoints included the primary composite endpoint of first hospitalization for HF or cardiovascular death, rate of decline of estimated glomerular filtration rate, composite renal outcome and rates of sustained insulin initiation. Results: Among 4794 patients with diabetes, 1333 (658 in empagliflozin, 675 in placebo) were using insulin at baseline. The treatment effect of empagliflozin on the primary endpoint was consistent irrespective of insulin use [no insulin, hazard ratio 0.74, 95% confidence interval (CI) 0.63‐0.86; using insulin, hazard ratio 0.81, 95% CI 0.66‐1.00, pinteraction =.49], as was the effect on the rate of decline of the estimated glomerular filtration rate (pinteraction =.75). There was no effect of empagliflozin on the composite renal outcome in patients using or not using insulin (pinteraction =.30). Among patients not using insulin at baseline, those randomized to empagliflozin initiated insulin less frequently throughout the follow‐up period compared with those receiving placebo (2.6% vs. 3.8%, odds ratio 0.66, 95% CI 0.50‐0.88). Conclusions: Empagliflozin exerts a consistent benefit on cardiovascular outcomes and renal function decline, irrespective of baseline insulin use, and reduces the need for sustained insulin initiation in patients with HF and diabetes. [ABSTRACT FROM AUTHOR]

Aims: Biologically active adrenomedullin (bio‐ADM) is a promising marker of residual congestion. The STRONG‐HF trial showed that high‐intensity care (HIC) of guideline‐directed medical therapy (GDMT) improved congestion and clinical outcomes in heart failure (HF) patients. The association between bio‐ADM, decongestion, outcomes and the effect size of HIC of GDMT remains to be elucidated. Methods and results: We measured plasma bio‐ADM concentrations in 1005 patients within 2 days prior to anticipated discharge (baseline) and 90 days later. Bio‐ADM correlated with most signs of congestion, with the exception of rales. Changes in bio‐ADM were strongly correlated with change in congestion status from baseline to day 90 (gamma −0.24; p = 0.0001). Patients in the highest tertile of baseline bio‐ADM concentrations were at greater risk than patients in the lowest tertile for the primary outcome of 180‐day all‐cause mortality or HF rehospitalization (hazard ratio [HR] 2.14, 95% confidence interval [CI] 1.42–3.22) and 180‐day HF rehospitalization (HR 2.33, 95% CI 1.38–3.94). Areas under the receiver‐operating characteristic curves were 0.5977 (95% CI 0.5561–0.6393), 0.5800 (95% CI 0.5356–0.6243), and 0.6159 (95% CI 0.5711–0.6607) for bio‐ADM, N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and their combination, respectively, suggesting that both bio‐ADM and NT‐proBNP provided similarly modest discrimination for this outcome. A trend towards better discrimination by combined bio‐ADM and NT‐proBNP than NT‐proBNP alone was found (p = 0.059). HIC improved the primary outcome, irrespective of baseline bio‐ADM concentration (interaction p = 0.37). In contrast to NT‐proBNP, the 90‐day change in bio‐ADM did not differ significantly between HIC and usual care. Conclusions: Bio‐ADM is a marker of congestion and predicts congestion at 3 months after a HF hospitalization. Higher bio‐ADM was modestly associated with a higher risk of death and early hospital readmission and may have added value when combined with NT‐proBNP. [ABSTRACT FROM AUTHOR]

Aim: The RESHAPE‐HF2 trial is designed to assess the efficacy and safety of the MitraClip device system for the treatment of clinically important functional mitral regurgitation (FMR) in patients with heart failure (HF). This report describes the baseline characteristics of patients enrolled in the RESHAPE‐HF2 trial compared to those enrolled in the COAPT and MITRA‐FR trials. Methods and results: The RESHAPE‐HF2 study is an investigator‐initiated, prospective, randomized, multicentre trial including patients with symptomatic HF, a left ventricular ejection fraction (LVEF) between 20% and 50% with moderate‐to‐severe or severe FMR, for whom isolated mitral valve surgery was not recommended. Patients were randomized 1:1 to a strategy of delivering or withholding MitraClip. Of 506 patients randomized, the mean age of the patients was 70 ± 10 years, and 99 of them (20%) were women. The median EuroSCORE II was 5.3 (2.8–9.0) and median plasma N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) was 2745 (1407–5385) pg/ml. Most patients were prescribed beta‐blockers (96%), diuretics (96%), angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor–neprilysin inhibitors (82%) and mineralocorticoid receptor antagonists (82%). The use of sodium–glucose cotransporter 2 inhibitors was rare (7%). Cardiac resynchronization therapy (CRT) devices had been previously implanted in 29% of patients. Mean LVEF, left ventricular end‐diastolic volume and effective regurgitant orifice area (EROA) were 31 ± 8%, 211 ± 76 ml and 0.25 ± 0.08 cm2, respectively, whereas 44% of patients had mitral regurgitation severity of grade 4+. Compared to patients enrolled in COAPT and MITRA‐FR, those enrolled in RESHAPE‐HF2 were less likely to have mitral regurgitation grade 4+ and, on average, HAD lower EROA, and plasma NT‐proBNP and higher estimated glomerular filtration rate, but otherwise had similar age, comorbidities, CRT therapy and LVEF. Conclusion: Patients enrolled in RESHAPE‐HF2 represent a third distinct population where MitraClip was tested in, that is one mainly comprising of patients with moderate‐to‐severe FMR instead of only severe FMR, as enrolled in the COAPT and MITRA‐FR trials. The results of RESHAPE‐HF2 will provide crucial insights regarding broader application of the transcatheter edge‐to‐edge repair procedure in clinical practice. [ABSTRACT FROM AUTHOR]

Aims: Both low and high body mass index (BMI) are associated with poor heart failure outcomes. Whether BMI modifies benefits of sodium–glucose cotransporter 2 inhibitors (SGLT2i) in heart failure with preserved ejection fraction (HFpEF) requires further investigation. Methods and results: Using EMPEROR‐Preserved data, the effects of empagliflozin versus placebo on the risks for the primary outcome (hospitalization for heart failure [HHF] or cardiovascular [CV] death), change in estimated glomerular filtration rate (eGFR) slopes, change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ‐CSS), and secondary outcomes across baseline BMI categories (<25 kg/m2, 25 to <30 kg/m2, 30 to <35 kg/m2, 35 to <40 kg/m2 and ≥40 kg/m2) were examined, and a meta‐analysis conducted with DELIVER. Forty‐five percent had a BMI of ≥30 kg/m2. For the primary outcome, there was a consistent treatment effect of empagliflozin versus placebo across the BMI categories with no formal interaction (p trend = 0.19) by BMI categories. There was also no difference in the effects on secondary outcomes including total HHF (p trend = 0.19), CV death (p trend = 0.20), or eGFR slope with slower declines with empagliflozin regardless of BMI (range 1.12–1.71 ml/min/1.73 m2 relative to placebo, p trend = 0.85 for interaction), though there was no overall impact on the composite renal endpoint. The difference in weight change between empagliflozin and placebo was −0.59, −1.48, −1.54, −0.87, and − 2.67 kg in the lowest to highest BMI categories (p trend = 0.016 for interaction). A meta‐analysis of data from EMPEROR‐Preserved and DELIVER showed a consistent effect of SGLT2i versus placebo across BMI categories for the outcome of HHF or CV death. There was a trend toward greater absolute KCCQ‐CSS benefit at 32 weeks with empagliflozin at higher BMIs (p = 0.08). Conclusions: Empagliflozin treatment resulted in broadly consistent cardiac effects across the range of BMI in patients with HFpEF. SGLT2i treatment yields benefit in patients with HFpEF regardless of baseline BMI. [ABSTRACT FROM AUTHOR]

Aims: Lower respiratory tract infections (LRTI) are common worldwide. Patients with heart failure and mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) have a high risk of developing LRTI. Prior studies were able to show that sodium–glucose cotransporter 2 inhibitors may reduce the incidence of LRTI in patients with type 2 diabetes. The aim of this study was to evaluate patient characteristics and prognosis according to LRTI status and to assess the effect of empagliflozin on LRTI in 5988 patients with HFmrEF/HFpEF enrolled in the EMPEROR‐Preserved trial randomized to either empagliflozin or placebo over a median follow‐up of 26 months. Methods and results: Time‐updated models were used to study the mortality risk after a LRTI. Cox regression was used to study the effect of empagliflozin on incident LRTI. Throughout the follow‐up, 699 of 5988 (11.7%) patients developed LRTI: these were older, were more frequently hospitalized within the previous year, had type 2 diabetes, chronic kidney disease, and had higher N‐terminal pro‐B‐type natriuretic peptide levels than patients without incident LRTI. Patients who developed LRTI had a 2.7‐fold higher risk of subsequent mortality compared to patients without LRTI. The incidence of LRTI was 5.2 (95% confidence interval [CI] 4.6–5.8) events per 100 person‐years in the empagliflozin group and 6.2 (95% CI 5.6–6.9) events per 100 person‐years in the placebo group (hazard ratio 0.83, 95% CI 0.71–0.96, p = 0.014). The total number of LRTI events was reduced in the empagliflozin group (incidence rate ratio 0.80, 95% CI 0.68–0.94, p = 0.008). No effect of empagliflozin was observed on COVID‐19 incidence. Conclusion: In EMPEROR‐Preserved, LRTI was frequent and associated with a poor prognosis. Empagliflozin was associated with a reduced risk of LRTI compared to placebo. [ABSTRACT FROM AUTHOR]

Aims: Renal function (estimated glomerular filtration rate [eGFR]) changes early after the introduction of empagliflozin have not been described in heart failure with preserved ejection fraction (HFpEF). The aim of this study was to describe early eGFR changes, assess its determinants and its clinical impact on cardiovascular and renal outcomes in patients with HFpEF enrolled in EMPEROR‐Preserved. Methods and results: Estimated glomerular filtration rate changes (absolute and relative) from randomization to week 4 were calculated and landmark analyses performed. Initial eGFR change was available in 5836 patients (97.5% of the population). Empagliflozin induced a mean eGFR change of −3.2 ml/min/1.73 m2 versus placebo from baseline to week 4. After week 4, in the empagliflozin group, the risk of the primary outcome (composite of heart failure hospitalization or cardiovascular death), cardiovascular, all‐cause mortality and sustained ≥50% eGFR decrease or end‐stage renal disease (ESRD) did not differ by eGFR change levels. In contrast, in the placebo group, patients included in the tertile with most profound eGFR decrease (i.e. ≥5.1% from baseline) had a higher risk of the primary outcome (hazard ratio [HR] 1.46, 95% confidence interval [CI] 1.17–1.82), cardiovascular mortality (HR 1.38, 95% CI 1.01–1.89) and sustained ≥50% eGFR decrease or ESRD (HR 2.20, 95% CI 1.20–4.04) versus tertile with eGFR increase. Conclusion: An initial relatively small eGFR decrease may be expected after empagliflozin initiation. Such small eGFR decrease was not associated with adverse cardiovascular outcomes with empagliflozin. In contrast, eGFR decrease was associated with poor cardiovascular outcomes with placebo. [ABSTRACT FROM AUTHOR]

Cardio‐oncology is a rapidly growing field of cardiovascular (CV) medicine that has resulted from the continuously increasing clinical demand for specialized CV evaluation, prevention and management of patients suffering or surviving from malignant diseases. Dealing with CV disease in patients with cancer requires special knowledge beyond that included in the general core curriculum for cardiology. Therefore, the European Society of Cardiology (ESC) has developed a special core curriculum for cardio‐oncology, a consensus document that defines the level of experience and knowledge required for cardiologists in this particular field. It is structured into 8 chapters, including (i) principles of cancer biology and therapy; (ii) forms and definitions of cancer therapy‐related cardiovascular toxicity (CTR‐CVT); (iii) risk stratification, prevention and monitoring protocols for CTR‐CVT; (iv) diagnosis and management of CV disease in patients with cancer; (v) long‐term survivorship programmes and cardio‐oncology rehabilitation; (vi) multidisciplinary team management of special populations; (vii) organization of cardio‐oncology services; (viii) research in cardio‐oncology. The core curriculum aims at promoting standardization and harmonization of training and evaluation in cardio‐oncology, while it further provides the ground for an ESC certification programme designed to recognize the competencies of certified specialists. [ABSTRACT FROM AUTHOR]

Aims: A high‐intensity care (HIC) strategy with rapid guideline‐directed medical therapy (GDMT) up‐titration and close follow‐up visits improved outcomes, compared to usual care (UC), in patients recently hospitalized for acute heart failure (AHF). Hypotension is a major limitation to GDMT implementation. We aimed to assess the impact of baseline systolic blood pressure (SBP) on the effects of HIC versus UC and the role of early SBP changes in STRONG‐HF. Methods and results: A total of 1075 patients hospitalized for AHF with SBP ≥100 mmHg were included in STRONG‐HF. For the purpose of this post‐hoc analysis, patients were stratified by tertiles of baseline SBP (<118, 118–128, and ≥129 mmHg) and, in the HIC arm, by tertiles of changes in SBP from the values measured before discharge to those measured at 1 week after discharge (≥2 mmHg increase, ≤7 mmHg decrease to <2 mmHg increase, and ≥8 mmHg decrease). The primary endpoint was 180‐day heart failure rehospitalization or death. The effect of HIC versus UC on the primary endpoint was independent of baseline SBP evaluated as tertiles (pinteraction = 0.77) or as a continuous variable (pinteraction = 0.91). In the HIC arm, patients with increased, stable and decreased SBP at 1 week reached 83.5%, 76.2% and 75.3% of target doses of GDMT at day 90. The risk of the primary endpoint was not significantly different between patients with different SBP changes at 1 week (adjusted p = 0.46). Conclusions: In STRONG‐HF, the benefits of HIC versus UC were independent of baseline SBP. Rapid GDMT up‐titration was performed also in patients with an early SBP drop, resulting in similar 180‐day outcome as compared to patients with stable or increased SBP. [ABSTRACT FROM AUTHOR]

Aim: Inhibition of microRNA (miR)‐132 effectively prevents and reverses adverse cardiac remodelling, making it an attractive heart failure (HF) target. CDR132L, a synthetic antisense oligonucleotide selectively blocking pathologically elevated miR‐132, demonstrated beneficial effects on left ventricular (LV) structure and function in relevant preclinical models, and was safe and well tolerated in a Phase 1b study in stable chronic HF patients. Patients with acute myocardial infarction (MI) and subsequent LV dysfunction and remodelling have limited therapeutic options, and may profit from early CDR132L treatment. Methods: The HF‐REVERT (Phase 2, multicenter, randomized, parallel, 3‐arm, placebo‐controlled Study to Assess Efficacy and Safety of CDR132L in Patients with Reduced Left Ventricular Ejection Fraction after Myocardial Infarction) evaluates the efficacy and safety of CDR132L in HF patients post‐acute MI (n = 280), comparing the effect of 5 and 10 mg/kg CDR132L, administered as three single intravenous doses 28 days apart, in addition to standard of care. Key inclusion criteria are the diagnosis of acute MI, the development of systolic dysfunction (LV ejection fraction ≤45%) and elevated N‐terminal pro‐B‐type natriuretic peptide. The study consists of a 6‐month double‐blinded treatment period with the primary endpoint LV end‐systolic volume index and relevant secondary endpoints, followed by a 6‐month open‐label observation period. Conclusion: The HF‐REVERT trial may underpin the concept of miR‐132 inhibition to prevent or reverse cardiac remodelling in post‐MI HF. The results will inform the design of subsequent outcome trials to test CDR132L in HF. [ABSTRACT FROM AUTHOR]

Aims: The therapeutic mechanism of sodium–glucose cotransporter 2 inhibitors (SGLT2i) on left cardiac remodelling in patients with heart failure with reduced ejection fraction (HFrEF) is not well‐established. This study meta‐analysed the impact of SGLT2i on left cardiac structure and function in patients with HFrEF. Methods and results: Online databases were queried up to April 2023 for trials reporting indicators of left cardiac structure and function in patients with HFrEF treated with SGLT2i. Data from studies were pooled using a random‐effects model to derive weighted mean differences (WMDs) and 95% confidence intervals (CIs). Six trials were included (n = 555). Compared with control, SGLT2i significantly improved left ventricular end‐diastolic volume (LVEDV; WMD: −17.07 ml [−23.84, −10.31]; p < 0.001), LVEDV index (WMD: −5.62 ml/m2 [−10.28, −0.97]; p = 0.02), left ventricular end‐systolic volume (LVESV; WMD: −15.63 ml [−26.15, −5.12]; p = 0.004), LVESV index (WMD: −6.90 ml/m2 [−10.68, −3.11]; p = 0.001), left ventricular ejection fraction (WMD: 2.71% [0.70, 4.72]; p = 0.008), and left atrial volume index (WMD: −2.19 ml/m2 [−4.26, −0.11]; p = 0.04) in patients with HFrEF. SGLT2i use was associated with a non‐significant trend towards a reduction in left ventricular mass index (WMD: −6.25 g/m2 [−12.79, 0.28]; p = 0.06). No significant impact on left ventricular global longitudinal strain was noted (WMD: 0.21% [−0.25, 0.67]; p = 0.38). Conclusions: Sodium–glucose cotransporter 2 inhibitors improve cardiac structure and function in patients with HFrEF. [ABSTRACT FROM AUTHOR]

Aims: Extracellular matrix remodelling is one of the key pathways involved in heart failure (HF) progression. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) may have a role in attenuating myocardial fibrosis. The impact of SGLT2i on blood markers of collagen turnover in humans is not fully elucidated. This study aimed to investigate the effect of empagliflozin on serum markers of collagen turnover in patients enrolled in the EMPEROR‐Preserved and EMPEROR‐Reduced trials. Methods and results: Overall, 1084 patients (545 in empagliflozin and 539 in placebo) were included in the analysis. Procollagen type I carboxy‐terminal propeptide (PICP), a fragment of N‐terminal type III collagen (PRO‐C3), procollagen type I amino‐terminal peptide (PINP), a fragment of C‐terminal type VIa3 collagen (PRO‐C6), a fragment of type I collagen (C1M), and a fragment of type III collagen (C3M) were measured in serum at baseline, 12 and 52 weeks. A mixed model repeated measurements model was used to evaluate the effect of empagliflozin versus placebo on the analysed biomarkers. Higher baseline PICP, PRO‐C6 and PINP levels were associated with older age, a more severe HF presentation, higher levels of natriuretic peptides and high‐sensitivity troponin T, and the presence of comorbid conditions such as chronic kidney disease and atrial fibrillation. Higher PICP levels were associated with the occurrence of the study primary endpoint (a composite of HF hospitalization or cardiovascular death), and PRO‐C6 and PINP were associated with the occurrence of sustained worsening of kidney function. On the other hand, PRO‐C3, C1M, and C3M were not associated with worse HF severity or study outcomes. Compared to placebo, empagliflozin reduced PICP at week 12 by 5% and at week 52 by 8% (week 12: geometric mean ratio = 0.95, 95% confidence interval [CI] 0.91–0.99, p = 0.012; week 52: geometric mean ratio = 0.92, 95% CI 0.88–0.97, p = 0.003). Additionally, empagliflozin reduced PRO‐C3 at week 52 by 7% (week 12: geometric mean ratio = 0.98, 95% CI 0.95–1.02, p = 0.42; week 52: geometric mean ratio = 0.93, 95% CI 0.89–0.98, p = 0.003), without impact on other collagen markers. Conclusion: Our observations are consistent with experimental observations that empagliflozin down‐regulates profibrotic signalling. The importance of such an effect for the clinical benefits of SGLT2i in HF remains to be elucidated. [ABSTRACT FROM AUTHOR]

Aim: Investigating the effect of finerenone on liver function, cardiovascular and kidney composite outcomes in patients with chronic kidney disease and type 2 diabetes, stratified by their risk of liver steatosis, inflammation and fibrosis. Materials and Methods: Post hoc analysis stratified patients (N = 13 026) by liver fibrosis and enzymes: high risk of steatosis (hepatic steatosis index >36); elevated transaminases [alanine transaminase (ALT) >33 (males) and >25 IU/L (females)]; and fibrosis‐4 (FIB‐4) index scores >3.25, >2.67 and >1.30. Liver enzymes were assessed by changes in ALT, aspartate aminotransferase and gamma‐glutamyl transferase. Composite kidney outcome was defined as onset of kidney failure, sustained estimated glomerular filtration rate decline ≥57% from baseline over ≥4 weeks or kidney death. Composite cardiovascular outcome was defined as cardiovascular death, non‐fatal myocardial infarction, non‐fatal stroke or hospitalization for heart failure. Results: ALT, aspartate aminotransferase and gamma‐glutamyl transferase levels were consistent between treatment groups and remained stable throughout. Finerenone consistently reduced the risk of composite kidney outcome, irrespective of altered liver tests. Higher FIB‐4 score was associated with higher incidence rates of composite cardiovascular outcome. Finerenone reduced the risk of composite cardiovascular outcome versus placebo in FIB‐4 subgroups by 52% (>3.25), 39% (>2.67) and 24% (>1.30) (p values for interaction =.01,.13 and.03, respectively). Conclusions: Finerenone has neutral effects on liver parameters in patients with chronic kidney disease and type 2 diabetes. Finerenone showed robust and consistent kidney benefits in patients with altered liver tests, and profound cardiovascular benefits even in patients with higher FIB‐4 scores who were at high risk of developing cardiovascular complications. [ABSTRACT FROM AUTHOR]

Aims: Growth differentiation factor‐15 (GDF‐15) is upregulated in part in response to cardiomyocyte stretch and stress, and it exerts a protective role that is mediated by its action to suppress signalling through insulin‐like growth factor (IGF) and enhance signalling through adenosine monophosphate‐activated protein kinase (AMPK). Sodium–glucose cotransporter 2 (SGLT2) inhibitors improve outcomes in heart failure, which has been experimentally linked to AMPK. This study aimed at evaluating the associations of GDF‐15 with baseline characteristics, the prognostic significance of GDF‐15, and the effect of empagliflozin on GDF‐15 in patients with heart failure with a reduced and preserved ejection fraction. Methods and results: Growth differentiation factor‐15 was determined in serum samples from the EMPEROR‐Reduced and EMPEROR‐Preserved trials. Cox regression and mixed models for repeated measures were used to study the association with outcomes and the effect of empagliflozin on GDF‐15, respectively. We studied 1124 patients (560 placebo and 564 empagliflozin) with median GDF‐15 levels at baseline of 2442 (interquartile range 1603–3780) pg/ml. Patients with higher GDF‐15 levels were typically older men with more severe symptoms, higher N‐terminal pro‐B‐type natriuretic peptide levels, worse kidney function and who were prescribed metformin. Baseline levels of GDF‐15 were well correlated with levels of IGF‐binding protein 7 (rho = 0.64). Higher levels of GDF‐15 were independently associated with an increased risk of cardiovascular death, heart failure hospitalizations, and worse kidney outcomes. When considered as a continuous variable, for each doubling in GDF‐15, the adjusted hazard ratio for cardiovascular death or heart failure hospitalization was 1.40 (95% confidence interval 1.15–1.71; p < 0.001). The relative effect of empagliflozin on cardiovascular death and hospitalization for heart failure was most pronounced in patients with higher baseline levels of GDF‐15 (interaction p‐trend = 0.031). At week 52, when compared with placebo, empagliflozin increased GDF‐15 by an additional 8% (p = 0.020), an effect that was primarily seen in patients not receiving metformin, a known AMPK activator. Conclusions: Growth differentiation factor‐15 is a marker of worse heart failure severity, is an independent predictor of major heart failure outcomes and may be associated with more pronounced benefits of empagliflozin. GDF‐15 is increased among metformin users, and empagliflozin was associated with an increase in GDF‐15 levels, primarily in patients not receiving metformin. [ABSTRACT FROM AUTHOR]

Right‐sided heart failure and tricuspid regurgitation are common and strongly associated with poor quality of life and an increased risk of heart failure hospitalizations and death. While medical therapy for right‐sided heart failure is limited, treatment options for tricuspid regurgitation include surgery and, based on recent developments, several transcatheter interventions. However, the patients who might benefit from tricuspid valve interventions are yet unknown, as is the ideal time for these treatments given the paucity of clinical evidence. In this context, it is crucial to elucidate aetiology and pathophysiological mechanisms leading to right‐sided heart failure and tricuspid regurgitation in order to recognize when tricuspid regurgitation is a mere bystander and when it can cause or contribute to heart failure progression. Notably, early identification of right heart failure and tricuspid regurgitation may be crucial and optimal management requires knowledge about the different mechanisms and causes, clinical course and presentation, as well as possible treatment options. The aim of this clinical consensus statement is to summarize current knowledge about epidemiology, pathophysiology and treatment of tricuspid regurgitation in right‐sided heart failure providing practical suggestions for patient identification and management. [ABSTRACT FROM AUTHOR]

Aim: It is unknown whether safety and clinical endpoints by use of sacubitril/valsartan (an angiotensin receptor–neprilysin inhibitor [ARNI]) are affected by mineralocorticoid receptor antagonists (MRA) in high‐risk myocardial infarction (MI) patients. The aim of this study was to examine whether MRA modifies safety and clinical endpoints by use of sacubitril/valsartan in patients with a MI and left ventricular systolic dysfunction (LVSD) and/or pulmonary congestion. Methods and results: Patients (n = 5661) included in the PARADISE MI trial (Prospective ARNI vs. ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI) were stratified according to MRA. Primary outcomes in this substudy were worsening heart failure or cardiovascular death. Safety was defined as symptomatic hypotension, hyperkalaemia >5.5 mmol/L, or permanent drug discontinuation. A total of 2338 patients (41%) were treated with MRA. Safety of ARNI compared to ramipril was not altered significantly by ± MRA, and both groups had similar increase in symptomatic hypotension with ARNI. In patients taking MRA, the risk of hyperkalaemia or permanent drug discontinuation was not significantly altered by ARNI (p > 0.05 for all comparisons). The effect of ARNI compared with ramipril was similar in those who were and were not taking MRA (hazard ratio [HR]MRA 0.96, 95% confidence interval [CI] 0.77–1.19 and HRMRA– 0.87, 95% CI 0.71–1.05, for the primary endpoint; p = 0.51 for interaction [Clinical Endpoint Committee adjudicated]); similar findings were observed if investigator‐reported endpoints were evaluated (p = 0.61 for interaction). Conclusions: Use of a MRA did not modify safety or clinical endpoints related to initiation of ARNI compared to ramipril in the post‐MI setting in patients with LVSD and/or congestion. [ABSTRACT FROM AUTHOR]

Cardiomyopathies are a significant contributor to cardiovascular morbidity and mortality, mainly due to the development of heart failure and increased risk of sudden cardiac death (SCD). Despite improvement in survival with contemporary treatment, SCD remains an important cause of mortality in cardiomyopathies. It occurs at a rate ranging between 0.15% and 0.7% per year (depending on the cardiomyopathy), which significantly surpasses SCD incidence in the age‐ and sex‐matched general population. The risk of SCD is affected by multiple factors including the aetiology, genetic basis, age, sex, physical exertion, the extent of myocardial disease severity, conduction system abnormalities, and electrical instability, as measured by various metrics. Over the past decades, the knowledge on the mechanisms and risk factors for SCD has substantially improved, allowing for a better‐informed risk stratification. However, unresolved issues still challenge the guidance of SCD prevention in patients with cardiomyopathies. In this review, we aim to provide an in‐depth discussion of the contemporary concepts pertinent to understanding the burden, risk assessment and prevention of SCD in cardiomyopathies (dilated, non‐dilated left ventricular, hypertrophic, arrhythmogenic right ventricular, and restrictive). The review first focuses on SCD incidence in cardiomyopathies and then summarizes established and emerging risk factors for life‐threatening arrhythmias/SCD. Finally, it discusses validated approaches to the risk assessment and evidence‐based measures for SCD prevention in cardiomyopathies, pointing to the gaps in evidence and areas of uncertainties that merit future clarification. [ABSTRACT FROM AUTHOR]

Aims: Heart failure outcomes remain poor despite advances in therapy. The European Society of Cardiology Heart Failure III Registry (ESC HF III Registry) aims to characterize HF clinical features and outcomes and to assess implementation of guideline‐recommended therapy in Europe and other ESC affiliated countries. Methods: Between 1 November 2018 and 31 December 2020, 10 162 patients with chronic or acute/worsening HF with reduced, mildly reduced, or preserved ejection fraction were enrolled from 220 centres in 41 European or ESC affiliated countries. The ESC HF III Registry collected data on baseline characteristics (hospital or clinic presentation), hospital course, diagnostic and therapeutic decisions in hospital and at the clinic visit; and on outcomes at 12‐month follow‐up. These data include demographics, medical history, physical examination, biomarkers and imaging, quality of life, treatments, and interventions – including drug doses and reasons for non‐use, and cause‐specific outcomes. Conclusion: The ESC HF III Registry will provide comprehensive and unique insight into contemporary HF characteristics, treatment implementation, and outcomes, and may impact implementation strategies, clinical discovery, trial design, and public policy. [ABSTRACT FROM AUTHOR]

Aim: In this subgroup analysis of STRONG‐HF, we explored the association between changes in renal function and efficacy of rapid up‐titration of guideline‐directed medical therapy (GDMT) according to a high‐intensity care (HIC) strategy. Methods and results: In patients randomized to the HIC arm (n = 542), renal function was assessed at baseline and during follow‐up visits. We studied the association with clinical characteristics and outcomes of a decrease in estimated glomerular filtration rate (eGFR) at week 1, defined as ≥15% decrease from baseline. Patients in the usual care group (n = 536) were seen at day 90. The treatment effect of HIC versus usual care was independent of baseline eGFR (p‐interaction = 0.4809). A decrease in eGFR within 1 week occurred in 77 (15.5%) patients and was associated with more rales on examination (p = 0.004), and a higher New York Heart Association class at the corresponding visit. Following the decrease in eGFR at 1 week, lower average optimal doses of GDMT were prescribed during follow‐up (p = 0.0210) and smaller reductions in N‐terminal pro‐B‐type natriuretic peptide occurred (geometrical mean 0.81 in no eGFR decrease vs 1.12 in GFR decrease, p = 0.0003). The rate of heart failure (HF) readmission or death at 180 days was 12.3% in no eGFR decrease versus 18.5% in eGFR decrease (p = 0.2274) and HF readmissions were 7.8% versus 16.6% (p = 0.0496). Conclusions: In the STRONG‐HF study, HIC reduced 180‐day HF readmission or death regardless of baseline eGFR. An early decrease in eGFR during rapid up‐titration of GDMT was associated with more evidence of congestion, yet lower doses of GDMT during follow‐up. [ABSTRACT FROM AUTHOR]

Aims: To assess the potential interaction between non‐cardiac comorbidities (NCCs) and the efficacy and safety of high‐intensity care (HIC) versus usual care (UC) in the STRONG‐HF trial, including stable patients with improved but still elevated natriuretic peptides. Methods and results: In the trial, eight NCCs were reported: anaemia, diabetes, renal dysfunction, severe liver disease, chronic obstructive pulmonary disease/asthma, stroke/transient ischaemic attack, psychiatric/neurological disorders, and malignancies. Patients were classified by NCC number (0, 1, 2 and ≥3). The treatment effect of HIC versus UC on the primary endpoint, 180‐day death or heart failure (HF) rehospitalization, was compared by NCC number and by each individual comorbidity. Among the 1078 patients, the prevalence of 0, 1, 2 and ≥3 NCCs was 24.3%, 39.8%, 24.5% and 11.4%, respectively. Achievement of full doses of HF therapies at 90 and 180 days in the HIC was similar irrespective of NCC number. In HIC, the primary endpoint occurred in 10.0%, 16.6%, 13.6% and 26.2%, in those with 0, 1, 2 and ≥3 NCCs, respectively, as compared to 19.1%, 25.4%, 23.3% and 26.2% in UC (interaction‐p = 0.80). The treatment benefit of HIC versus UC on the primary endpoint did not differ significantly by each individual comorbidity. There was no significant treatment interaction by NCC number in quality‐of‐life improvement (p = 0.98) or the incidence of serious adverse events (p = 0.11). Conclusions: In the STRONG‐HF trial, NCCs neither limited the rapid up‐titration of HF therapies, nor attenuated the benefit of HIC on the primary endpoint. In the context of a clinical trial, the benefit–risk ratio favours the rapid up‐titration of HF therapies even in patients with multiple NCCs. [ABSTRACT FROM AUTHOR]

Aims: A high resting heart rate (RHR) and low systolic blood pressure (SBP) are a risk factor and a risk indicator, respectively, for poor heart failure (HF) outcomes. This analysis evaluated the associations between baseline RHR and SBP with outcomes and treatment patterns in patients with HF and reduced ejection fraction (HFrEF) in the QUALIFY (QUality of Adherence to guideline recommendations for LIFe‐saving treatment in heart failure surveY) international registry. Methods and results: Between September 2013 and December 2014, 7317 HFrEF patients with a previous HF hospitalization within 1–15 months were enrolled in the QUALIFY registry. Complete follow‐up data were available for 5138 patients. The relationships between RHR and SBP and outcomes were assessed using a Cox proportional hazards model and were analysed according to baseline values as high RHR (H‐RHR) ≥75 bpm versus low RHR (L‐RHR) <75 bpm and high SBP (H‐SBP) ≥110 mmHg versus low SBP (L‐SBP) <110 mmHg and analysed according to each of the following four phenotypes: H‐RHR/L‐SBP, L‐RHR/L‐SBP, H‐RHR/H‐SBP and L‐RHR/H‐SBP (reference group). Compared to the reference group, H‐RHR/L‐SBP was associated with the worst outcomes for the combined primary endpoint of cardiovascular death and HF hospitalization (hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.51–2.21, p < 0.001), cardiovascular death (HR 2.70, 95% CI 1.69–4.33, p < 0.001), and HF hospitalization (HR 1.62, 95% CI 1.30–2.01, p < 0.001). Low‐risk patients with L‐RHR/H‐SBP achieved more frequently ≥50% of target doses of angiotensin‐converting enzyme inhibitors (ACEIs) and beta‐blockers (BBs) than the other groups. However, 48% and 46% of low‐risk patients were not well treated with ACEIs and BBs, respectively (≤50% of target dose or no treatment). Conclusion: In patients with HFrEF and recent hospitalization, elevated RHR and lower SBP identify patients at increased risk for cardiovascular endpoints. While SBP and RHR are often recognized as barriers that deter physicians from treating with high doses of recommended drugs, they are not the only reason leaving many patients suboptimally treated. [ABSTRACT FROM AUTHOR]

Cardiomyopathies represent significant contributors to cardiovascular morbidity and mortality. Over the past decades, a progress has occurred in characterization of the genetic background and major pathophysiological mechanisms, which has been incorporated into a more nuanced diagnostic approach and risk stratification. Furthermore, medications targeting core disease processes and/or their downstream adverse effects have been introduced for several cardiomyopathies. Combined with standard care and prevention of sudden cardiac death, these novel and emerging targeted therapies offer a possibility of improving the outcomes in several cardiomyopathies. Therefore, the aim of this document is to summarize practical approaches to the treatment of cardiomyopathies, which includes the evidence‐based novel therapeutic concepts and established principles of care, tailored to the individual patient aetiology and clinical presentation of the cardiomyopathy. The scope of the document encompasses contemporary treatment of dilated, hypertrophic, restrictive and arrhythmogenic cardiomyopathy. It was based on an expert consensus reached at the Heart Failure Association online Workshop, held on 18 March 2021. [ABSTRACT FROM AUTHOR]

Aim: To assess the effect of finerenone on the risk of cardiovascular and kidney outcomes in patients with chronic kidney disease and type 2 diabetes, with and without obesity. Materials and methods: A post hoc analysis of the prespecified pooled FIDELITY dataset assessed the association between waist circumference (WC), composite cardiovascular and kidney outcomes, and the effects of finerenone. Participants were stratified by WC risk groups (representing visceral obesity) as low‐risk or high–very high‐risk (H‐/VH‐risk). Results: Of 12 986 patients analysed, 90.8% occupied the H‐/VH‐risk WC group. Incidence of the composite cardiovascular outcome was similar between finerenone and placebo in the low‐risk WC group (hazard ratio [HR] 1.03; 95% confidence interval [CI], 0.72‐1.47); finerenone reduced the risk in the H‐/VH‐risk WC group (HR 0.85; 95% CI, 0.77‐0.93). For the kidney outcome, the risk was similar in the low‐risk WC group (HR 0.98; 95% CI, 0.66‐1.46) and reduced within the H‐/VH‐risk WC group (HR 0.75; 95% CI, 0.65‐0.87) with finerenone versus placebo. There was no significant heterogeneity between the low‐risk and H‐/VH‐risk WC groups for cardiovascular and kidney composite outcomes (P interaction =.26 and.34, respectively). The apparent greater benefit of finerenone on cardiorenal outcomes but lack of significant heterogeneity observed in H‐/VH‐risk WC patients may be because of the small size of the low‐risk group. Adverse events were consistent across WC groups. Conclusion: In FIDELITY, benefits of finerenone in lowering the risk of cardiovascular and kidney outcomes were not significantly modified by patient obesity. [ABSTRACT FROM AUTHOR]

Aims: Hospital admission during nighttime and off hours may affect the outcome of patients with various cardiovascular conditions due to suboptimal resources and personnel availability, but data for acute heart failure remain controversial. Therefore, we studied outcomes of acute heart failure patients according to their time of admission from the global International Registry to assess medical practice with lOngitudinal obseRvation for Treatment of Heart Failure. Methods and results: Overall, 18 553 acute heart failure patients were divided according to time of admission into 'morning' (7:00–14:59), 'evening' (15:00–22:59), and 'night' (23:00–06:59) shift groups. Patients were also dichotomized to admission during 'working hours' (9:00–16:59 during standard working days) and 'non‐working hours' (any other time). Clinical characteristics, treatments, and outcomes were compared across groups. The hospital length of stay was longer for morning (odds ratio: 1.08; 95% confidence interval: 1.06–1.10, P < 0.001) and evening shift (odds ratio: 1.10; 95% confidence interval: 1.07–1.12, P < 0.001) as compared with night shift. The length of stay was also longer for working vs. non‐working hours (odds ratio: 1.03; 95% confidence interval: 1.02–1.05, P < 0.001). There were no significant differences in in‐hospital mortality among the groups. Admission during working hours, compared with non‐working hours, was associated with significantly lower mortality at 1 year (hazard ratio: 0.88; 95% confidence interval: 0.80–0.96, P = 0.003). Conclusions: Acute heart failure patients admitted during the night shift and non‐working hours had shorter length of stay but similar in‐hospital mortality. However, patients admitted during non‐working hours were at a higher risk for 1 year mortality. These findings may have implications for the health policies and heart failure trials. [ABSTRACT FROM AUTHOR]

Aims: There are limited data on health status and changes in it over time across major subgroups of patients with heart failure and preserved ejection fraction (HFpEF), including ejection fraction spectrum, age, sex, region, body mass index (BMI), and comorbidities including diabetes, chronic kidney disease (CKD), anaemia, and atrial fibrillation/flutter. Methods and results: In the EMPEROR‐Preserved trial, the Kansas City Cardiomyopathy Questionnaire (KCCQ) was assessed at baseline, 12, 32 and 52 weeks. Determinants of baseline KCCQ score and change over time, and the impact of empagliflozin on KCCQ scores were studied in specified subgroups. A Cox model was used to assess the association between 5‐ and 10‐point increase and 5‐point decrease in KCCQ score from baseline to week 12 and later outcomes. Among 2979 participants in the placebo arm, mean KCCQ clinical summary score (CSS) was 70.7 (20.8). Older age, female sex, BMI, anaemia, and a history of diabetes, and CKD were associated with worse scores. KCCQ‐CSS score improved during follow‐up; patients with atrial fibrillation/flutter at enrollment (p trend = 0.014) and CKD (p trend < 0.001) had less improvement. A 5‐point increase in KCCQ‐CSS at week 12 was associated with lower risk of cardiovascular death or heart failure hospitalization (5%), cardiovascular death (8%), and first heart failure hospitalization (4%) subsequently. A similar trend was seen with KCCQ total symptom score (TSS) and overall summary score (OSS). Empagliflozin improved KCCQ‐CSS, ‐TSS and ‐OSS scores similarly across subgroups studied except for greater improvement in patients with the highest BMI (p trend = 0.153, 0.08 and 0.078, respectively). Conclusion: Health status in patients with HFpEF is impaired, especially in elderly, women, and those with obesity and comorbidities. Empagliflozin improved health status among all key subgroups studied with a greater effect in obese patients. [ABSTRACT FROM AUTHOR]

Aims: Decongestion strategies for acute decompensated heart failure (ADHF) characterized by volume overload differ widely. The aim of this independent international academic web‐based survey was to capture the therapeutic strategies that physicians use to treat ADHF and to assess differences in therapeutic approaches between cardiologists versus non‐cardiologists. Methods and results: Physicians were invited to complete a web‐based questionnaire, capturing anonymized data on physicians' characteristics and treatment preferences based on a hypothetical clinical scenario of a patient hospitalized with ADHF. A total of 641 physicians from 60 countries participated. A wide variation in the management of the patient was observed. There was conservative use of diuretics, i.e. only 7% started intravenous furosemide at a dose ≥2 times the baseline oral dose, and infrequent use of ultrasound in assessing congestion (20.4%). Spot urinary sodium was infrequently or never measured by ≥85% of physicians. A third considered a patient with ongoing oedema as being stabilized. There were significant differences between cardiologists and non‐cardiologists in the management of ADHF, the targets for daily body weight loss and urine output, diuretic escalation strategies (66.3% vs. 40.7% would escalate diuresis by adding a thiazide) and assessment of response to treatment (27.0% vs. 52.9% considered patients with minimal congestion as stabilized). Conclusions: There is substantial variability amongst physicians and between cardiologists and non‐cardiologists in the management of patients with ADHF, with regard to clinical parameters used to tailor treatment, treatment goals, diuretic dosing and escalation strategies. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) guidelines recommend initiation and optimization of guideline‐directed medical therapy, including mineralocorticoid receptor antagonists (MRAs), before hospital discharge. However, scientific evidence for this recommendation is lacking. Our objective was to determine whether initiation of MRA prior to hospital discharge is associated with improved outcomes. Methods and results: We performed a secondary analysis of 6197 patients enrolled in the RELAX‐AHF‐2 study. Patients were divided into four groups according to MRA therapy at baseline and discharge. At baseline 30% of patients received MRA therapy, which increased to 50% of patients at discharge. In‐hospital initiation of an MRA was observed in 1690 (27%) patients, 1438 (23%) patients remained on MRA therapy, 418 (7%) patients discontinued MRA treatment, and 2651 (43%) patients did not receive an MRA during hospital stay. Compared with patients who did not receive MRA therapy, in‐hospital initiation of an MRA was independently associated with lower risks of mortality (multivariable hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.60–0.96; p = 0.02), cardiovascular death (HR 0.77, 95% CI 0.59–1.01; p = 0.06), hospitalization for HF or renal failure (HR 0.72, 95% CI 0.60–0.86; p = 0.0003) and the composite endpoint of cardiovascular death and/or rehospitalization for HF or renal failure (HR 0.71, 95% CI 0.61–0.83; p < 0.0001) at 180 days. These results were independent of baseline left ventricular ejection fraction. Conclusion: In patients hospitalized for acute HF, in‐hospital initiation of an MRA was associated with improved post‐discharge outcomes, independent of left ventricular ejection fraction and other potential confounders. [ABSTRACT FROM AUTHOR]

Aim: The prognostic implication of elevated liver tests in heart failure with preserved ejection fraction (HFpEF) is uncertain. This analysis investigates the association of liver markers with hospitalization for heart failure (HHF) and cardiovascular death (CVD), and the treatment effect of empagliflozin across the range of liver marker levels. Methods and results: The double‐blind, placebo‐controlled EMPEROR‐Preserved (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure with Preserved Ejection Fraction) enrolled 5988 patients with HFpEF (ejection fraction >40%). Patients in New York Heart Association class II–IV and elevated N‐terminal pro‐B‐type natriuretic peptide were randomized to receive empagliflozin 10 mg daily or placebo in addition to usual therapy. Patients with significant liver disease were excluded. The primary endpoint was time to first adjudicated HHF or CVD. We explored the association of liver function abnormalities with heart failure outcomes in patients on placebo, the effects of empagliflozin on liver tests and the treatment effects of empagliflozin on heart failure outcomes across categories of liver laboratory values. High alkaline phosphatase (p trend < 0.0001), low albumin (p trend < 0.0001) and high bilirubin (p = 0.02) were associated with poorer outcomes for HHF or CVD, while high aspartate aminotransferase was not, and high alanine aminotransferase was associated with better outcomes. Empagliflozin had no significant effects on liver tests compared to placebo except for albumin which was significantly increased. The treatment effect of empagliflozin on outcomes was not modified by liver tests. Conclusion: Abnormalities of liver function tests are associated differently with heart failure outcomes. Salutary effects of empagliflozin on liver tests were not observed although albumin increased. The treatment benefits of empagliflozin were not affected by baseline values of liver parameters. [ABSTRACT FROM AUTHOR]

Aims: Acetazolamide, an inhibitor of proximal tubular sodium reabsorption, leads to more effective decongestion in acute heart failure (AHF). It is unknown whether acetazolamide alters serum sodium and potassium levels on top of loop diuretics and if baseline values modify the treatment effect of acetazolamide. Methods and results: This is a pre‐specified sub‐analysis of the ADVOR trial that randomized 519 patients with AHF and volume overload in a 1:1 ratio to intravenous acetazolamide or matching placebo on top of standardized intravenous loop diuretics. Mean potassium and sodium levels at randomization were 4.2 ± 0.6 and 139 ± 4 mmol/L in the acetazolamide arm versus 4.2 ± 0.6 and 140 ± 4 mmol/L in the placebo arm. Hypokalaemia (<3.5 mmol/L) on admission was present in 44 (9%) patients and hyponatraemia (≤135 mmol/L) in 82 (16%) patients. After 3 days of treatment, 44 (17%) patients in the acetazolamide arm and 35 (14%) patients in the placebo arm developed hyponatraemia (p = 0.255). Patients randomized to acetazolamide demonstrated a slight decrease in mean potassium levels during decongestion, which was non‐significant over time (p = 0.053) and had no significant impact on hypokalaemia incidence (p = 0.061). Severe hypokalaemia (<3.0 mmol/L) occurred in only 7 (1%) patients, similarly distributed between the two treatment arms (p = 0.676). Randomization towards acetazolamide improved decongestive response irrespective of baseline serum sodium and potassium levels. Conclusions: Acetazolamide on top of standardized loop diuretic therapy does not lead to clinically important hypokalaemia or hyponatraemia and improves decongestion over the entire range of baseline serum potassium and sodium levels. [ABSTRACT FROM AUTHOR]

Aim: In the EMPEROR‐Preserved trial, empagliflozin improved clinical outcomes of patients with heart failure (HF) with preserved ejection fraction. In this pre‐specified analysis, we aim to study the effect of empagliflozin on cardiovascular and kidney outcomes across the spectrum of kidney function. Methods and results: Patients were categorized by the presence or absence of chronic kidney disease (CKD) at baseline (CKD defined by an estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2 or urine albumin to creatinine ratio >300 mg/g). The primary and key secondary outcomes were (i) a composite of cardiovascular death or first HF hospitalization (primary outcome); (ii) total number of HF hospitalization, (iii) eGFR slope; and a pre‐specified exploratory composite kidney outcome including a sustained ≥40% decline in eGFR, chronic dialysis or renal transplant. The median follow‐up was 26.2 months. A total of 5988 patients were randomized to empagliflozin or placebo, of whom 3198 (53.5%) had CKD. Irrespective of CKD status, empagliflozin reduced the primary outcome (with CKD: hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.69–0.94; without CKD: HR 0.75, 95% CI 0.60–0.95; interaction p = 0.67) and total (first and recurrent) hospitalizations for HF (with CKD: HR 0.68, 95% CI 0.54–0.86; without CKD: HR 0.89, 95% CI 0.66–1.21; interaction p = 0.17). Empagliflozin slowed the slope of eGFR decline by 1.43 (1.01–1.85) ml/min/1.73 m2/year in patients with CKD and 1.31 (0.88–1.74) ml/min/1.73 m2/year in patients without CKD (interaction p = 0.70). Empagliflozin did not reduce the pre‐specified kidney outcome in patients with or without CKD (with CKD: HR 0.97, 95% CI 0.71–1.34; without CKD: HR 0.92, 95% CI 0.58–1.48; interaction p = 0.86) but slowed progression to macroalbuminuria and reduced the risk of acute kidney injury. The effect of empagliflozin on the primary composite outcome and the key secondary outcomes was consistent across five baseline eGFR categories (all interaction p >0.05). Empagliflozin was well tolerated independent of CKD status. Conclusions: In EMPEROR‐Preserved, empagliflozin had a beneficial effect on the key efficacy outcomes in patients with and without CKD. Overall, the benefit and safety of empagliflozin was consistent across a wide range of kidney function spectrum, down to a baseline eGFR of 20 ml/min/1.73 m2. [ABSTRACT FROM AUTHOR]

Aims: Atrial fibrillation/flutter (AF) is common in heart failure (HF) with preserved left ventricular ejection fraction (LVEF) and associated with worse outcomes. Empagliflozin reduces cardiovascular death or HF hospitalizations and slows estimated glomerular filtration rate (eGFR) decline in patients with HF and LVEF >40%. We aimed to assess the efficacy and safety of empagliflozin in improving outcomes in patients with HF and LVEF >40% with and without AF. Methods and results: In this pre‐defined secondary analysis of EMPEROR‐Preserved, we compared the effects of empagliflozin versus placebo on the primary and secondary endpoints and safety outcomes, stratified by baseline AF, defined as AF reported in any electrocardiogram before empagliflozin initiation or in medical history. Among 5988 patients randomized, 3135 (52%) had baseline AF; these patients were older, with worse functional class, more previous HF hospitalizations and higher natriuretic peptides compared to those without AF (all p < 0.001). After a median of 26 months, empagliflozin reduced cardiovascular death or HF hospitalization compared to placebo to a similar extent in patients with and without AF (hazard ratio [HR] 0.78 [95% confidence interval 0.66–0.93] vs. 0.78 [0.64–0.95], interaction p = 0.96). Empagliflozin also reduced total HF hospitalizations (HR 0.73 [0.57–0.94] vs. 0.72 [0.54–0.95], interaction p = 0.94) and annual eGFR decline (difference = 1.368 vs. 1.372 ml/min/1.73 m2/year, interaction p = 0.99) consistently in patients with and without AF. There was no increase in serious adverse events with empagliflozin versus placebo in patients with and without AF. Conclusions: In patients with HF and ejection fraction >40%, empagliflozin reduced the risk of serious HF events and slowed the eGFR decline regardless of baseline AF. [ABSTRACT FROM AUTHOR]

Aim: Mitral regurgitation (MR) and tricuspid regurgitation (TR) are common in patients with heart failure (HF). The aim of this study was to investigate prevalence, clinical characteristics and outcomes of patients with or without isolated or combined MR and TR across the entire HF spectrum. Methods and results: The ESC‐HFA EORP HF Long‐Term Registry is a prospective, multicentre, observational study including patients with HF and 1‐year follow‐up data. Outpatients without aortic valve disease were included and stratified according to isolated or combined moderate/severe MR and TR. Among 11 298 patients, 7541 (67%) had no MR/TR, 1931 (17%) isolated MR, 616 (5.5%) isolated TR and 1210 (11%) combined MR/TR. Baseline characteristics were differently distributed across MR/TR categories. Compared to HF with reduced ejection fraction, HF with mildly reduced ejection fraction was associated with a lower risk of isolated MR (odds ratio [OR] 0.69; 95% confidence interval [CI] 0.60–0.80), and distinctly lower risk of combined MR/TR (OR 0.51; 95% CI 0.41–0.62). HF with preserved ejection fraction (HFpEF) was associated with a distinctly lower risk of isolated MR (OR 0.42; 95% CI 0.36–0.49), and combined MR/TR (OR 0.59; 95% 0.50–0.70), but a distinctly increased risk of isolated TR (OR 1.94; 95% CI 1.61–2.33). All‐cause death, cardiovascular death, HF hospitalization and combined outcomes occurred more frequently in combined MR/TR, isolated TR and isolated MR versus no MR/TR. The highest incident rates were observed in isolated TR and combined MR/TR. Conclusion: In a large cohort of outpatients with HF, prevalence of isolated and combined MR and TR was relatively high. Isolated TR was driven by HFpEF and was burdened by an unexpectedly poor outcome. [ABSTRACT FROM AUTHOR]

Aims: STRONG‐HF examined a high‐intensity care (HIC) strategy of rapid up‐titration of guideline‐directed medical therapy (GDMT) and close follow‐up after acute heart failure (AHF) admission. We assess the role of age on efficacy and safety of HIC. Methods and results: Hospitalized AHF patients, not treated with optimal GDMT were randomized to HIC or usual care. The primary endpoint of 180‐day death or HF readmission occurred equally in older (>65 years, n = 493, 74 ± 5 years) and younger patients (53 ± 11 years, adjusted hazard ratio [aHR] 1.02, 95% confidence interval [CI] 0.73–1.43, p = 0.89). Older patients received slightly lower GDMT to day 21, but same doses at day 90 and 180. The effect of HIC on the primary endpoint was numerically higher in younger (aHR 0.51, 95% CI 0.32–0.82) than older patients (aHR 0.73, 95% CI 0.46–1.15, adjusted interaction p = 0.30), partially related to COVID‐19 deaths. After exclusion of COVID‐19 deaths, the effect of HIC was similar in younger (aHR 0.51, 95% CI 0.32–0.82) and older patients (aHR 0.63, 95% CI 0.32–1.02, adjusted interaction p = 0.56), with no treatment‐by‐age interaction (interaction p = 0.57). HIC induced larger improvements in quality of life to day 90 in younger (EQ‐VAS adjusted‐mean difference 5.51, 95% CI 3.20–7.82) than in older patients (1.77, 95% CI −0.75 to 4.29, interaction p = 0.032). HIC was associated with similar rates of adverse events in older and younger patients. Conclusion: High‐intensity care after AHF was safe and resulted in a significant reduction of all‐cause death or HF readmission at 180 days across the study age spectrum. Older patients have smaller benefits in terms of quality of life. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to evaluate efficacy and safety of rapid up‐titration of guideline‐directed medical therapies (GDMT) in men and women hospitalized for acute heart failure (AHF). Methods and results: In STRONG‐HF, AHF patients were randomized just prior to discharge to either usual care (UC) or a high‐intensity care (HIC) strategy of GDMT up‐titration. In these analyses, we compared the implementation, efficacy, and safety of the HIC strategy between men and women. In the randomized AHF population, 416/1078 (39%) were women. By day 90, a higher proportion of both sexes in the HIC group had been up‐titrated to full doses of GDMT compared to UC. Overall, there were no differences in the primary endpoint between the sexes. The primary endpoint, 180‐day heart failure readmission or death, occurred in 15.8% HIC women versus 23.5% women in the UC group (adjusted hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.40–1.13) and in 14.9% HIC men versus 23.5% UC men (adjusted HR 0.57, 95% CI 0.38–0.88) (adjusted interaction p = 0.65). There was no significant treatment‐by‐sex interaction in quality‐of‐life improvement or in adverse events, including serious or fatal adverse events. Conclusion: The results of the current analyses suggest that a rapid up‐titration of GDMT immediately after an AHF hospitalization can and should be implemented similarly in men and women, as it results in reduction of 180‐day all‐cause death or heart failure readmission, quality‐of‐life improvement in both men and women with a similar safety profile. [ABSTRACT FROM AUTHOR]

Acute heart failure is a major cause of urgent hospitalizations. These are followed by marked increases in death and rehospitalization rates, which then decline exponentially though they remain higher than in patients without a recent hospitalization. Therefore, optimal management of patients with acute heart failure before discharge and in the early post‐discharge phase is critical. First, it may prevent rehospitalizations through the early detection and effective treatment of residual or recurrent congestion, the main manifestation of decompensation. Second, initiation at pre‐discharge and titration to target doses in the early post‐discharge period, of guideline‐directed medical therapy may improve both short‐ and long‐term outcomes. Third, in chronic heart failure, medical treatment is often left unchanged, so the acute heart failure hospitalization presents an opportunity for implementation of therapy. The aim of this scientific statement by the Heart Failure Association of the European Society of Cardiology is to summarize recent findings that have implications for clinical management both in the pre‐discharge and the early post‐discharge phase after a hospitalization for acute heart failure. [ABSTRACT FROM AUTHOR]

Aims: To assess the prevalence, clinical characteristics, and outcomes of patients with heart failure (HF) with or without moderate to severe aortic valve disease (AVD) (aortic stenosis [AS], aortic regurgitation [AR], mixed AVD [MAVD]). Methods and results: Data from the prospective ESC HFA EORP HF Long‐Term Registry including both chronic and acute HF were analysed. Of 15 216 patients with HF (62.5% with reduced ejection fraction, HFrEF; 14.0% with mildly reduced ejection fraction, HFmrEF; 23.5% with preserved ejection fraction, HFpEF), 706 patients (4.6%) had AR, 648 (4.3%) AS and 234 (1.5%) MAVD. The prevalence of AS, AR and MAVD was 6%, 8%, and 3% in HFpEF, 6%, 3%, and 2% in HFmrEF and 4%, 3%, and 1% in HFrEF. The strongest associations were observed for age and HFpEF with AS, and for left ventricular end‐diastolic diameter with AR. AS (adjusted hazard ratio [HR] 1.43, 95% confidence interval [CI] 1.23–1.67), and MAVD (adjusted HR 1.37, 95% CI 1.07–1.74) but not AR (adjusted HR 1.13, 95% CI 0.96–1.33) were independently associated with the 12‐month composite outcome of cardiovascular death and HF hospitalization. The associations between AS and the composite outcome were observed regardless of ejection fraction category. Conclusions: In the ESC HFA EORP HF Long‐Term Registry, one in 10 patients with HF had AVD, with AS and MAVD being especially common in HFpEF and AR being similarly distributed across all ejection fraction categories. AS and MAVD, but not AR, were independently associated with increased risk of in‐hospital mortality and 12‐month composite outcome, regardless of ejection fraction category. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) represents a highly heterogeneous clinical syndrome affected in its development and progression by many comorbidities. The left ventricular diastolic dysfunction may be a manifestation of various combinations of cardiovascular, metabolic, pulmonary, renal, and geriatric conditions. Thus, in addition to treatment with sodium–glucose cotransporter 2 inhibitors in all patients, the most effective method of improving clinical outcomes may be therapy tailored to each patient's clinical profile. To better outline a phenotype‐based approach for the treatment of HFpEF, in this joint position paper, the Heart Failure Association of the European Society of Cardiology, the European Heart Rhythm Association and the European Hypertension Society, have developed an algorithm to identify the most common HFpEF phenotypes and identify the evidence‐based treatment strategy for each, while taking into account the complexities of multiple comorbidities and polypharmacy. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effect of finerenone by baseline HbA1c, HbA1c variability, diabetes duration and baseline insulin use on cardiorenal outcomes and diabetes progression. Materials and Methods: Composite efficacy outcomes included cardiovascular (cardiovascular death, non‐fatal myocardial infarction, non‐fatal stroke or hospitalization for heart failure), kidney (kidney failure, sustained ≥ 57% estimated glomerular filtration rate decline or renal death) and diabetes progression (new insulin initiation, increase in antidiabetic medication, 1.0% increase in HbA1c from baseline, new diabetic ketoacidosis diagnosis or uncontrolled diabetes). Results: In 13 026 participants, risk reductions in the cardiovascular and kidney composite outcomes with finerenone versus placebo were consistent across HbA1c quartiles (P interaction.52 and.09, respectively), HbA1c variability (P interaction.48 and.10), diabetes duration (P interaction.12 and.75) and insulin use (P interaction.16 and.52). HbA1c variability in the first year of treatment was associated with a higher risk of cardiovascular and kidney events (hazard ratio [HR] 1.20; 95% confidence interval [CI] 1.07‐1.35; P =.0016 and HR 1.36; 95% CI 1.21‐1.52; P <.0001, respectively). There was no effect on diabetes progression with finerenone or placebo (HR 1.00; 95% CI 0.95‐1.04). Finerenone was well‐tolerated across subgroups; discontinuation and hospitalization because of hyperkalaemia were low. Conclusions: Finerenone efficacy was not modified by baseline HbA1c, HbA1c variability, diabetes duration or baseline insulin use. Greater HbA1c variability appeared to be associated with an increased risk of cardiorenal outcomes. [ABSTRACT FROM AUTHOR]

Episodes of worsening symptoms and signs characterize the clinical course of patients with chronic heart failure (HF). These events are associated with poorer quality of life, increased risks of hospitalization and death and are a major burden on healthcare resources. They usually require diuretic therapy, either administered intravenously or by escalation of oral doses or with combinations of different diuretic classes. Additional treatments may also have a major role, including initiation of guideline‐recommended medical therapy (GRMT). Hospital admission is often necessary but treatment in the emergency service or in outpatient clinics or by primary care physicians has become increasingly used. Prevention of first and recurring episodes of worsening HF is an essential component of HF treatment and this may be achieved through early and rapid administration of GRMT. The aim of the present clinical consensus statement by the Heart Failure Association of the European Society of Cardiology is to provide an update on the definition, clinical characteristics, management and prevention of worsening HF in clinical practice. [ABSTRACT FROM AUTHOR]

Aim: Evidence on healthcare resource utilization (HCRU) for hospitalized patients with heart failure (HF) and reduced (HFrEF), mildly reduced (HFmrEF) and preserved (HFpEF) ejection fraction is limited. Methods and results: We analysed HCRU in relation to left ventricular ejection fraction (LVEF) phenotypes, clinical features and in‐hospital and 12‐month outcomes in 16 943 patients hospitalized for HF in a worldwide registry. HFrEF was more prevalent (53%) than HFmrEF (17%) or HFpEF (30%). Patients with HFmrEF and HFpEF were older, more often women, with milder symptoms and more comorbidities, but differences were not pronounced. HCRU was high in all three groups; two or more in‐ and out‐of‐hospital services were required by 51%, 49% and 52% of patients with HFrEF, HFmrEF and HFpEF, respectively, and intensive care unit by 41%, 41% and 37%, respectively. Hospitalization length was similar (median, 8 days). Discharge prescription of neurohormonal inhibitors was <80% for each agent in HFrEF and only slightly lower in HFmrEF and HFpEF (74% and 67%, respectively, for beta‐blockers). Compared to HFrEF, 12‐month all‐cause and cardiovascular mortality were lower for HFmrEF (adjusted hazard ratios 0.78 [95% confidence interval 0.59–0.71] and 0.80 [0.70–0.92]) and HFpEF (0.64 [0.59–0.87] and 0.63 [0.56–0.71]); 12‐month HF hospitalization was also lower for HFpEF and HFmrEF (21% and 20% vs. 25% for HFrEF). In‐hospital mortality, 12‐month non‐cardiovascular mortality and 12‐month all‐cause hospitalization were similar among groups. Conclusions: In patients hospitalized for HF, overall HCRU was similarly high across LVEF spectrum, reflecting the subtle clinical differences among LVEF phenotypes during hospitalization. Discharge prescription of neurohormonal inhibitors was suboptimal in HFrEF and lower but significant in patients with HFpEF and HFmrEF, who had better long‐term cardiovascular outcomes than HFrEF, but similar risk for non‐cardiovascular events. [ABSTRACT FROM AUTHOR]

Natriuretic peptides, brain (B‐type) natriuretic peptide (BNP) and N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP) are globally and most often used for the diagnosis of heart failure (HF). In addition, they can have an important complementary role in the risk stratification of its prognosis. Since the development of angiotensin receptor–neprilysin inhibitors (ARNIs), the use of natriuretic peptides as therapeutic agents has grown in importance. The present document is the result of the Trilateral Cooperation Project among the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America and the Japanese Heart Failure Society. It represents an expert consensus that aims to provide a comprehensive, up‐to‐date perspective on natriuretic peptides in the diagnosis and management of HF, with a focus on the following main issues: (1) history and basic research: discovery, production and cardiovascular protection; (2) diagnostic and prognostic biomarkers: acute HF, chronic HF, inclusion/endpoint in clinical trials, and natriuretic peptide‐guided therapy; (3) therapeutic use: nesiritide (BNP), carperitide (ANP) and ARNIs; and (4) gaps in knowledge and future directions. [ABSTRACT FROM AUTHOR]

This clinical consensus statement reviews the use of inotropic support in patients with advanced heart failure. The current guidelines only support use of inotropes in the setting of acute decompensated heart failure with evidence of organ malperfusion or shock. However, inotropic support may be reasonable in other patients with advanced heart failure without acute severe decompensation. The clinical evidence supporting use of inotropes in these situations is reviewed. Particularly, patients with persistent congestion, systemic hypoperfusion, or advanced heart failure with need for palliation, and specific situations relevant to implantation of left ventricular assist devices or heart transplantation are discussed. Traditional and novel drugs with inotropic effects are discussed and use of guideline‐directed therapy during inotropic support is reviewed. Finally, home inotropic therapy is described, and palliative care and end‐of‐life aspects are reviewed in relation to management of ongoing inotropic support (including guidance for maintenance and weaning of chronic inotropic therapy support). [ABSTRACT FROM AUTHOR]

Aims: The impact of mitral regurgitation (MR) in patients hospitalized for acute heart failure (AHF) is not well established. We assessed the role of MR in patients enrolled in the Relaxin in Acute Heart Failure 2 (RELAX‐AHF‐2) trial. Methods and results: Patients enrolled in RELAX‐AHF‐2 with available data regarding MR status were included in this analysis. Baseline characteristics, in‐hospital data, and clinical outcomes through 180‐day follow‐up were evaluated. The impact of moderate/severe MR was assessed. Among 6420 AHF patients with known MR status, 1810 patients (28.2%) had moderate/severe MR. Compared to patients with no/mild MR, those with moderate/severe MR were more likely to have history of heart failure (HF), prior HF hospitalization, more comorbidities, symptoms/signs of HF, lower left ventricular ejection fraction and higher N‐terminal pro‐B‐type natriuretic peptide levels. Moderate/severe MR was associated with longer length of hospital stay, higher rates of residual dyspnoea, increased jugular venous pressure through the index hospitalization and a higher unadjusted risk of the composite of cardiovascular (CV) death or rehospitalization for HF/renal failure (RF) through 180 days (crude hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.03–1.27, p = 0.01). The association between moderate/severe MR and poorer outcomes was not maintained in a multivariable model including several covariates of interest (adjusted HR 1.03, 95% CI 0.91–1.17, p = 0.65). Similar findings were observed for HF/RF rehospitalization alone. Conclusions: In patients with AHF, moderate/severe MR was associated with a worse clinical profile but did not have an independent prognostic impact on clinical outcomes. [ABSTRACT FROM AUTHOR]

Aims: To explore the modifying effect of glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) use on outcomes with finerenone across a wide spectrum of patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) in the pooled analysis of FIDELIO‐DKD and FIGARO‐DKD. Materials and methods: Patients with T2D and CKD treated with optimized renin‐angiotensin system blockade were randomized to finerenone or placebo. Effects of finerenone on a cardiovascular composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and a kidney composite outcome (kidney failure, sustained ≥57% estimated glomerular filtration rate [eGFR] decline, or renal death), change in urine albumin‐to‐creatinine ratio (UACR), and safety were analysed by GLP‐1RA use. Results: Of 13 026 patients, 944 (7.2%) used GLP‐1RAs at baseline. Finerenone reduced the risk of the cardiovascular composite outcome (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.52–1.11 with GLP‐1RA; HR 0.87, 95% CI 0.79–0.96 without GLP‐1RA; P‐interaction = 0.63) and the kidney composite outcome (HR 0.82, 95% CI 0.45–1.48 with GLP‐1RA; HR 0.77, 95% CI 0.67–0.89 without GLP‐1RA; P‐interaction = 0.79) irrespective of baseline GLP‐1RA use. Reduction in UACR with finerenone at Month 4 was –38% in patients with baseline GLP‐1RA use compared with –31% in those without GLP‐1RA use (P‐interaction = 0.03). Overall safety and incidence of hyperkalaemia were similar, irrespective of GLP‐1RA use. Conclusions: The cardiorenal benefits of finerenone on composite cardiovascular and kidney outcomes and UACR reduction in patients with CKD and T2D appear to be maintained, regardless of GLP‐1RA use. Subsequent studies are needed to investigate any potential benefit of this combination. [ABSTRACT FROM AUTHOR]

Aims: Kidney function changes dynamically during AHF treatment, but risk factors for and consequences of worsening renal function (WRF) at hospital admission are uncertain. We aimed to determine the significance of WRF at admission for acute heart failure (AHF). Methods and results: We evaluated a subgroup of 406 patients from The Acute Kidney Injury Neutrophil gelatinase–associated lipocalin Evaluation of Symptomatic heart failure Study (AKINESIS) who had serum creatinine measurements available within 3 months before and at the time of admission. Admission WRF was primarily defined as a 0.3 mg/dL or 50% creatinine increase from preadmission. Alternative definitions evaluated were a ≥0.5 mg/dL creatinine increase, ≥25% glomerular filtration rate decrease, and an overall change in creatinine. Predictors of admission WRF were evaluated. Outcomes evaluated were length of hospitalization, a composite of adverse in‐hospital events, and the composite of death or HF readmission at 30, 90, and 365 days. Biomarkers' prognostic ability for these outcomes were evaluated in patients with admission WRF. One‐hundred six patients (26%) had admission WRF. These patients had features of more severe AHF with lower blood pressure, higher BUN, and lower serum sodium concentrations at admission. Higher BNP (odds ratio [OR] per doubling 1.16–1.28, 95% confidence interval [CI] 1.00–1.55) and lower diastolic blood pressure (OR 0.97–0.98, 95% CI 0.96–0.99) were associated with a higher odds for the three definitions of admission WRF. The primary WRF definition was not associated with a longer hospitalization, but alternative WRF definitions were (1.3 to 1.6 days longer, 95% CI 1.0–2.2). WRF across definitions was not associated with a higher odds of adverse in‐hospital events or a higher risk of death or HF readmission. In the subset of patients with WRF, biomarkers were not prognostic for any outcome. Conclusions: Admission WRF is common in AHF patients and is associated with an increased length of hospitalization, but not adverse in‐hospital events, death, or HF readmission. Among those with admission WRF, biomarkers did not risk stratify for adverse events. [ABSTRACT FROM AUTHOR]

Aims: Baseline body mass index (BMI) and weight loss promoted by sodium–glucose cotransporter 2 inhibitors may impact outcomes in patients with heart failure with reduced ejection fraction (HFrEF). We assessed in the EMPEROR‐Reduced population treated with empagliflozin versus placebo the relationship between baseline BMI, weight loss and effects on the primary (time to first hospitalization for heart failure [HHF] or cardiovascular death) and key secondary outcomes. Methods and results: We categorized patients according to their baseline BMI: <20 kg/m2 (n = 180); 20 to <25 kg/m2 (n = 1038); 25 to <30 kg/m2 (n = 1345); 30 to <35 kg/m2 (n = 774) and ≥35 kg/m2 (n = 393). The treatment effect of empagliflozin on the primary outcome was consistent across all BMI categories (hazard ratios in subgroups 0.66–0.88, interaction trend p = 0.32), as was the effect on total (first plus recurrent) HHF (interaction trend p = 0.31). Empagliflozin reduced the rate of estimated glomerular filtration rate decline consistently across the BMI categories (interaction trend p = 0.67). Overall, incidence rates of any or serious adverse events were comparable between the treatment groups across all BMI categories. A total of 313 (17.4%) patients treated with empagliflozin experienced a weight loss of more than 5% at week 52 versus 230 (12.8%) in placebo. When analysed separately within each treatment group, presence of weight loss was similarly associated with an increased risk of all‐cause mortality. Conclusion: The benefits of empagliflozin versus placebo were consistently present across all BMI categories in HFrEF patients. Weight loss was associated with higher risk of all‐cause mortality, regardless of treatment group. [ABSTRACT FROM AUTHOR]

Aim: Acute heart failure can be a life‐threatening medical condition. Delaying administration of intravenous furosemide (time‐to‐diuretics) has been postulated to increase mortality, but prior reports have been inconclusive. We aimed to evaluate the association between time‐to‐diuretics and mortality in the international REPORT‐HF registry. Methods and results: We assessed the association of time‐to‐diuretics within the first 24 h with in‐hospital and 30‐day post‐discharge mortality in 15 078 patients from seven world regions in the REPORT‐HF registry. We further tested for effect modification by baseline mortality risk (ADHERE risk score), left ventricular ejection fraction (LVEF) and region. The median time‐to‐diuretics was 67 (25th–75th percentiles 17–190) min. Women, patients with more signs and symptoms of heart failure, and patients from Eastern Europe or Southeast Asia had shorter time‐to‐diuretics. There was no significant association between time‐to‐diuretics and in‐hospital mortality (p > 0.1). The 30‐day mortality risk increased linearly with longer time‐to‐diuretics (administered between hospital arrival and 8 h post‐hospital arrival) (p = 0.016). This increase was more significant in patients with a higher ADHERE risk score (pinteraction = 0.008), and not modified by LVEF or geographic region (pinteraction > 0.1 for both). Conclusion: In REPORT‐HF, longer time‐to‐diuretics was not associated with higher in‐hospital mortality. However, we did found an association with increased 30‐day mortality, particularly in high‐risk patients, and irrespective of LVEF or geographic region. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT02595814. [ABSTRACT FROM AUTHOR]