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Objectives: Patients with rheumatic disease (RD) have an increased mortality risk compared with the general population, mainly due to cardiovascular disease (CVD). We aimed to identify patients at high risk of CVD and mortality by comparing three screening tools suitable for clinical practice.Method: In this prospective, single-centre study, consecutive patients with rheumatoid arthritis (RA), systemic autoimmune disease (SAI), or spondyloarthritides (SpA) including psoriatic arthritis underwent a comprehensive cardiovascular risk assessment. Patients were predefined as being at high risk for cardiovascular events or death if any of the following were present: European Systematic COronary Risk Evaluation (SCORE) ≥ 3%, N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥ 200 pg/mL, or any pathological electrocardiogram pattern.Results: The patient population (n = 764) comprised 352 patients with RA, 260 with SAI, and 152 with SpA. After a median follow-up of 5.2 years, 6.0% of RD patients had died (7.0%, 7.2%, and 1.4% of patients in the RA, SAI, and SpA subgroups), and 5.0% had experienced a cardiovascular event (5.0%, 6.4%, and 2.8%, respectively). For all RD patients and the RA and SAI subgroups, NT-proBNP ≥ 200 pg/mL and SCORE ≥ 3% identified patients with a 3.5-5-fold increased risk of all-cause death and cardiovascular events. Electrocardiogram pathology was associated with increased mortality risk, but not with cardiovascular events.Conclusion: NT-proBNP ≥ 200 pg/mL or SCORE ≥ 3% identifies RA and SAI patients with increased risk of cardiovascular events and death. Both tools are suitable as easy screening tools in daily practice to identify patients at risk for further diagnostics and closer long-term follow-up. [ABSTRACT FROM AUTHOR]

BACKGROUND: To examine whether depression and heart failure severity are independent predictors of both the physical and psychologic domains of health-related quality of life (HRQoL) in patients with chronic heart failure. METHODS AND RESULTS: A sample of 206 outpatients with chronic heart failure (mean age 64 years, 69% male) was evaluated. Depression was measured with the Patient Health Questionnaire and disease-specific HRQoL with the Kansas City Cardiomyopathy Questionnaire. Heart failure severity was assessed with physician ratings of the New York Heart Association (NYHA) functional class. The simultaneous effects of predictor variables on outcomes were estimated using structural equation modeling. Both depression and NYHA functional class independently predicted the physical domain of HRQoL. By contrast, the psychologic domain was only predicted by depression, but not by NYHA functional class. CONCLUSIONS: Our results suggest that comorbid depression has an independent impact on both physical and psychologic HRQoL in patients with chronic heart failure after controlling for the severity of heart failure symptoms, while heart failure severity only impacts physical HRQoL. Thus, assessment of comorbid depression may help interpreting reduced HRQoL in heart failure patients. Research seems warranted evaluating whether the amelioration of depression may enhance patients' HRQoL in chronic heart failure. [ABSTRACT FROM AUTHOR]

Aim: To assess the level of self-efficacy in patients with heart failure (HF), and identify differences between important subgroups including sex, and to identify the determinants of high self-efficacy., Methods and Results: This was a pooled cross-sectional analysis of 2,030 patients from four prospective studies conducted within the German Competence Network Heart Failure. We used the Self-efficacy Subscale and the Overall Summary Score (OSS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ-23) to assess self-efficacy and health-related quality of life. The cut-off of 75 score points was used for the dichotomization into high (≥75) vs low (<75) self-efficacy. Depressive symptoms were measured by the Patient Health Questionnaire (PHQ-9). A total of 1,615 patients with HF provided complete self-efficacy scores: mean age 66.6±12.3 years, 431 (27%) women. Mean self-efficacy was 67.5±24.9, with 907 patients (56.2%) showing high self-efficacy and 708 patients (43.8%) showing low self-efficacy. Men had higher self-efficacy scores than women (68.7±24.5 vs. 64.2±26.0; p=0.001). Multivariable logistic regression identified KCCQ-OSS (OR per 5-point increase 1.08, 95%CI 1.04-1.12), female sex (OR 0.72, 95%CI 0.56-0.94), depressive symptoms (OR per 3-point increase in PHQ-9 0.90, 95%CI 0.83-0.98), and acute HF (0.46, 95% CI 0.34-0.62) as important predictors of high self-efficacy., Conclusion: In patients with HF, women seemed to exhibit lower self-efficacy than men. Health-related quality of life and psychological well-being were dominant determinants of self-efficacy. Future studies should investigate the role of self-efficacy as a therapeutic target for tailored and sex-specific nursing interventions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aims: Patients hospitalized for acute heart failure (HF) could be enrolled in EMPULSE (NCT04157751) upon haemodynamic stabilization and between 24 h and 5 days after hospital admission. The timing of treatment initiation may influence the efficacy and safety of drugs such as empagliflozin. The aim of this study was to evaluate patient characteristics, clinical events, and treatment effects according to time from admission to randomization., Methods and Results: The EMPULSE population was dichotomized by median time from hospital admission to randomization (1-2 days vs. 3-5 days). The primary outcome was a hierarchical composite endpoint of time to all-cause death, number of HF events, time to first HF event, and a ≥5-point difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline after 90 days, analysed using the win ratio (WR) method. Patients randomized later (3-5 days, average time 3.9 days; n = 312) had a higher risk of experiencing clinical events than patients randomized earlier (1-2 days, average time 1.7 days; n = 215). The treatment effect favoured empagliflozin versus placebo in patients randomized later (3-5 days: WR 1.69, 95% confidence interval [CI] 1.26-2.25) but was attenuated in patients randomized earlier (1-2 days: WR 1.04, 95% CI 0.74-1.44) (interaction p = 0.029). A similar pattern was observed for the composite of HF hospitalization or cardiovascular death and all-cause hospitalizations (interaction p < 0.1 for both). The reduction of N-terminal pro-B-type natriuretic peptide levels was more pronounced with empagliflozin among patients randomized later than in patients randomized earlier (interaction p = 0.004)., Conclusions: Among patients hospitalized for acute HF enrolled in EMPULSE, those randomized later after hospital admission (3-5 days) experienced greater clinical benefit with empagliflozin than those randomized earlier (1-2 days). These findings should be confirmed in future studies before clinical application., (© 2024 European Society of Cardiology.)

Aim: The EMPULSE (EMPagliflozin in patients hospitalised with acUte heart faiLure who have been StabilizEd) trial showed that, compared to placebo, the sodium-glucose cotransporter 2 inhibitor empagliflozin (10 mg/day) improved clinical outcomes of patients hospitalized for acute heart failure (HF). We investigated whether efficacy and safety of empagliflozin were consistent across the spectrum of left ventricular ejection fraction (LVEF)., Methods and Results: A total of 530 patients hospitalized for acute de novo or decompensated HF were included irrespective of LVEF. For the present analysis, patients were classified as HF with reduced (HFrEF, LVEF ≤40%), mildly reduced (HFmrEF, LVEF 41-49%) or preserved (HFpEF, LVEF ≥50%) ejection fraction at baseline. The primary endpoint was a hierarchical outcome of death, worsening HF events (HFE) and quality of life over 90 days, assessed by the win ratio. Secondary endpoints included individual components of the primary endpoint and safety. Out of 523 patients with baseline data, 354 (67.7%) had HFrEF, 54 (10.3%) had HFmrEF and 115 (22.0%) had HFpEF. The clinical benefit (hierarchical composite of all-cause death, HFE and Kansas City Cardiomyopathy Questionnaire total symptom score) of empagliflozin at 90 days compared to placebo was consistent across LVEF categories (≤40%: win ratio 1.35 [95% confidence interval 1.04, 1.75]; 41-49%: win ratio 1.25 [0.66, 2.37)] and ≥50%: win ratio 1.40 [0.87, 2.23], p interaction  = 0.96) with a favourable safety profile. Results were consistent across individual components of the hierarchical primary endpoint., Conclusion: The clinical benefit of empagliflozin proved consistent across LVEF categories in the EMPULSE trial. These results support early in-hospital initiation of empagliflozin regardless of LVEF., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Multimorbidity (two or more comorbidities) is common among patients with acute heart failure, but comprehensive global information on its prevalence and clinical consequences across different world regions and income levels is scarce. This study aimed to investigate the prevalence of multimorbidity and its effect on pharmacotherapy and prognosis in participants of the REPORT-HF study., Methods: REPORT-HF was a prospective, multicentre, global cohort study that enrolled adults (aged ≥18 years) admitted to hospital with a primary diagnosis of acute heart failure from 358 hospitals in 44 countries on six continents. Patients who currently or recently participated in a clinical treatment trial were excluded. Follow-up data were collected at 1-year post-discharge. The primary outcome was 1-year post-discharge mortality. All patients in the REPORT-HF cohort with full data on comorbidities were eligible for the present study. We stratified patients according to the number of comorbidities, and countries by world region and country income level. We used one-way ANOVA, χ 2 test, or Mann-Whitney U test for comparisons between groups, as applicable, and Cox regression to analyse the association between multimorbidity and 1-year mortality., Findings: Between July 23, 2014, and March 24, 2017, 18 553 patients were included in the REPORT-HF study. Of these, 18 528 patients had full data on comorbidities, of whom 11 360 (61%) were men and 7168 (39%) were women. Prevalence rates of multimorbidity were lowest in southeast Asia (72%) and highest in North America (92%). Fewer patients from lower-middle-income countries had multimorbidity than patients from high-income countries (73% vs 85%, p<0·0001). With increasing comorbidity burden, patients received fewer guideline-directed heart failure medications, yet more drugs potentially causing or worsening heart failure. Having more comorbidities was associated with worse outcomes: 1-year mortality increased from 13% (no comorbidities) to 26% (five or more comorbidities). This finding was independent of common baseline risk factors, including age and sex. The population-attributable fraction of multimorbidity for mortality was higher in high-income countries than in upper-middle-income or lower-middle-income countries (for patients with five or more comorbidities: 61% vs 27% and 31%, respectively)., Interpretation: Multimorbidity is highly prevalent among patients with acute heart failure across world regions, especially in high-income countries, and is associated with higher mortality, less prescription of guideline-directed heart failure pharmacotherapy, and increased use of potentially harmful medications., Funding: Novartis Pharma., Translations: For the Arabic, French, German, Hindi, Mandarin, Russian and Spanish translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests JGFC reports grants and personal fees from Amgen, Bayer, Bristol Myers Squibb, and Torrent Pharmaceuticals; personal fees from AstraZeneca, Myokardia, Servier, and Abbott; grants, personal fees, and non-financial support from Medtronic, Novartis, and Vifor; and grants and non-financial support from Pharmacosmos and PharmaNord. UD reports research support from AstraZeneca, Pfizer, Boehringer Ingelheim, Vifor, Roche Diagnostics, and Boston Scientific; and speaker's honoraria and consultancies from AstraZeneca, Novartis, and Amgen. GE reports personal fees from AstraZeneca, Abbott, Boehringer Ingelheim, Novartis, and Vifor, all outside the submitted work; non-financial support from the University Hospital Würzburg, and the Comprehensive Heart Failure Center Würzburg; and grant support from German Ministry for Education and Research (BMBF). SVP reports support from Novartis for the present manuscript; consulting fees from Abbott and Bago; and personal fees from Abbott, Boehringer Ingelheim, and Bago. MG and AO were formerly Novartis employees. AS is employed by Novartis. SPC reports research grants from the National Institutes of Health, Agency for Research and Quality, American Heart Association, and the Patient-Centered Outcomes Research Institute; and consulting fees from Novartis, Medtronic, Aiphia, Boehringer Ingelheim, Siemens, and Ortho Clinical. GF reports research grants from the EU; committee fees from Novartis related to REPORT-HF; and lecture fees or being a committee member in trials or registries sponsored by Servier, Boehringer Ingelheim, Medtronic, Vifor, Amgen, and Bayer. CSPL is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the Advisory Board, Steering Committee, or Executive Committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma, EchoNous, Eli Lilly, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research & Development, Medscape WebMD Global, Merck, Novartis, Novo Nordisk, Prosciento, Radcliffe Group, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as co-founder and non-executive director of Us2.ai. JT has received consulting or speaker fees from Daiichi-Sankyo, Boehringer Ingelheim, Roche Diagnostics, and Us2.ai; and owns patent US-10702247-B2 unrelated to the present work. CEA reports grant support, personal fees, or non-financial support from Abbott, AstraZeneca, Boehringer Ingelheim, Medtronik, Novartis, Novo Nordisk, Radcliffe Group, and Vifor Pharma, all outside of the submitted work; and acknowledges non-financial support from the University Hospital Würzburg, and the Comprehensive Heart Failure Center Würzburg, and grant support from BMBF. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve clinical outcomes in patients with heart failure (HF), but mechanisms of action are incompletely understood. In the EMPA-TROPISM trial, empagliflozin reversed cardiac remodeling and increased physical capacity in stable non-diabetic patients with systolic HF. Here we explore, post hoc, whether treatment effects in this cohort, comprising patients who had a high prevalence of iron deficiency, were related to iron metabolism. Myocardial iron content estimated by cardiac magnetic resonance T2* quantification increased after initiation of empagliflozin but not placebo (treatment effect: P = 0.01). T2* changes significantly correlated with changes in left ventricular volumes, mass and ejection fraction, peak oxygen consumption and 6-minute walking distance; concomitant changes in red blood cell indices were consistent with augmented hematopoiesis. Exploratory causal mediation analysis findings indicated that changes in myocardial iron content after treatment with empagliflozin may be an important mechanism to explain its beneficial clinical effects in patients with HF.ClinicalTrials.gov: NCT03485222 ., (© 2023. The Author(s).)

Background: Patients with heart failure with reduced ejection fraction (HFrEF) and central sleep apnea (CSA) are at a very high risk of fatal outcomes., Objective: To test whether the circulating miRNome provides additional information for risk stratification on top of clinical predictors in patients with HFrEF and CSA., Methods: The study included patients with HFrEF and CSA from the SERVE-HF trial. A three-step protocol was applied: microRNA (miRNA) screening (n = 20), technical validation (n = 60), and biological validation (n = 587). The primary outcome was either death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening of heart failure, whatever occurred first. MiRNA quantification was performed in plasma samples using miRNA sequencing and RT-qPCR., Results: Circulating miR-133a-3p levels were inversely associated with the primary study outcome. Nonetheless, miR-133a-3p did not improve a previously established clinical prognostic model in terms of discrimination or reclassification. A customized regression tree model constructed using the Classification and Regression Tree (CART) algorithm identified eight patient subphenotypes with specific risk patterns based on clinical and molecular characteristics. MiR-133a-3p entered the regression tree defining the group at the lowest risk; patients with log(NT-proBNP) ≤ 6 pg/mL (miR-133a-3p levels above 1.5 arbitrary units). The overall predictive capacity of suffering the event was highly stable over the follow-up (from 0.735 to 0.767)., Conclusions: The combination of clinical information, circulating miRNAs, and decision tree learning allows the identification of specific risk subphenotypes in patients with HFrEF and CSA., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Aims: Agonistic antibodies against neurohumoral receptors can induce cardio-noxious effects by altering the baseline receptor activity. To estimate the prevalence of autoantibodies directed against the beta-1 receptor (b1-AAB) in patients admitted to the hospital for acute heart failure (HF) at (i) baseline and (ii) after 6 months of follow-up (F6) and (iii) after another 12 months of follow-up (i.e. 18 months after index hospitalization), to estimate their prognostic impact on clinical outcome (death or first hospitalization for HF)., Methods and Results: In 47 patients, b1-AAB were serially determined in serum samples collected at index hospitalization and at 6 months of follow-up (F6) with a flow cytometry-based assay: median age 71 years (quartiles 60, 80), 23 (49%) women, 24 (51%) HF with preserved ejection fraction. Beta1-AAB were detected in three subjects at index hospitalization (6%), and in eight subjects at F6 (17%). There were no differences apparent between patients with and without b1-AAB at F6 with regard to age, sex, type, duration, or main cause of HF. During the 12 month period following F6 (i.e. up to month 18), eight events occurred. Event-free survival was associated with prevalence of b1-AAB at F6. Compared with patients without b1-AAB at F6, age-adjusted Cox regression indicated a higher event risk in patients harbouring b1-AAB, with a hazard ratio of 8.96 (95% confidence interval 1.81-44.50, P = 0.007)., Conclusions: Our results suggest a possible adverse prognostic relevance of b1-AAB in patients with acute HF, but this observation needs to be confirmed in larger patient collectives., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

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., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: In patients hospitalized for acute heart failure (AHF) empagliflozin produced greater clinical benefit than placebo. Many patients with AHF are treated with mineralocorticoid receptor antagonists (MRAs). The interplay between empagliflozin and MRAs in AHF is yet to be explored. This study aimed to evaluate the efficacy and safety of empagliflozin versus placebo according to MRA use at baseline in the EMPULSE trial (NCT04157751)., Methods and Results: In this analysis all comparisons were performed between empagliflozin and placebo, stratified by baseline MRA use. The primary outcome included all-cause death, heart failure events, and a ≥5 point difference in Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score at 90 days, assessed using the win ratio (WR). First heart failure hospitalization or cardiovascular death was a secondary outcome. From the 530 patients randomized, 276 (52%) were receiving MRAs at baseline. MRA users were younger, had lower ejection fraction, better renal function, and higher KCCQ scores. The primary outcome showed benefit of empagliflozin irrespective of baseline MRA use (WR 1.46, 95% confidence interval [CI] 1.08-1.97 and WR 1.27, 95% CI 0.93-1.73 in MRA users and non-users, respectively; interaction p = 0.52). The effect of empagliflozin on first heart failure hospitalization or cardiovascular death was not modified by MRA use (hazard ratio [HR] 0.58, 95% CI 0.30-1.11 and HR 0.85, 95% CI 0.47-1.52 in MRA users and non-users, respectively; interaction p = 0.39). Investigator-reported and severe hyperkalaemia events were infrequent (<6%) irrespective of MRA use., Conclusions: In patients admitted for AHF, initiation of empagliflozin produced clinical benefit and was well tolerated irrespective of background MRA use. These findings support the early use of empagliflozin on top of MRA therapy in patients admitted for AHF., (© 2023 European Society of Cardiology.)

Aims: Systolic ejection time (SET) is discussed as a treatment target in patients with heart failure (HF) and a reduced left ventricular (LV) ejection fraction (EF). We derived reference values for SET correcting for its dependence on heart rate (SETc), and explored its prognostic utility in patients admitted with decompensated HF., Methods and Results: SETc was derived in 4836 participants of the population-based STAAB study (mean age 55 ± 12 years, 52% women). There, mean SETc was 328 ± 18 ms, increased with age (+4.7 ms per decade), was shorter in men than women (-14.9 ms), and correlated with arterial elastance ( r = 0.30; all P < 0.001). In 134 patients hospitalized with acute HF, SETc at admission was shorter when compared with the general population and differed between patients with HF with reduced EF (HFrEF; LVEF ≤40%; 269 ± 35 ms), HF with mildly reduced EF (HFmrEF; LVEF 41-49%; 294 ± 27 ms), and HF with preserved EF (HFpEF; LVEF ≥50%; 317 ± 35 ms; P < 0.001). In proportional hazard regression, an in-hospital increase in SETc was associated with an age- and sex-adjusted hazard ratio of 0.38 (95% confidence interval 0.18-0.79) in patients with HFrEF, but a hazard ratio of 2.39 (95% confidence interval 1.24-4.64) in patients with HFpEF., Conclusion: In the general population, SETc increased with age and an elevated afterload. SETc was mildly reduced in patients hospitalized with HFpEF, but markedly reduced in patients with HFrEF. In-hospital prolongation of SETc predicted a favourable outcome in HFrEF, but an adverse outcome in HFpEF. Our results support the concept of a U-shaped relationship between cardiac systolic function and risk, providing a rationale for a more individualized treatment approach in patients with HF., Competing Interests: Conflicts of interest: C.M. reports research cooperation with the University of Würzburg and Tomtec Imaging Systems funded by a research grant from the Bavarian Ministry of Economic Affairs, Regional Development and Energy, Germany; advisory and speakers honoraria as well as travel grants from Amgen, Tomtec, Alnylam, Sobi, Alexion, Janssen, Pfizer, and EBR Systems; principal investigator in trials sponsored by Alnylam, AstraZeneca, and Bayer. J.A. reports a clinician scientist scholarship from the Interdisciplinary Center for Clinical Research (IZKF) at the University of Würzburg. G.Ge. reports research cooperation with the University Hospital Würzburg and Tomtec Imaging Systems funded by a research grant from the Bavarian Ministry of Economic Affairs, Regional Development and Energy, Germany. Ch.M. reports honoraria for medical advice and speaker duties from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Berlin Chemie, Bayer, Edwards, NovoNordisk, Novartis, and Servier. S.S. is supported by the CHFC Würzburg, and by the German Federal Ministry of Education and Research (BMBF). He has received consultancy and lecture fees as well as reimbursement of travel costs from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Pfizer, and Servier. The rest of the authors have no conflicts of interest regarding the present work., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Previous reports suggest that risk factors, management, and outcomes of acute heart failure (AHF) may differ by sex, but they rarely extended analysis to low- and middle-income countries., Objectives: In this study, the authors sought to analyze sex differences in treatment and outcomes in patients hospitalized for AHF in 44 countries., Methods: The authors investigated differences between men and women in treatment and outcomes in 18,553 patients hospitalized for AHF in 44 countries in the REPORT-HF (Registry to Assess Medical Practice With Longitudinal Observation for the Treatment of Heart Failure) registry stratified by country income level, income disparity, and world region. The primary outcome was 1-year all-cause mortality., Results: Women (n = 7,181) were older than men (n = 11,372), were more likely to have heart failure with preserved left ventricular ejection fraction, had more comorbid conditions except for coronary artery disease, and had more severe signs and symptoms at admission. Coronary angiography, cardiac stress tests, and coronary revascularization were less frequently performed in women than in men. Women with AHF and reduced left ventricular ejection fraction were less likely to receive an implanted device, regardless of region or country income level. Women were more likely to receive treatments that could worsen HF than men (18% vs 13%; P < 0.0001). In countries with low-income disparity, women had better 1-year survival than men. This advantage was lost in countries with greater income disparity (P interaction  < 0.001)., Conclusions: Women were less likely to have diagnostic testing or receive guideline-directed care than men. A survival advantage for women was observed only in countries with low income disparity, suggesting that equity of HF care between sexes remains an unmet goal worldwide., Competing Interests: Funding Support and Author Disclosures REPORT-HF was funded by Novartis Pharma. Dr Tromp is supported by a National University of Singapore start-up grant, a tier 1 grant from the Ministry of Education, and a CS-IRG New Investigator grant from the National Medical Research Council; has received consulting or speaker fees from Daiichi-Sankyo, Boehringer Ingelheim, Roche Diagnostics, and Us2.ai; and owns patent US-10702247-B2 unrelated to the present work. Dr Angermann has received grant support, personal fees, and nonfinancial support from Abbott, AstraZeneca, Boehringer Ingelheim, Biotronik, Novartis, Novo Nordisk, Radcliffe Group, and Vifor, all outside of the submitted work; nonfinancial support from the University Hospital Würzburg and the Comprehensive Heart Failure Center Würzburg; and grant support from the German Ministry for Education and Research (BMBF). Dr Dahlstrom has received research support from AstraZeneca, Pfizer, Boehringer Ingelheim, Vifor, Roche Diagnostics, and Boston Scientific and speaker honoraria from and consultancies for AstraZeneca, Novartis, and Amgen. Dr Hassanein has received honoraria as a lecturer from Novartis, Aventis, Amgen, Merck Sharp & Dohme, AstraZeneca, and Merck. Drs Ghadanfar, Schweizer, and Obergfell are employed by Novartis. Dr Collins has received research grants from the National Institutes of Health, Agency for Healthcare Research and Quality, and Patient-Centered Outcomes Research Institute and consulting fees from Novartis, Aiphia, Boehringer Ingelheim, Siemens, and Ortho Clinical. Dr Filippatos has received research grants from the European Union, committee fees from Novartis related to REPORT-HF, and committee membership in trials and registries sponsored by Servier, BI, Medtronic, and Vifor. Dr Cleland has received grants and personal fees from Amgen, Bayer, Bristol Myers Squibb, Philips, and Torrent Pharmaceuticals; personal fees from AstraZeneca, Myokardia, Servier, Stealth Biopharmaceuticals, Sanofi, and Abbott; grants, personal fees, and nonfinancial support from Medtronic, Novartis, and Vifor; and grants and nonfinancial support from Pharmacosmos and PharmaNord. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, and Vifor Pharma; has served as consultant or on the advisory board, steering committee, or executive committee for Boston Scientific, Bayer, Roche Diagnostics, AstraZeneca, Medtronic, Vifor Pharma, Novartis, Amgen, Merck, Janssen Research and Development, Menarini, Boehringer Ingelheim, Novo Nordisk, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global, Radcliffe Group, and Corpus; and serves as co-founder and nonexecutive director of eKo.ai. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The importance of chronic kidney disease (CKD) and anaemia has not been comprehensively studied in asymptomatic patients at risk for heart failure (HF) versus those with symptomatic HF. We analysed the prevalence, characteristics and prognostic impact of both conditions across American College of Cardiology/American Heart Association (ACC/AHA) precursor and HF stages A-D., Methods and Results: 2496 participants from three non-pharmacological German Competence Network HF studies were categorized by ACC/AHA stage; stage C patients were subdivided into C1 and C2 (corresponding to NYHA classes I/II and III, respectively). Overall, patient distribution was 8.1%/35.3%/32.9% and 23.7% in ACC/AHA stages A/B/C1 and C2/D, respectively. These subgroups were stratified by the absence ( - ) or presence ( +) of CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73m 2 ) and anaemia (haemoglobin in women/men < 12/ < 13 g/dL). The primary outcome was all-cause mortality at 5-year follow-up. Prevalence increased across stages A/B/C1 and C2/D (CKD: 22.3%/23.6%/31.6%/54.7%; anaemia: 3.0%/7.9%/21.7%/33.2%, respectively), with concordant decreases in median eGFR and haemoglobin (all p < 0.001). Across all stages, hazard ratios [95% confidence intervals] for all-cause mortality were 2.1 [1.8-2.6] for CKD + , 1.7 [1.4-2.0] for anaemia, and 3.6 [2.9-4.6] for CKD + /anaemia + (all p < 0.001). Population attributable fractions (PAFs) for 5-year mortality related to CKD and/or anaemia were similar across stages A/B, C1 and C2/D (up to 33.4%, 30.8% and 34.7%, respectively)., Conclusions: Prevalence and severity of CKD and anaemia increased across ACC/AHA stages. Both conditions were individually and additively associated with increased 5-year mortality risk, with similar PAFs in asymptomatic patients and those with symptomatic HF., (© 2022. The Author(s).)

Competing Interests: I declare personal fees from Abbott for serving as the Chair of the Steering Committee for the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF) study, which evaluated the CardioMEMS pulmonary artery pressure monitoring technology (manufactured by Abbott). I also disclose consulting fees and speaker honoraria and reimbursement of travel costs from Abbott.

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., (© 2023 European Society of Cardiology.)

Aims: The EMPULSE trial evaluated the clinical benefit of empagliflozin versus placebo using the stratified win ratio approach in 530 patients with acute heart failure (HF) after initial stabilization. We aim to elucidate how this method works and what it means, thereby giving guidance for use of the win ratio in future trials., Methods and Results: The primary trial outcome is a hierarchical composite of death, number of HF events, time to first HF event, or a ≥5-point difference in Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score change at 90 days. In an overall (unstratified) analysis we show how comparison of all 265 x 265 patients pairs contribute to 'wins' for empagliflozin and placebo at all four levels of the hierarchy, leading to an unstratified win ratio of 1.38 (95% confidence interval [CI] 1.11-1.71; p = 0.0036). How such a win ratio should (and should not) be interpreted is then described. The more complex primary analysis using a stratified win ratio is then presented in detail leading to a very similar overall result. Win ratios for de novo acute HF and decompensated chronic HF patients were 1.29 and 1.39, respectively, their weighted combination yielding an overall stratified win ratio of 1.36 (95% CI 1.09-1.68) (p = 0.0054). Alternative ways of including HF events and KCCQ scores in the clinical hierarchy are presented, leading to recommendations for their use in future trials. Specifically, inclusion of both number of HF events and time-to-first HF event appears an unnecessary complication. Also, the use of a 5-point margin for KCCQ score paired comparisons is not statistically necessary., Conclusions: The EMPULSE trial findings illustrate how deaths, clinical events and patient-reported outcomes can be integrated into a win ratio analysis strategy that yields clinically meaningful findings of patient benefit. This has implications for future trial designs that recognize the clinical priorities of patient evaluation and the need for efficient progress towards approval of new treatments., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The randomized INH (Interdisciplinary Network Heart Failure) trial (N = 715) reported that 6 months' remote patient management (RPM) (HeartNetCare-HF) did not reduce the primary outcome (time to all-cause death/rehospitalization) vs usual care (UC) in patients discharged after admission for acute heart failure, but suggested lower mortality and better quality of life in the RPM group., Objectives: The Extended (E)-INH trial investigated the effects of 18 months' HeartNetCare-HF on the same primary outcome in an expanded population (N = 1,022) and followed survivors up to 60 months (primary outcome events) or up to 120 months (mortality) after RPM termination., Methods: Eligible patients aged ≥18 years, hospitalized for acute heart failure, and with predischarge ejection fraction ≤40% were randomized to RPM (RPM+UC; n = 509) or control (UC; n = 513). Follow-up visits were every 6 months during RPM, and then at 36, 60, and 120 months., Results: The primary outcome did not differ between groups at 18 months (60.7% [95% CI: 56.5%-65.0%] vs 61.2% [95% CI: 57.0%-65.4%]) or 60 months (78.1% [95% CI: 74.4%-81.6%] vs 82.8% [95% CI: 79.5%-86.0%]). At 60 and 120 months, all-cause mortality was lower in patients previously undergoing RPM (41.1% [95% CI: 37.0%-45.5%] vs 47.4% [95% CI: 43.2%-51.8%]; P = 0.040 and 64.0% [95% CI: 59.8%-68.2%] vs 69.6% [95% CI: 65.6%-73.5%]; P = 0.019). At all visits, health-related quality of life was better in patients exposed to HeartNetCare-HF vs UC., Conclusions: Although 18 months' HeartNetCare-HF did not significantly reduce the primary outcome of death or rehospitalization at 60 months, lower 120-month mortality in patients previously undergoing HeartNetCare-HF suggested beneficial longer-term effects, although the possibility of a chance finding remains., Competing Interests: Funding Support and Author Disclosures This work was funded by Federal Ministry of Education and Research (BMBF), Berlin, Germany, BMBF grant 01GL0304; Competence Network Heart Failure, Berlin, Germany, BMBF grants 01GI0205 and 01GI1202A; and Comprehensive Heart Failure Center Würzburg, Würzburg, Germany, BMBF grants 01EO1004 and 01EO1504. Prof Angermann has received grant support, personal fees, advisory boards, and/or nonfinancial support from Abbott, AstraZeneca, Boehringer Ingelheim, Biotronik, Novartis, ResMed, Thermo Fisher, and Vifor, all outside of the submitted work; has received nonfinancial support from the University Hospital Würzburg and the Comprehensive Heart Failure Center Würzburg; and has received grant support from German BMBF. Ms Sehner has received personal fees from Boston Scientific; and grant support from German BMBF, Atrial Fibrillation NETwork (AFNET), German Centre for Cardiovascular Research, EU Horizon 2020, Adrenomed AG, and Biotronik, outside the submitted work. Dr Güder has received personal fees from AstraZeneca, Abiomed, Bayer, Boehringer Ingelheim, Novartis, Orion GmbH, Pfizer, and Vifor, all outside of the submitted work; and has received grant support from the BMBF, the German Heart Foundation, and the German Cardiac Society. Dr Morbach has received research cooperation with the University of Würzburg and Tomtec Imaging Systems funded by a research grant from the Bavarian Ministry of Economic Affairs, Regional Development and Energy, Germany; has received advisory and speaker honoraria and travel grants from AKCEA, Alnylam, Amgen, Boehringer Ingelheim, EBR Systems, Orion Pharma, Pfizer, SOBI, and Tomtec; has been a principal investigator in trials sponsored by Alnylam, AstraZeneca, and Bayer; and has received financial support from the Interdisciplinary Centre for Clinical Research–IZKF Würzburg (advanced clinician-scientist program). Dr Frantz has received personal fees from Amgen Europe, AstraZeneca, Bayer Vital, Boehringer Ingelheim, Bristol Meyers Squibb GmbH, Daiichi Sankyo, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Sanofi, Servier, and Vifor, all outside of the submitted work; and has received grant support from the BMBF and the German Heart Foundation. Dr Wegscheider has received personal fees from German BMBF, Atrial Fibrillation NETwork (AFNET), German Centre for Cardiovascular Research, EU Horizon 2020, Biotronik, Boston Scientific, and Novartis; and has received grant support from Adrenomed AG and Biotronik, outside the submitted work. Dr Ertl has received personal fees from AstraZeneca, Abbott, Boehringer Ingelheim, Medtronic, Novartis, ResMed, Thermo Fisher, and Vifor; has participated in advisory boards for AstraZeneca, Abbott, Novartis, and Vifor, all outside the submitted work; has received nonfinancial support from the University Hospital Würzburg Comprehensive Heart Failure Center Würzburg; and has received grant support from the German BMBF. Prof Störk has received grant support and/or personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Pfizer, and Sanofi, all outside the submitted work; has received case payments for participation in trials from Akcea, Amgen, AstraZeneca, Bayer, Boehringer, Ionis, Novartis, Pfizer, Sanofi, and Vifor; and has received grant support from the German BMBF, European Union, and University Hospital Würzburg. Dr Faller has reported that he has no relationships relevant to the contents of this paper to disclose. The data that support the findings of this study are available from the corresponding author upon reasonable request., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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 (p interaction  = 0.008), and not modified by LVEF or geographic region (p interaction  > 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., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Effective and safe decongestion remains a major goal for optimal management of patients with acute heart failure (AHF). The effects of the sodium-glucose cotransporter 2 inhibitor empagliflozin on decongestion-related endpoints in the EMPULSE trial (NCT0415775) were evaluated., Methods and Results: A total of 530 patients hospitalized for AHF were randomized 1:1 to either empagliflozin 10 mg once daily or placebo for 90 days. The outcomes investigated were: weight loss (WL), WL adjusted for mean daily loop diuretic dose (WL-adjusted), area under the curve of change from baseline in N-terminal pro-B-type natriuretic peptide levels, hemoconcentration, and clinical congestion score after 15, 30, and 90 days of treatment. Compared with placebo, patients treated with empagliflozin demonstrated significantly greater reductions in all studied markers of decongestion at all time-points, adjusted mean differences (95% confidence interval) at Days 15, 30, and 90 were: for WL -1.97 (-2.86, -1.08), -1.74 (-2.73, -0.74); -1.53 (-2.75, -0.31) kg; for WL-adjusted: -2.31 (-3.77, -0.85), -2.79 (-5.03, -0.54), -3.18 (-6.08, -0.28) kg/40 mg furosemide i.v. or equivalent; respectively (all P < 0.05). Greater WL at Day 15 (i.e. above the median WL in the entire population) was associated with significantly higher probability for clinical benefit at Day 90 (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline to 90 days) with the win ratio of 1.75 (95% confidence interval 1.37, 2.23; P < 0.0001)., Conclusion: Initiation of empagliflozin in patients hospitalized for AHF resulted in an early, effective and sustained decongestion which was associated with clinical benefit at Day 90., Competing Interests: Conflict of interest: A.A.V. has received research support and/or has been a consultant for Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Cytokinetics, Merck, Myokardia, Novo Nordisk, Novartis, and Roche Diagnostics. S.P.C. is a consultant for Aiphia, Siemens, Bristol Myers Squibb, Boehringer Ingelheim, and Vixiar and receives research support from the NIH, PCORI, AstraZeneca, and Beckman Coulter. M.N.K. has received research grants from AstraZeneca and Boehringer Ingelheim, and has served as a consultant for Alnylam, AstraZeneca, Amgen, Applied Therapeutics, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Sanofi, and Vifor. J.R.T. has received research support and/or has been a consultant for Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics. C.E.A. has received research support from and/or has been a consultant for Abbott, Boehringer Ingelheim, Medtronic, Novartis, ResMed, Thermo Fisher, Vifor, and German Federal Ministry of Education and Research. J.T. is supported by the National University of Singapore Start-up grant, the tier 1 grant from the ministry of education and the CS-IRG New Investigator Grant from the National Medical Research Council; has received consulting or speaker fees from Daiichi-Sankyo, Boehringer Ingelheim, Roche diagnostics, and Us2.ai, owns patent US-10702247-B2 unrelated to the present work. J.P.F. is a consultant for Boehringer Ingelheim and receives research support from AstraZeneca. M.E.N. has received speaking honoraria from Abbott, and is a consultant for Vifor, Roche, and Amgen. P.P. reports personal fees from Boehringer Ingelheim, AstraZeneca, Servier, Bristol Myers Squibb, Amgen, Novartis, Merck, Pfizer, Berlin Chemie, and grants and personal fees from Vifor Pharma. J.P.B. is an employee of Elderbrook Solutions. M.B. and A.S. are employees of Boehringer Ingelheim. J.B. and M.A.P. have no competing interests., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Aim: The CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF) investigated safety and efficacy of pulmonary artery pressure (PAP)-guided remote patient management (RPM) in New York Heart Association (NYHA) class III outpatients with at least one heart failure hospitalization (HFH) during the previous 12 months. This pre-specified subgroup analysis investigated whether RPM effects depended on presence and subtype of pulmonary hypertension (PH)., Methods and Results: In 106/234 MEMS-HF participants, Swan-Ganz catheter tracings obtained during sensor implant were available for off-line manual analysis jointly performed by two experts. Patients were classified into subgroups according to current PH definitions. Isolated post-capillary PH (IpcPH) and combined post- and pre-capillary PH (CpcPH) were present in 38 and 36 patients, respectively, whereas 31 patients had no PH. Clinical characteristics were comparable between subgroups, but among patients with PH pulmonary vascular resistance was higher (p = 0.029) and pulmonary artery compliance lower (p = 0.003) in patients with CpcPH. During 12 months of PAP-guided RPM, all PAPs declined in IpcPH and CpcPH subgroups (all p < 0.05), whereas only mean and diastolic PAP decreased in patients without PH (both p < 0.05). Improvements in post- versus pre-implant HFH rates were similar in CpcPH (0.639 events/patient-year; hazard ratio [HR] 0.37) and IpcPH (0.72 events/patient-year; HR 0.45) patients. Participants without PH benefited most (0.26 events/patient-year; HR 0.17, p = 0.04 vs. IpcPH/CpcPH patients). Quality of life and NYHA class improved significantly in all subgroups., Conclusions: Outpatients with NYHA class III symptoms with at least one HFH during 1 year pre-implant benefitted significantly from PAP-guided RPM during post-implant follow-up irrespective of presence or subtype of PH at baseline., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin improved clinical outcomes in patients hospitalized for acute heart failure. In patients with chronic heart failure, SGLT2 inhibitors cause an early decline in estimated glomerular filtration rate (eGFR) followed by a slower eGFR decline over time than placebo. However, the effects of SGLT2 inhibitors on renal function during a hospital admission for acute heart failure remain largely unknown., Methods and Results: Between 1 and 5 days after a hospitalization for acute heart failure, 530 patients with an eGFR >20 ml/min/1.73 m 2 were randomized to 10 mg of empagliflozin or placebo and treated for 90 days. Renal function and electrolytes were measured at baseline, and after 15, 30 and 90 days. We evaluated the effect of empagliflozin on eGFR over time and the impact of baseline eGFR on the primary hierarchical outcome of death, worsening heart failure events and quality of life. Mean baseline eGFR was 52.4 ml/min/1.73 m 2 in the empagliflozin group and 55.7 ml/min/1.73 m 2 in the placebo group. Empagliflozin caused an initial decline in eGFR (-2 ml/min/1.73 m 2 at day 15 compared to placebo). At day 90, eGFR was similar between empagliflozin and placebo. Investigator-reported acute renal failure occurred in 7.7% of empagliflozin versus 12.1% of placebo patients. The overall clinical benefit (hierarchical composite of all-cause death, heart failure events and quality of life) of empagliflozin was unaffected by baseline eGFR., Conclusion: In patients hospitalized for acute heart failure, empagliflozin caused an early modest decline in renal function which was no longer evident after 90 days. Acute renal events were similar in both groups. The clinical benefit of empagliflozin was consistent regardless of baseline renal function., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Patients hospitalized for acute heart failure experience poor health status, including a high burden of symptoms and physical limitations, and poor quality of life. SGLT2 (sodium-glucose cotransporter 2) inhibitors improve health status in chronic heart failure, but their effect on these outcomes in acute heart failure is not well characterized. We investigated the effects of the SGLT2 inhibitor empagliflozin on symptoms, physical limitations, and quality of life, using the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the EMPULSE trial (Empagliflozin in Patients Hospitalized With Acute Heart Failure Who Have Been Stabilized)., Methods: Patients hospitalized for acute heart failure were randomized to empagliflozin 10 mg daily or placebo for 90 days. The KCCQ was assessed at randomization and 15, 30, and 90 days. The effects of empagliflozin on the primary end point of clinical benefit (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in KCCQ Total Symptom Score [TSS] change from baseline to 90 days) were examined post hoc across the tertiles of baseline KCCQ-TSS. In prespecified analyses, changes (randomization to day 90) in KCCQ domains, including TSS, physical limitations, quality of life, clinical summary, and overall summary scores were evaluated using a repeated measures model., Results: In total, 530 patients were randomized (265 each arm). Baseline KCCQ-TSS was low overall (mean [SD], 40.8 [24.0] points). Empagliflozin-treated patients experienced greater clinical benefit across the range of KCCQ-TSS, with no treatment effect heterogeneity (win ratio [95% CIs] from lowest to highest tertile: 1.49 [1.01-2.20], 1.37 [0.94-1.99], and 1.48 [1.00-2.20], respectively; P for interaction=0.94). Beneficial effects of empagliflozin on health status were observed as early as 15 days and persisted through 90 days, at which point empagliflozin-treated patients experienced a greater improvement in KCCQ TSS, physical limitations, quality of life, clinical summary, and overall summary (placebo-adjusted mean differences [95% CI]: 4.45 [95% CI, 0.32-8.59], P =0.03; 4.80 [95% CI, 0.00-9.61], P =0.05; 4.66 [95% CI, 0.32-9.01], P =0.04; 4.85 [95% CI, 0.77-8.92], P =0.02; and 4.40 points [95% CI, 0.33-8.48], P =0.03, respectively)., Conclusions: Initiation of empagliflozin in patients hospitalized for acute heart failure produced clinical benefit regardless of the degree of symptomatic impairment at baseline, and improved symptoms, physical limitations, and quality of life, with benefits seen as early as 15 days and maintained through 90 days., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT0415775.

Background: Heart failure (HF) is a global challenge, with lower- and middle-income countries (LMICs) carrying a large share of the burden. Treatment for HF with reduced ejection fraction (HFrEF) improves survival but is often underused. Economic factors might have an important effect on the use of medicines., Methods and Results: This analysis assessed prescription rates and doses of renin-angiotensin system (RAS) inhibitors, β-blockers, and mineralocorticoid receptor antagonists at discharge and 6-month follow-up in 8669 patients with HFrEF (1458 from low-, 3363 from middle-, and 3848 from high-income countries) hospitalized for acute HF in 44 countries in the prospective REPORT-HF study. We investigated determinants of guideline-recommended treatments and their association with 1-year mortality, correcting for treatment indication bias.Only 37% of patients at discharge and 34% of survivors at 6 months were on all three medication classes, with lower proportions in LMICs than high-income countries (19 vs. 41% at discharge and 15 vs. 37% at 6 months). Women and patients without health insurance, or from LMICs, or without a scheduled medical follow-up within 6 months of discharge were least likely to be on guideline-recommended medical therapy at target doses, independent of confounders. Being on ≥50% of guideline-recommended doses of RAS inhibitors, and β-blockers were independently associated with better 1-year survival, regardless of country income level., Conclusion: Patients with HFrEF in LMICs are less likely to receive guideline-recommended drugs at target doses. Improved access to medications and medical care could reduce international disparities in outcome., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose of Review: In this article, we review a range of digital technologies for possible application in heart failure patients, with a focus on lessons learned. We also discuss a future model of heart failure management, as digital technologies continue to become part of standard care., Recent Findings: Digital technologies are increasingly used by healthcare professionals and those living with heart failure to support more personalised and timely shared decision-making, earlier identification of problems, and an improved experience of care. The COVID-19 pandemic has accelerated the acceptability and implementation of a range of digital technologies, including remote monitoring and health tracking, mobile health (wearable technology and smartphone-based applications), and the use of machine learning to augment data interpretation and decision-making. Much has been learned over recent decades on the challenges and opportunities of technology development, including how best to evaluate the impact of digital health interventions on health and healthcare, the human factors involved in implementation and how best to integrate dataflows into the clinical pathway. Supporting patients with heart failure as well as healthcare professionals (both with a broad range of health and digital literacy skills) is crucial to success. Access to digital technologies and the internet remains a challenge for some patients. The aim should be to identify the right technology for the right patient at the right time, in a process of co-design and co-implementation with patients., (© 2022. The Author(s).)

Aims: Recovery of well-being after hospitalisation for acute heart failure (AHF) is a measure of the success of interventions and the quality of care but has rarely been quantified. Accordingly, we measured health status after discharge in an international registry (REPORT-HF) of AHF., Methods and Results: The analysis included 4606 patients with AHF who survived to hospital discharge, had known vital status at 6 months, and were enrolled in the United States of America, Russian Federation, or Western Europe, where the Kansas City Cardiomyopathy Questionnaire (KCCQ) was administered. Median age was 69 years (quartiles 59-78), 40% were women, and 34% had a left ventricular ejection fraction (LVEF) <40%, and 12% patients died by 6 months. Of 2475 patients with a follow-up KCCQ, 28% were 'alive and well' (KCCQ >75), while 43% had poor health status (KCCQ ≤50). Being 'alive and well' was associated with new-onset AHF, LVEF <40%, younger age, higher baseline KCCQ, country, and race. Associations were similar for increasing health status, with the exception of country and addition of comorbidities., Conclusion: In this international global registry, health status recovery after AHF hospitalisation was highly variable. Those with the best health status at 6 months were younger, had new-onset heart failure, and higher baseline KCCQ; nearly one-third of survivors were 'alive and well'. Investigating reasons for changes in KCCQ after hospitalisation might identify new therapeutic targets to improve patient-centred outcomes., (© 2022 European Society of Cardiology.)

Aims: Few prior studies have investigated differences in precipitants leading to hospitalizations for acute heart failure (AHF) in a cohort with global representation., Methods and Results: We analysed the prevalence of precipitants and their association with outcomes in 18 553 patients hospitalized for AHF in REPORT-HF (prospective international REgistry to assess medical Practice with lOngitudinal obseRvation for Treatment of Heart Failure) according to left ventricular ejection fraction subtype (reduced [HFrEF] and preserved ejection fraction [HFpEF]) and presentation (new-onset vs. decompensated chronic heart failure [DCHF]). Patients were enrolled from 358 centres in 44 countries stratified according to Latin America, North America, Western Europe, Eastern Europe, Eastern Mediterranean and Africa, Southeast Asia, and Western Pacific. Precipitants were pre-with mutually exclusive categories and selected according to the local investigator's discretion. Outcomes included in-hospital and 1-year mortality. The median age was 67 (interquartile range 57-77) years, and 39% were women. Acute coronary syndrome (ACS) was the most common precipitant in patients with new-onset heart failure in all regions except for North America and Western Europe, where uncontrolled hypertension and arrhythmia, respectively, were the most common precipitants, independent of confounders. In patients with DCHF, non-adherence to diet/medication was the most common precipitant regardless of region. Uncontrolled hypertension was a more likely precipitant in HFpEF, non-adherence to diet/medication, and ACS were more likely precipitants in HFrEF. Patients admitted due to worsening renal function had the worst in-hospital (5%) and 1-year post-discharge (30%) mortality rates, regardless of region, heart failure subtype and admission type (p interaction  >0.05 for all)., Conclusion: Data on global differences in precipitants for AHF highlight potential regional differences in targets for preventing hospitalization for AHF and identifying those at highest risk for early mortality., (© 2022 European Society of Cardiology.)

The sodium-glucose cotransporter 2 inhibitor empagliflozin reduces the risk of cardiovascular death or heart failure hospitalization in patients with chronic heart failure, but whether empagliflozin also improves clinical outcomes when initiated in patients who are hospitalized for acute heart failure is unknown. In this double-blind trial (EMPULSE; NCT04157751 ), 530 patients with a primary diagnosis of acute de novo or decompensated chronic heart failure regardless of left ventricular ejection fraction were randomly assigned to receive empagliflozin 10 mg once daily or placebo. Patients were randomized in-hospital when clinically stable (median time from hospital admission to randomization, 3 days) and were treated for up to 90 days. The primary outcome of the trial was clinical benefit, defined as a hierarchical composite of death from any cause, number of heart failure events and time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, as assessed using a win ratio. More patients treated with empagliflozin had clinical benefit compared with placebo (stratified win ratio, 1.36; 95% confidence interval, 1.09-1.68; P = 0.0054), meeting the primary endpoint. Clinical benefit was observed for both acute de novo and decompensated chronic heart failure and was observed regardless of ejection fraction or the presence or absence of diabetes. Empagliflozin was well tolerated; serious adverse events were reported in 32.3% and 43.6% of the empagliflozin- and placebo-treated patients, respectively. These findings indicate that initiation of empagliflozin in patients hospitalized for acute heart failure is well tolerated and results in significant clinical benefit in the 90 days after starting treatment., (© 2022. The Author(s).)

Aims: Control of pulmonary pressures monitored remotely reduced heart failure hospitalizations mainly by lowering filling pressures through the use of loop diuretics. Sacubitril/valsartan improves heart failure outcomes and increases the kidney sensitivity for diuretics. We explored whether sacubitril/valsartan is associated with less utilization of loop diuretics in patients guided with haemodynamic monitoring in the CardioMEMS European Monitoring Study for Heart Failure (MEMS-HF)., Methods and Results: The MEMS-HF population (n = 239) was separated by the use of sacubitril/valsartan (n = 68) or no use of it (n = 164). Utilization of diuretics and their doses was prespecified in the protocol and was monitored in both groups. Multivariable regression, ANCOVA, and a generalized linear model were used to fit baseline covariates with furosemide equivalents and changes for 12 months. MEMS-HF participants (n = 239) were grouped in sacubitril/valsartan users [n = 68, 64 ± 11 years, left ventricular ejection fraction (LVEF) 25 ± 9%, cardiac index (CI) 1.89 ± 0.4 L/min/m 2 ] vs. non-users (n = 164, 70 ± 10 years, LVEF 36 ± 16%, CI 2.11 ± 0.58 L/min/m 2 , P = 0.0002, P < 0.0001, and P = 0.0015, respectively). In contrast, mean pulmonary artery pressure (PAP) values were comparable between groups (29 ± 11 vs. 31 ± 11 mmHg, P = 0.127). Utilization of loop diuretics was lower in patients taking sacubitril/valsartan compared with those without (P = 0.01). Significant predictor of loop diuretic use was a history of renal failure (P = 0.005) but not age (P = 0.091). After subjects were stratified by sacubitril/valsartan or other diuretic use, PAP was nominally, but not significantly lower in sacubitril/valsartan-treated patients (baseline: P = 0.52; 6 months: P = 0.07; 12 months: P = 0.53), while there was no difference in outcome or PAP changes. This difference was observed despite lower CI (P = 0.0015). Comparable changes were not observed for other non-loop diuretics (P = 0.21)., Conclusions: In patients whose treatment was guided by remote PAP monitoring, concomitant use of sacubitril/valsartan was associated with reduced utilization of loop diuretics, which could potentially be relevant for outcomes., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: There is an ongoing discussion whether the categorization of patients with heart failure according to left ventricular ejection fraction (LVEF) is scientifically justified and clinically relevant. Major efforts are directed towards the identification of appropriate cut-off values to correctly allocate heart failure-specific pharmacotherapy. Alternatively, an LVEF continuum without definite subgroups is discussed. This study aimed to evaluate the natural distribution of LVEF in patients presenting with acutely decompensated heart failure and to identify potential subgroups of LVEF in male and female patients., Methods and Results: We identified 470 patients (mean age 75 ± 11 years, n = 137 female) hospitalized for acute heart failure in whom LVEF could be quantified by Simpson's method in an in-hospital echocardiogram. Non-parametric modelling revealed a bimodal shape of the LVEF distribution. Parametric modelling identified two clusters suggesting two LVEF peaks with mean (variance) of 61% (9%) and 31% (10%), respectively. Sub-differentiation by sex revealed a sex-specific bimodal clustering of LVEF. The respective threshold differentiating between 'high' and 'low' LVEF was 45% in men and 52% in women., Conclusions: In patients presenting with acute heart failure, LVEF clustered in two subgroups and exhibited profound sex-specific distributional differences. These findings might enrich the scientific process to identify distinct subgroups of heart failure patients, which might each benefit from respectively tailored (pharmaco)therapies., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)