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© 2014 The Authors European Journal of Heart Failure.Aims We studied the characteristics and clinical outcome related to diuretic response and the effects of serelaxin in patients hospitalized for acute heart failure (AHF).Methods and results RELAX-AHF was

Hospitalization for worsening chronic heart failure results in high post-discharge mortality, morbidity, and cost. However, thorough characterization, soon after discharge of patients with early post-discharge events has not been previously performed. The objectives of this study were to describe the baseline, in-hospital, and post-discharge clinical, laboratory, and neurohormonal profiles of patients hospitalized for worsening heart failure with reduced ejection fraction (EF) who die or are re-admitted for cardiovascular (CV) causes within 90 days of initial hospitalization. Retrospective analysis of 4,133 patients hospitalized for worsening heart failure with EF ≤40% in the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial, which randomized patients to tolvaptan or placebo, both in addition to standard therapy. Clinical and laboratory parameters were obtained within 48 h of admission, during hospitalization, and post-discharge weeks 1, 4, 8, and every 8 weeks thereafter for a median of 9.9 months. Patients with events within 90 days were compared with those with later/no events. All-cause mortality (ACM) and CV re-hospitalization were independently adjudicated. Within 90 days of admission, 395 patients (9.6%) died and 801 patients (19.4%) were re-hospitalized for CV causes. Significant baseline and longitudinal differences were seen between groups with early versus later (>90 days) or no events at 12 months post-randomization. Post-discharge outcomes were similar in the tolvaptan and placebo groups. Patients with early post-discharge events experienced clinically significant worsening in signs and symptoms, laboratory values, and neurohormonal parameters soon after discharge. Identifying these abnormalities may facilitate efforts to reduce post-discharge mortality and re-hospitalization. [ABSTRACT FROM AUTHOR]

The majority of heart failure hospitalizations in the United States originate in the emergency department (ED). Current strategies for acute heart failure syndromes have largely been tailored after chronic heart failure guidelines and care. Prospective ED-based acute heart failure syndrome trials are lacking, and current guidelines for disposition are based on either little or no evidence. As a result, the majority of ED acute heart failure syndrome patients are admitted to the hospital. Recent registry data suggest there is a significant amount of heterogeneity in acute heart failure syndrome ED presentations, and diagnostics and therapeutics may need to be individualized to the urgency of the presentation, underlying pathophysiology, and acute hemodynamic characteristics. A paradigm shift is necessary in acute heart failure syndrome guidelines and research: prospective trials need to focus on diagnostic, therapeutic, and risk-stratification algorithms that rely on readily available ED data, focusing on outcomes more proximate to the ED visit (5 days). Intermediate outcomes (30 days) are more dependent on inpatient and outpatient care and patient behavior than ED management decisions. Without these changes, the burden of acute heart failure syndrome care is unlikely to change. This article proposes such a paradigm shift in acute heart failure syndrome care and discusses areas of further research that are necessary to promote this change in approach. [ABSTRACT FROM AUTHOR]

With over 1 million primary heart failure (HF) hospitalizations annually, nearly 80% of patients who present to the emergency department with decompensated HF (DHF) are hospitalized. Short stay units (SSU) present an alternative to hospitalization, yet the effectiveness of the SSU strategy of care is not well known. This study is to determine the effectiveness of a SSU strategy compared with hospitalization in lower-risk patients with DHF. Our primary outcome was a composite of 30-day mortality and re-hospitalization. Key secondary outcomes included 90-day mortality and re-hospitalization, costs, and 30-day days-alive-and-out-of-hospital (DAOOH). This is a systematic review and meta-analysis, following PRISMA guidelines. MEDLINE, EMBASE, CENTRAL, CINAHL, SCOPUS, and Web of Science were searched from inception through February 2024. Either randomized trials or comparative observational studies were included if they compared outcomes between low-risk ED DHF patients admitted to an SSU (defined as an observation unit with expected stay ≤ 48 h) vs. admitted to the hospital. Two authors independently screened all titles and abstracts and then identified full texts for inclusion. Data extraction and risk of bias assessments were performed by two authors in parallel. The primary outcome was a composite of death or readmission within 30 days, reported as relative risk (RR), where a RR < 1 favored the SSU strategy. Secondary outcomes included 90-day mortality and re-hospitalization, costs, and 1-month days-alive-and-out-of-hospital (DAOOH). Of the 467 articles identified by our search strategy, only 3 full text articles were included. In meta-analysis for the primary outcome of 30-day death or readmission, the RR was 0.95 (95% CI = 0.56 to 1.63; I 2  = 0%) for patients randomized to SSU vs hospitalization (2 studies, 241 patients). There were only 2 total deaths at 30 days in the 2 studies (total N = 258) which reported 30-day mortality, both in hospitalized patients. Only one study reported 90-day outcomes, showing no significant differences. Costs were lower in the SSU arm from one study, and 30-day DAOOH also favored SSU based on a single randomized trial. Based on very limited evidence, SSU provides similar efficacy for 30-day and 90-day mortality and readmission compared to hospitalization. An SSU strategy appears safe and may be cost effective., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Anemia is one of the most frequent comorbidities in patients with heart failure (HF), which potentially can interfere with the effect of guideline-recommended HF medical therapy and can be associated with the use of neurohormonal blockers., Aim: The aim of this analysis was to determine the prevalence and changes of anemia status in the STRONG-HF study, its association with clinical endpoints, and possible interaction of the presence of anemia with the efficacy and safety of high-intensity HF treatment., Methods: The design and main results of the study have been previously described. Patients were randomized within 2 days prior to anticipated hospital discharge after HF worsening in a 1:1 fashion to either high-intensity care (HIC) or usual care (UC). Baseline characteristics, clinical and safety outcomes, and treatment effect of HIC vs. UC on the primary and secondary outcomes were compared in groups based on baseline anemia. In addition, dynamics of hemoglobin during the study follow-up and predictors of incident anemia at 90 days were investigated., Results: The proportion of anemia in 1077 STRONG-HF patients at enrollment was 27.2%, while at 90 days, it changed to 32.1%. The primary composite outcome occurred in 18.2% of patients without baseline anemia, and 22.5% of patients with baseline anemia (unadjusted HR 1.27; 95% CI 0.90-1.80), a difference that did not reach statistical significance. However, patients with baseline anemia had significantly less improvement of EQ-VAS questionnaire values from baseline to day 90 (adjusted LS-Mean difference -2.34 (-4.37, -0.31), P = 0.02). During the study, anemia developed in 19.4 and 14.6% in HIC and UC groups, respectively. The opposite phenomenon-recovery of anemia-occurred in 27.6 and 28.8% in HIC and UC groups (P = 0.1379). The predictors of incident anemia at 90 days were male sex, geographical region other than Europe, ischemic etiology, higher glucose, and elevated uric acid at baseline. The percentages of optimal doses of renin-angiotensin system inhibitors, beta-blockers, and mineralocorticoid receptor antagonists were not different between anemic and non-anemic patients. High-intensity care strategy did not increase rate of incident anemia at 90 days and reduced the rate of primary and secondary endpoints regardless of baseline hemoglobin., Conclusion: Hemoglobin level and status of anemia have a dynamic nature in the acute HF patients in the post-discharge period dependent on multiple factors. High-intensity HF treatment is safe and beneficial regardless of baseline hemoglobin level and presence of anemia. The improvement of quality of life is significantly lower in anemic HF patients implying specific attention to correction of this condition., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Acute heart failure (AHF) is a major cause of hospitalizations and death in the elderly. However, elderly patients are often underrepresented in randomized clinical trials. We analysed the impact of age on clinical outcomes and response to treatment in patients enrolled in Relaxin in Acute Heart Failure (RELAX-AHF-2), a study that included older patients than in previous AHF trials., Methods and Results: The RELAX-AHF-2 randomized patients admitted for AHF to infusion of serelaxin or placebo. We examined the association of pre-specified clinical outcomes and treatment effect according to age categories [(years): <65 (n = 1411), 65-74 (n = 1832), 75-79 (n = 1222), 80-84 (n = 1156) and ≥85 (n = 924)]. The mean age of the 6545 patients enrolled in RELAX-AHF-2 was 73.0 ± 11 years. The risk of all-cause and cardiovascular (CV) death (all p < 0.001) as well as the composite endpoint of CV death or heart failure/renal failure rehospitalization through 180 days (p = 0.002) and hospital discharge through day 60 (p = 0.013) were all directly associated with age categories. Age remained independently associated with outcomes after adjustment for clinical confounders and the results were consistent when age was analysed continuously. No clinically significant change in treatment effects of serelaxin was observed across age categories for the pre-specified endpoints (interaction p > 0.05)., Conclusion: Elderly patients are at higher risk of short- and long-term CV outcomes after a hospitalization for AHF. Further efforts are needed to improve CV outcomes in this population., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Guideline-directed medical therapy (GDMT) decisions may be less affected by single patient variables such as blood pressure or kidney function and more by overall risk profile. In STRONG-HF (Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure), high-intensity care (HIC) in the form of rapid uptitration of heart failure (HF) GDMT was effective overall, but the safety, tolerability and efficacy of HIC across the spectrum of HF severity is unknown. Evaluating this with a simple risk-based framework offers an alternative and more clinically translatable approach than traditional subgroup analyses., Objectives: The authors sought to assess safety, tolerability, and efficacy of HIC according to the simple, powerful, and clinically translatable MAGGIC (Meta-Analysis Global Group in Chronic) HF risk score., Methods: In STRONG-HF, 1,078 patients with acute HF were randomized to HIC (uptitration of treatments to 100% of recommended doses within 2 weeks of discharge and 4 scheduled outpatient visits over the 2 months after discharge) vs usual care (UC). The primary endpoint was the composite of all-cause death or first HF rehospitalization at day 180. Baseline HF risk profile was determined by the previously validated MAGGIC risk score. Treatment effect was stratified according to MAGGIC risk score both as a categorical and continuous variable., Results: Among 1,062 patients (98.5%) with complete data for whom a MAGGIC score could be calculated at baseline, GDMT use at baseline was similar across MAGGIC tertiles. Overall GDMT prescriptions achieved for individual medication classes were higher in the HIC vs UC group and did not differ by MAGGIC risk score tertiles (interaction nonsignificant). The incidence of all-cause death or HF readmission at day 180 was, respectively, 16.3%, 18.9%, and 23.2% for MAGGIC risk score tertiles 1, 2, and 3. The HIC arm was at lower risk of all-cause death or HF readmission at day 180 (HR: 0.66; 95% CI: 0.50-0.86) and this finding was robust across MAGGIC risk score modeled as a categorical (HR: 0.51; 95% CI: 0.62-0.68 in tertiles 1, 2, and 3; interaction nonsignificant) for all comparisons and continuous (interaction nonsignificant) variable. The rate of adverse events was higher in the HIC group, but this observation did not differ based on MAGGIC risk score tertile (interaction nonsignificant)., Conclusions: HIC led to better use of GDMT and lower HF-related morbidity and mortality compared with UC, regardless of the underlying HF risk profile. (Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP testinG, of Heart Failure Therapies [STRONG-HF]; NCT03412201)., Competing Interests: Funding Support and Author Disclosures Funding for the STRONG-HF study was through an unrestricted grant provided to the Heart Initiative by Roche Diagnostics International (Rotkreuz, Switzerland). The funder had no role in study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit the manuscript for publication. Dr Ambrosy has received relevant research support through grants to his institution from the National Heart, Lung, and Blood Institute (K23HL150159), the American Heart Association (2nd Century Early Faculty Independence Award), The Permanente Medical Group, Northern California Community Benefits Programs, Garfield Memorial Fund, Abbott Laboratories, Amarin Pharma, Inc, Edwards Lifesciences LLC, Esperion Therapeutics, Inc, and Novartis. Dr Mebazaa has received grants from Roche Diagnostics, Abbott Laboratories, 4TEEN4, and Windtree Therapeutics; honoraria for lectures from Roche Diagnostics, Bayer, and Merck Sharp & Dohme; is a consultant for Corteria Pharmaceuticals, S-form Pharma, FIRE-1, Implicity, 4TEEN4, and Adrenomed; and is coinventor of a patent on combination therapy for patients having acute or persistent dyspnoea. Drs Cotter, Davison, Edwards, Mebazaa, Novosadova, and Takagi are employees of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. Drs Cotter and Davison are directors of Heart Initiative, a nonprofit organization. Dr Adamo has received speaker fees from Abbott Vascular and Medtronic. Dr Celutkiene has received personal fees from Novartis, AstraZeneca, Boehringer Ingelheim, Roche Diagnostics, and Pfizer. Dr Chioncel has received grants from Servier. Dr Cohen-Solal has received honoraria for lectures or consultancy from AstraZeneca, Novartis, Vifor, Bayer, Merck, Sanofi, Abbott, and Boehringer Ingelheim. Dr Damasceno works for the Faculty of Medicine, Eduardo Mondlane University (Maputo, Mozambique), which received research grants from the Heart Initiative for their participation in this study. Dr Diaz has received supporting fees for coordination of STRONG-HF trial activities. Dr Filippatos has received lecture fees or was a committee member for trials and registries sponsored by Bayer, Vifor, Boehringer Ingelheim, Medtronic, Servier, and Amgen. Dr Sliwa has received grants from Medtronic, Servier, and Amylam and honoraria from Merck Sharp & Dohme, Novartis, and Sanofi. Dr Lam 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/ Executive Committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Redcardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and serves as co-founder and nonexecutive director of Us2.ai. Dr Metra has received personal fees from Amgen, Livanova, and Vifor Pharma as a member of executive committees of sponsored clinical trials and from AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, and Roche Diagnostics for participation to advisory boards or for speaking at sponsored meetings. Dr Pagnesi has received personal fees from Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, and Vifor Pharma. Dr Pang has received grants or research contracts from American Heart Association, Roche, Siemens, Ortho Diagnostics, Abbott, Beckman Coulter, and Siemens; consulting fees from Roche; honoraria from WebMD; and he has financial interest in The Heart Course. Dr Voors has received consultancy fees or research support from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cytokinetics, Myocardia, Merck, Novartis, Novo Nordisk, and Roche Diagnostics. Dr Filippatos has received lecture fees and/or advisory and/or trial committee membership by Bayer, Boehringer Ingelheim, Servier, Novartis, Impulse Dynamics, Vifor, Medtronic, Cardior, Novo Nordisc and Research Grants from the European Union. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Rapid uptitration of guideline-directed medical therapy (GDMT) before and after discharge in hospitalized heart failure (HF) patients is feasible, is safe, and improves outcomes; whether this is also true in patients with coexistent atrial fibrillation/flutter (AF/AFL) is not known., Objectives: This study sought to investigate whether rapid GDMT uptitration before and after discharge for HF is feasible, safe and beneficial in patients with and without AF/AFL., Methods: In this secondary analysis of the STRONG-HF (Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies) trial, GDMT uptitration and patient outcomes were analyzed by AF/AFL status and type (permanent, persistent, paroxysmal)., Results: Among 1,078 patients enrolled in STRONG-HF, 496 (46%) had a history of AF, including 238 assigned to high-intensity care (HIC) and 258 to usual care (UC), and 581 did not have a history of AF/AFL, including 304 assigned to HIC and 277 to UC. By day 90, the average percent optimal dose of neurohormonal inhibitors achieved in the HIC arm was similar in patients with and without AF/AFL, reaching approximately 80% of the optimal dose (average absolute difference between AF/AFL and non-AF/AFL groups: -0.81%; 95% CI: -3.51 to 1.89). All-cause death or HF readmission by day 180 occurred less frequently in the HIC than the UC arm, both in patients with and without AF (adjusted HR: 0.75 [95% CI: 0.48-1.19] in AF vs adjusted HR: 0.50 [95% CI: 0.31-0.79] in non-AF/AFL patients; P for interaction = 0.2107). Adverse event rates were similar in patients with and without AF/AFL. AF/AFL type did not affect either uptitration or patient outcomes., Conclusions: Nearly half of acute HF patients have AF/AFL history. Rapid GDMT uptitration before and early after discharge is feasible, is safe, and may improve outcomes regardless of AF presence or type. (Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies [STRONG-HF]; NCT03412201)., Competing Interests: Funding Support and Author Disclosures Dr Farmakis has received lecture honoraria or consulting or Advisory Board fees and/or grants from AstraZeneca, Bayer, Boehringer Ingelheim, Leo, Myocardial Solutions, Novartis, Remedica, Roche Diagnostics, and Viatris, all outside the present work. Dr Davison is an employee of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics and is the director of Heart Initiative, a nonprofit organization. Dr Fountoulaki has received honoraria for lectures from Boehringer Ingelheim and AstraZeneca. Dr Chioncel has received support from Servier for the European Society of Cardiology Congress. Dr Metra has received personal fees from Actelion, Amgen, Livanova, and Vifor Pharma as a member of Executive or Data Monitoring Committees of sponsored clinical trials and from AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, and Roche Diagnostics for participation to Advisory Boards or for speaking at sponsored meetings. Dr Celutkiene has received support from Novartis for New York Cardiovascular Seminars and speaker fees from AstraZeneca, Boehringer Ingelheim, Bayer, and Grindex. Dr Cohen-Solal has received honoraria for lectures or consultancy from AstraZeneca, Novartis, Vifor, Bayer, Merck, Sanofi, Abbott, and Boehringer Ingelheim. Dr Damasceno is an employee of the Faculty of Medicine, Eduardo Mondlane University, Maputo, Mozambique, which has received research grants from the Heart Initiative for its participation in this study. Dr Diaz has received supporting fees for the coordination of STRONG-HF trial activities. Dr Edwards is an employee of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. Dr Novosadova is an employee of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. Dr Bistola has received honoraria for lectures or Advisory Boards from AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Pfizer, and Roche Diagnostics. Dr Pang has served as a consultant for Heart Initiative (Data and Safety Monitorin Board), Roche Diagnostics, Eagle Pharmaceuticals, and Kowa Pharmaceuticals; has served as a former or current investigator for industry studies funded by Abbott, Beckman Coulter, OrthoDiagnostics, and Siemens; and is a 5% owner in the HeartCourse, a Continuing Medical Education course. Dr Saidu has received grants from Medtronic, Servier, and Amylam and honoraria from Merck Sharp & Dohme, Novartis, and Sanofi. Dr Takagi is an employee of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. Dr Voors has received consultancy fees and or research support paid to his employer from AstraZeneca, Anacardio, BMS, Bayer, Boehringer Ingelheim, Corteria, Cytokinetics, Eli Lilly, Merck, Moderna, Novartis, Novo Nordisk, and Roche Diagnostics. Dr Mebazaa has received grants from Roche Diagnostics, Abbott Laboratories, 4TEEN4, and Windtree Therapeutics and honoraria for lectures from Roche Diagnostics, Bayer, and Merck Sharp & Dohme; has served as a consultant for Corteria Pharmaceuticals, S-form Pharma, FIRE-1, Implicity, 4TEEN4, and Adrenomed; and is the coinventor of a patent on combination therapy for patients having acute or persistent dyspnea. Dr Cotter is an employee of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics, and is director of Heart Initiative, a nonprofit organization. Dr Filippatos has received research support from the European Union and has received lecture fees from, served on the Advisory Board of, and/or made committee member contributions in clinical trials sponsored by Bayer, Medtronic, Vifor, Servier, Novartis, Impulse Dynamics, Novo Nordisk, and Boehringer Ingelheim. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The STRONG-HF trial showed that high-intensity care (HIC) consisting of rapid up-titration of guideline-directed medical therapy (GDMT) and close follow-up reduced all-cause death or heart failure (HF) readmission at 180 days compared to usual care (UC). We hypothesized that significant differences in patient characteristics, management, and outcomes over the enrolment period may exist., Methods: Two groups of the 1,078 patients enrolled in STRONG-HF were created according to the order of enrolment within center. The early group consisted of the first 10 patients enrolled at each center (N = 342) and the late group consisted of the following patients (N = 736)., Results: Late enrollees were younger, had more frequently reduced ejection fraction, slightly lower NT-proBNP and creatinine levels compared with early enrollees. The primary outcome occurred less frequently in early compared to late enrollees (15% vs. 21%, aHR 0.65, 95% CI 0.42-0.99, P = .044). No treatment-by-enrolment interaction was seen in respect to the average percentage of optimal dose of GDMT after randomization, which was consistently higher in early and late patients randomized to HIC compared to UC. The higher use of renin-angiotensin-inhibitors in the HIC arm was more pronounced in the late enrollees both after randomization (interaction-P = .013) and at 90 days (interaction-P < .001). No interaction was observed for safety events. Patients randomized late to UC displayed a trend toward more severe outcomes (26% vs. 16%, P = .10), but the efficacy of HIC showed no interaction with the enrolment group (aHR 0.77, 95% CI 0.35-1.67 in early and 0.58, 95% CI 0.40-0.83 in late enrollees, adjusted interaction-P = .51) with similar outcomes in the HIC arm in late and early enrollees (16% vs. 13%, P = .73)., Conclusions: Late enrollees have different clinical characteristics and higher event rates compared to early enrollees. GDMT implementation in the HIC arm robustly achieved similar doses with consistent efficacy in early and late enrollees, mitigating the higher risk of adverse outcome in late enrollees., Trial Registration: ClinicalTrials.gov Identifier: NCT03412201., Competing Interests: Conflict of interest AM has received grants from Roche Diagnostics, Abbott Laboratories, 4TEEN4, and Windtree Therapeutics; honoraria for lectures from Roche Diagnostics, Bayer, and MSD; is a consultant for Corteria Pharmaceuticals, S-form Pharma, FIRE-1, Implicity, 4TEEN4, and Adrenomed; and is coinventor of a patent on combination therapy for patients having acute or persistent dyspnoea. BD, MB, CE, MN, KT, GC are employees of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. BD and GC are directors of Heart Initiative, a non-profit organisation. MAd has received speaker fees from Abbott Vascular and Medtronic. JC has received personal fees from Novartis, AstraZeneca, Boehringer Ingelheim, Roche Diagnostics, and Pfizer. AC-S has received honoraria for lectures or consultancy from AstraZeneca, Novartis, Vifor, Bayer, Merck, Sanofi, Abbott, and Boehringer Ingelheim. OC received grants from Servier. AD works for the Faculty of Medicine, Eduardo Mondlane University (Maputo, Mozambique), which received research grants from the Heart Initiative for their participation in this study. RD has received supporting fees for coordination of STRONG-HF trial activities. GF has received lecture fees or was a committee member for trials and registries sponsored by Bayer, Vifor, Boehringer Ingelheim, Medtronic, Servier and Amgen. 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/ Executive Committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc., EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd., Redcardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and serves as co-founder & non-executive director of Us2.ai. MP has received personal fees from Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, Novartis, Roche Diagnostics and Vifor Pharma. PSP has received grants or research contracts from American Heart Association, Roche, Siemens, Ortho Diagnostics, Abbott, Beckman Coulter, and Siemens; consulting fees from Roche; honoraria from WebMD; and he has financial interest in The Heart Course. KS has received grants from Medtronic, Servier, and Amylam and honoraria from MSD, Novartis, and Sanofi. AAV has received consultancy fees or research support from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cytokinetics, Myocardia, Merck, Novartis, Novo Nordisk, and Roche Diagnostics. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Comprehensive uptitration of neurohormonal blockade targets fundamental mechanisms underlying development of congestion and may be an additional approach for decongestion after acute heart failure (AHF)., Objectives: This hypothesis was tested in the STRONG-HF (Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by N-Terminal Pro-Brain Natriuretic Peptide Testing of Heart Failure Therapies) trial., Methods: In STRONG-HF, patients with AHF were randomized to the high-intensity care (HIC) arm with fast up-titration of neurohormonal blockade or to usual care (UC). Successful decongestion was defined as an absence of peripheral edema, pulmonary rales, and jugular venous pressure <6 cm., Results: At baseline, the same proportion of patients in both arms had successful decongestion (HIC 48% vs UC 46%; P = 0.52). At day 90, higher proportion of patients in the HIC arm (75%) experienced successful decongestion vs the UC arm (68%) (P = 0.0001). Each separate component of the congestion score was significantly better in the HIC arm (all, P < 0.05). Additional markers of decongestion also favored the HIC: weight reduction (adjusted mean difference: -1.36 kg; 95% CI: -1.92 to -0.79 kg), N-terminal pro-B-type natriuretic peptide level, and lower orthopnea severity (all, P < 0.001). More effective decongestion was achieved despite a lower mean daily dose of loop diuretics at day 90 in the HIC arm. Among patients with successful decongestion at baseline, those in the HIC arm had a significantly better chance of sustaining decongestion at day 90. Successful decongestion in all subjects was associated with a lower risk of 180-day HF readmission or all-cause death (HR: 0.40; 95% CI: 0.27-0.59; P < 0.0001)., Conclusions: In STRONG-HF, intensive uptitration of neurohormonal blockade was associated with more efficient and sustained decongestion at day 90 and a lower risk of the primary endpoint., Competing Interests: Funding Support and Author Disclosures The study was funded through a grant provided to Heart Initiative by Roche Diagnostics International. Dr Mebazaa has received grants from Roche Diagnostics, Abbott Laboratories, 4TEEN4, and Windtree Therapeutics; has received honoraria for lectures from Roche Diagnostics, Bayer, and MSD; is a consultant for Corteria Pharmaceuticals, S-form Pharma, FIRE-1, Implicity, 4TEEN4, and Adrenomed; and is coinventor of a patent on combination therapy for patients having acute or persistent dyspnea. Drs Cotter and Davison are directors of Heart Initiative, a nonprofit organization, and employees of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. Dr Cohen-Solal has received honoraria for lectures or consultancy from AstraZeneca, Novartis, Vifor, Bayer, Merck, Sanofi, Abbott, and Boehringer Ingelheim. Dr Metra has received personal fees from Amgen, LivaNova, and Vifor Pharma as a member of executive committees of sponsored clinical trials; and from AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, and Roche Diagnostics for participation to advisory boards or for speaking at sponsored meetings. Mr Edwards, Drs Barros, Novosadova, and Takagi are employees of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. Dr Chioncel has received grants from Servier. Dr Diaz has received supporting fees for coordination of STRONG-HF trial activities. Dr Filippatos has received lecture fees or was a committee member for trials and registries sponsored by Bayer, Vifor, Boehringer Ingelheim, Medtronic, Servier, and Amgen. Dr Sliwa has received grants from Medtronic and Servier; and has received honoraria from MSD, Novartis, and Sanofi. Dr Voors has received consultancy fees or research support from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cytokinetics, Myocardia, Merck, Novartis, Novo Nordisk, and Roche Diagnostics. Dr Damasceno works for the Faculty of Medicine, Eduardo Mondlane University (Maputo, Mozambique), which received research grants from the Heart Initiative for their participation in this study. Dr Pang has received grants or research contracts from the American Heart Association, Roche, Siemens, Ortho Diagnostics, Abbott, Beckman Coulter, and Siemens; has received consulting fees from Roche; has received honoraria from WebMD; and has financial interest in The Heart Course. Dr Čelutkienė has received personal fees from Novartis, AstraZeneca, Boehringer Ingelheim, Roche Diagnostics, and Pfizer. Dr Lam 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 a consultant for or on the Advisory Board/Steering Committee/Executive Committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc., EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd., Redcardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as co-founder and nonexecutive director of Us2.ai. Dr Pagnesi has received personal fees from Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, and Vifor Pharma. Dr Arrigo has received speaker fees from Abbott Vascular and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Influenza A results in significant morbidity and mortality. VIR-2482, an engineered human monoclonal antibody with extended half-life, targets a highly conserved epitope on the stem region of influenza A hemagglutinin, and may protect against seasonal and pandemic influenza., Methods: This double-blind, randomized, placebo-controlled, phase 2 study examined the safety and efficacy of VIR-2482 for seasonal influenza A illness prevention in unvaccinated healthy adults. Participants (N = 2977) were randomized 1:1:1 to receive VIR-2482 450 mg, VIR-2482 1200 mg, or placebo via intramuscular (IM) injection. Primary and secondary efficacy endpoints were the proportions of participants with reverse transcriptase-polymerase chain reaction (RT-PCR)-confirmed influenza A infection and either protocol-defined influenza-like illness (ILI) and Centers for Disease Control and Prevention (CDC)-defined ILI or World Health Organization (WHO)-defined ILI, respectively., Results: VIR-2482 450 mg and 1200 mg prophylaxis did not reduce the risk of protocol-defined ILI with RT-PCR-confirmed influenza A versus placebo (relative risk reduction [RRR], 3.8% [95% CI: -67.3, 44.6] and 15.9% [95% CI: -49.3, 52.3], respectively). At the 1200 mg dose, the RRRs in influenza A illness were 57.2% [95% CI: -2.5, 82.2] using CDC-ILI and 44.1% [95% CI: -50.5, 79.3] using WHO-ILI definitions, respectively. Serum VIR-2482 levels were similar regardless of influenza status; variants with reduced VIR-2482 susceptibility were not detected. Local injection-site reactions were mild and similar across groups., Conclusion: VIR-2482 1200 mg IM was well tolerated but did not significantly prevent protocol-defined ILI. Secondary endpoint analyses suggest this dose may have reduced influenza A illness., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The Accreditation Council for Graduate Medical Education has tasked residency programs to prioritize resident wellness, reduce trainee stress, and prevent burnout. Grief and bereavement can significantly impact residents' wellness during difficult clinical training schedules. There are no best practices on how to support residents during this time., Methods: In a split academic county emergency medicine (EM) residency, this pilot study documents a resident-driven change to scheduling practices for bereavement leave. An advisory group of residents, chief residents, and program directors informally polled peer institutions to develop bereavement leave guidelines. Considerations were made to balance resident wellness, education, and patient care in developing a bereavement scheduling policy., Results: The bereavement policy was adopted in January 2023, aiming to "support the resident during a difficult time and reduce concerns around shift coverage" following the death of a family member without impacting sick call. The number of covered days depended on the relationship of the resident to the deceased. Residents covering bereavement days for their peers were financially compensated. During the first 7 months following implementation, five residents utilized the policy. These residents noted this to be the most positive impact on the residency during the past year. Based on resident feedback, the scope was expanded to include grave medical illness of a family member as an implementation criterion., Conclusions: This article outlines the creation, implementation, and benefits of a bereavement scheduling policy within an EM residency. Describing this approach will provide guidance for other residencies to adopt similar wellness-focused strategies., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). AEM Education and Training published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.)

Background and Objectives: Hospitals and clinicians increasingly are reimbursed based on quality of care through financial incentives tied to value-based purchasing. Patient-centered care, measured through patient experience surveys, is a key component of many quality incentive programs. We hypothesize that operational aspects such as wait times are an important element of emergency department (ED) patient experience. The objectives of this paper are to determine (1) the association between ED wait times and patient experience and (2) whether patient comments show awareness of wait times., Methods: This is a cross-sectional observational study from January 1, 2019, to December 31, 2020, across 16 EDs within a regional health care system. Patient and operations data were obtained as secondary data through internal sources and merged with primary patient experience data from our data analytics team. Dependent variables are (1) the association between ED wait times in minutes and patient experience ratings and (2) the association between wait times in minutes and patient comments including the term wait (yes/no). Patients rated their "likelihood to recommend (LTR) an ED" on a 0 to 10 scale (categories: "Promoter" = 9-10, "Neutral" = 7-8, or "Detractor" = 0-6). Our aggregate experience rating, or Net Promoter Score (NPS), is calculated by the following formula for each distinct wait time (rounded to the nearest minute): NPS = 100* (# promoters - # detractors)/(# promoters + # neutrals + # detractors). Independent variables for patient age and gender and triage acuity, were included as potential confounders. We performed a mixed-effect multivariate ordinal logistic regression for the rating category as a function of 30 minutes waited. We also performed a logistic regression for the percentage of patients commenting on the wait as a function of 30 minutes waited. Standard errors are adjusted for clustering between the 16 ED sites., Results: A total of 50 833 unique participants completed an experience survey, representing a response rate of 8.1%. Of these respondents, 28.1% included comments, with 10.9% using the term "wait." The odds ratio for association of a 30-minute wait with LTR category is 0.83 [0.81, 0.84]. As wait times increase, the odds of commenting on the wait increase by 1.49 [1.46, 1.53]. We show policy-relevant bubble plot visualizations of these two relationships., Conclusions: Patients were less likely to give a positive patient experience rating as wait times increased, and this was reflected in their comments. Improving on the factors contributing to ED wait times is essential to meeting health care systems' quality initiatives., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies (STRONG-HF) demonstrated the safety and efficacy of rapid up-titration of guideline-directed medical therapy (GDMT) with high-intensity care (HIC) compared with usual care in patients hospitalized for acute heart failure (HF). In the HIC group, the following safety indicators were used to guide up-titration: estimated glomerular filtration rate of <30 mL/min/1.73 m 2 , serum potassium of >5.0 mmol/L, systolic blood pressure (SBP) of <95 mmHg, heart rate of <55 bpm, and N-terminal pro-B-type natriuretic peptide concentration of >10% higher than predischarge values., Methods and Results: We examined the impact of protocol-specified safety indicators on achieved dose of GDMT and clinical outcomes. Three hundred thirteen of the 542 patients in the HIC arm (57.7%) met ≥1 safety indicator at any follow-up visit 1-6 weeks after discharge. As compared with those without, patients meeting ≥1 safety indicator had more severe HF symptoms, lower SBP, and higher heart rate at baseline and achieved a lower average percentage of GDMT optimal doses (mean difference vs the HIC arm patients not reaching any safety indicator, -11.0% [95% confidence interval [CI] -13.6 to -8.4%], P < .001). The primary end point of 180-day all-cause death or HF readmission occurred in 15.0% of patients with any safety indicator vs 14.2% of those without (adjusted hazard ratio 0.84, 95% CI 0.48-1.46, P = .540). None of each of the safety indicators, considered alone, was significantly associated with the primary end point, but an SBP of <95 mm Hg was associated with a trend toward increased 180-day all-cause mortality (adjusted hazard ratio 2.68, 95% CI 0.94-7.64, P = .065) and estimated glomerular filtration rate decreased to <30 mL/min/1.73 m 2 with more HF readmissions (adjusted hazard ratio 3.60, 95% CI 1.22-10.60, P = .0203). The occurrence of a safety indicator was associated with a smaller 90-day improvement in the EURO-QoL 5-Dimension visual analog scale (adjusted mean difference -3.32 points, 95% CI -5.97 to -0.66, P = .015)., Conclusions: Among patients with acute HF enrolled in STRONG-HF in the HIC arm, the occurrence of any safety indicator was associated with the administration of slightly lower GDMT doses and less improvement in quality of life, but with no significant increase in the primary outcome of 180-day HF readmission or death when appropriately addressed according to the study protocol., Competing Interests: Declaration of Competing Interest None, (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This analysis provides details on baseline and changes in quality of life (QoL) and its components as measured by EQ-5D-5L questionnaire, as well as association with objective outcomes, applying high-intensity heart failure (HF) care in patients with acute HF., Methods: In STRONG-HF trial (Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by NT-proBNP Testing, of Heart Failure Therapies) patients with acute HF were randomized just before discharge to either usual care or a high-intensity care strategy of guideline-directed medical therapy up-titration. Patients ranked their state of health on the EQ-5D visual analog scale score ranging from 0 (the worst imaginable health) to 100 (the best imaginable health) at baseline and at 90 days follow-up., Results: In 1072 patients with acute HF with available assessment of QoL (539/533 patients assigned high-intensity care/usual care) the mean baseline EQ-visual analog scale score was 59.2 (SD, 15.1) with no difference between the treatment groups. Patients with lower baseline EQ-visual analog scale (meaning worse QoL) were more likely to be women, self-reported Black and non-European ( P <0.001). The strongest independent predictors of a greater improvement in QoL were younger age ( P <0.001), no HF hospitalization in the previous year ( P <0.001), lower NYHA class before hospital admission ( P <0.001) and high-intensity care treatment (mean difference, 4.2 [95% CI, 2.5-5.8]; P <0.001). No statistically significant heterogeneity in the benefits of high-intensity care was seen across patient subgroups of different ages, with left ventricular ejection fraction above or below 40%, NT-proBNP (N-terminal pro-B-type natriuretic peptide) and systolic blood pressure above or below the median value. The treatment effect on the primary end point did not vary significantly across baseline EQ-visual analog scale ( P interaction =0.87)., Conclusions: Early up-titration of guideline-directed medical therapy significantly improves all dimensions of QoL in patients with HF and improves prognosis regardless of baseline self-assessed health status. The likelihood of achieving optimal doses of HF medications does not depend on baseline QoL., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03412201., Competing Interests: Disclosures Dr Mebazaa has received grants from Roche Diagnostics, Abbott Laboratories, 4TEEN4, and Windtree Therapeutics; honoraria for lectures from Roche Diagnostics, Bayer, and MSD; is a consultant for Corteria Pharmaceuticals, S-form Pharma, FIRE-1, Implicity, 4TEEN4, and Adrenomed; and is coinventor of a patent on combination therapy for patients having acute or persistent dyspnoea. Drs Davison, Barros, Novosadova, Takagi, Cotter, and C. Edwards are employees of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. Drs Davison and Cotter are directors of Heart Initiative a nonprofit organization. Dr Adamo has received speaker fees from Abbott Vascular and Medtronic. Dr Čelutkienė has received personal fees from Novartis, AstraZeneca, Boehringer Ingelheim, Roche Diagnostics, and Pfizer. Dr Cohen-Solal has received honoraria for lectures or consultancy from AstraZeneca, Novartis, Vifor, Bayer, Merck, Sanofi, Abbott, and Boehringer Ingelheim. Dr Chioncel received grants from Servier. Dr Damasceno works for the Faculty of Medicine, Eduardo Mondlane University (Maputo, Mozambique), which received research grants from the Heart Initiative for their participation in this study. Dr Diaz has received supporting fees for coordination of STRONG-HF trial activities. Dr Filippatos has received lecture fees or was a committee member for trials and registries sponsored by Bayer, Vifor, Boehringer Ingelheim, Medtronic, Servier and Amgen. Dr Pagnesi has received personal fees from Abbott Laboratories, AstraZeneca, Boehringer Ingelheim and Vifor Pharma. Dr Pang has received grants or research contracts from American Heart Association, Roche, Siemens, Ortho Diagnostics, Abbott, Beckman Coulter, and Siemens; consulting fees from Roche; honoraria from WebMD; and he has financial interest in The Heart Course. Dr Sliwa has received grants from Medtronic, Servier, and Amylam and honoraria from MSD, Novartis, and Sanofi. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Novo Nordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd, Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as cofounder and nonexecutive director of Us2.ai. Dr Voors has received consultancy fees or research support from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cytokinetics, Myocardia, Merck, Novartis, Novo Nordisk, and Roche Diagnostics. All other authors declare no conflicts.

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 (p interaction  = 0.77) or as a continuous variable (p interaction  = 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., (© 2024 European Society of Cardiology.)

Importance: The Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by N-Terminal Pro-Brain Natriuretic Peptide Testing of Heart Failure Therapies (STRONG-HF) trial strived for rapid uptitration aiming to reach 100% optimal doses of guideline-directed medical therapy (GDMT) within 2 weeks after discharge from an acute heart failure (AHF) admission., Objective: To assess the association between degree of GDMT doses achieved in high-intensity care and outcomes., Design, Setting, and Participants: This was a post hoc secondary analysis of the STRONG-HF randomized clinical trial, conducted from May 2018 to September 2022. Included in the study were patients with AHF who were not treated with optimal doses of GDMT before and after discharge from an AHF admission. Data were analyzed from January to October 2023., Interventions: The mean percentage of the doses of 3 classes of HF medications (renin-angiotensin system inhibitors, β-blockers, and mineralocorticoid receptor antagonists) relative to their optimal doses was computed. Patients were classified into 3 dose categories: low (<50%), medium (≥50% to <90%), and high (≥90%). Dose and dose group were included as a time-dependent covariate in Cox regression models, which were used to test whether outcomes differed by dose., Main Outcome Measures: Post hoc secondary analyses of postdischarge 180-day HF readmission or death and 90-day change in quality of life., Results: A total of 515 patients (mean [SD] age, 62.7 [13.4] years; 311 male [60.4%]) assigned high-intensity care were included in this analysis. At 2 weeks, 39 patients (7.6%) achieved low doses, 254 patients (49.3%) achieved medium doses, and 222 patients (43.1%) achieved high doses. Patients with lower blood pressure and more congestion were less likely to be uptitrated to optimal GDMT doses at week 2. As a continuous time-dependent covariate, an increase of 10% in the average percentage optimal dose was associated with a reduction in 180-day HF readmission or all-cause death (primary end point: adjusted hazard ratio [aHR], 0.89; 95% CI, 0.81-0.98; P = .01) and a decrease in 180-day all-cause mortality (aHR, 0.84; 95% CI, 0.73-0.95; P = .007). Quality of life at 90 days, measured by the EQ-5D visual analog scale, improved more in patients treated with higher doses of GDMT (mean difference, 0.10; 95% CI, -4.88 to 5.07 and 3.13; 95% CI, -1.98 to 8.24 points in the medium- and high-dose groups relative to the low-dose group, respectively; P = .07). Adverse events to day 90 occurred less frequently in participants with HIC who were prescribed higher GDMT doses at week 2., Conclusions and Relevance: Results of this post hoc analysis of the STRONG-HF randomized clinical trial show that, among patients randomly assigned to high-intensity care, achieving higher doses of HF GDMT 2 weeks after discharge was feasible and safe in most patients., Trial Registration: ClinicalTrials.gov Identifier: NCT03412201.

Importance: More than 80% of patients who present to the emergency department (ED) with acute heart failure (AHF) are hospitalized. With more than 1 million annual hospitalizations for AHF in the US, safe and effective alternatives are needed. Care for AHF in short-stay units (SSUs) may be safe and more efficient than hospitalization, especially for lower-risk patients, but randomized clinical trial data are lacking., Objective: To compare the effectiveness of SSU care vs hospitalization in lower-risk patients with AHF., Design, Setting, and Participants: This multicenter randomized clinical trial randomly assigned low-risk patients with AHF 1:1 to SSU or hospital admission from the ED. Patients received follow-up at 30 and 90 days post discharge. The study began December 6, 2017, and was completed on July 22, 2021. The data were analyzed between March 27, 2020, and November 11, 2023., Intervention: Randomized post-ED disposition to less than 24 hours of SSU care vs hospitalization., Main Outcomes and Measures: The study was designed to detect at least 1-day superiority for a primary outcome of days alive and out of hospital (DAOOH) at 30-day follow-up for 534 participants, with an allowance of 10% participant attrition. Due to the COVID-19 pandemic, enrollment was truncated at 194 participants. Before unmasking, the primary outcome was changed from DAOOH to an outcome with adequate statistical power: quality of life as measured by the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12). The KCCQ-12 scores range from 0 to 100, with higher scores indicating better quality of life., Results: Of the 193 patients enrolled (1 was found ineligible after randomization), the mean (SD) age was 64.8 (14.8) years, 79 (40.9%) were women, and 114 (59.1%) were men. Baseline characteristics were balanced between arms. The mean (SD) KCCQ-12 summary score between the SSU and hospitalization arms at 30 days was 51.3 (25.7) vs 45.8 (23.8) points, respectively (P = .19). Participants in the SSU arm had 1.6 more DAOOH at 30-day follow-up than those in the hospitalization arm (median [IQR], 26.9 [24.4-28.8] vs 25.4 [22.0-27.7] days; P = .02). Adverse events were uncommon and similar in both arms., Conclusions and Relevance: The findings show that the SSU strategy was no different than hospitalization with regard to KCCQ-12 score, superior for more DAOOH, and safe for lower-risk patients with AHF. These findings of lower health care utilization with the SSU strategy need to be definitively tested in an adequately powered study., Trial Registration: ClinicalTrials.gov Identifier: NCT03302910.

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

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., (© 2023 European Society of Cardiology.)

Background & Aims: Current therapy for chronic hepatitis B virus (cHBV) infection involves lifelong treatment. New treatments that enable HBV functional cure would represent a clinically meaningful advance. ALN-HBV and VIR-2218 are investigational RNA interference therapeutics that target all major HBV transcripts., Methods: We report on: i) the safety of single doses of VIR-2218 (modified from ALN-HBV by enhanced stabilization chemistry plus technology to reduce off-target, seed-mediated binding while maintaining on-target antiviral activity) and ALN-HBV in humanized mice; ii) a cross-study comparison of the safety of single doses of VIR-2218 and ALN-HBV in healthy human volunteers (n = 24 and n = 49, respectively); and iii) the antiviral activity of two doses of 20, 50, 100, 200 mg of VIR-2218 (total n = 24) vs. placebo (n = 8), given 4 weeks apart, in participants with cHBV infection., Results: In humanized mice, alanine aminotransferase (ALT) levels were markedly lower following administration of VIR-2218 compared with ALN-HBV. In healthy volunteers, post-treatment ALT elevations occurred in 28% of participants receiving ALN-HBV compared with none in those receiving VIR-2218. In participants with cHBV infection, VIR-2218 was associated with dose-dependent reductions in hepatitis B surface antigen (HBsAg). The greatest mean reduction of HBsAg at Week 20 in participants receiving 200 mg was 1.65 log IU/ml. The HBsAg reduction was maintained at 0.87 log IU/ml at Week 48. No participants had serum HBsAg loss or hepatitis B surface antibody seroconversion., Conclusions: VIR-2218 demonstrated an encouraging hepatic safety profile in preclinical and clinical studies as well as dose-dependent HBsAg reductions in patients with cHBV infection. These data support future studies with VIR-2218 as part of combination regimens with a goal of HBV functional cure., Trial Registration: ClinicalTrials.gov identifiers: NCT02826018 and NCT03672188., Impact and Implications: A significant unmet need exists for therapies for chronic HBV (cHBV) infection that achieve functional cure. We report clinical and non-clinical data on two investigational small-interfering RNAs that target HBx, ALN-HBV and VIR-2218, demonstrating that incorporation of enhanced stabilization chemistry plus technology in VIR-2218 reduces its propensity to cause ALT elevations relative to its parent compound, ALN-HBV. We also show that VIR-2218 reduces hepatitis B surface antigen levels in a dose-dependent manner in participants with cHBV infection. These studies support the continued development of VIR-2218 as part of therapeutic regimens for cHBV infection, with the goal of a functional cure, and are important for HBV researchers and physicians., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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

Aims: STRONG-HF showed that rapid up-titration of guideline-recommended medical therapy (GRMT), in a high intensity care (HIC) strategy, was associated with better outcomes compared with usual care. The aim of this study was to assess the role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and its changes early during up-titration., Methods and Results: A total of 1077 patients hospitalized for acute heart failure (HF) and with a >10% NT-proBNP decrease from screening (i.e. admission) to randomization (i.e. pre-discharge), were included. Patients in HIC were stratified by further NT-proBNP changes, from randomization to 1 week later, as decreased (≥30%), stable (<30% decrease to ≤10% increase), or increased (>10%). The primary endpoint was 180-day HF readmission or death. The effect of HIC vs. usual care was independent of baseline NT-proBNP. Patients in the HIC group with stable or increased NT-proBNP were older, with more severe acute HF and worse renal and liver function. Per protocol, patients with increased NT-proBNP received more diuretics and were up-titrated more slowly during the first weeks after discharge. However, by 6 months, they reached 70.4% optimal GRMT doses, compared with 80.3% for those with NT-proBNP decrease. As a result, the primary endpoint at 60 and 90 days occurred in 8.3% and 11.1% of patients with increased NT-proBNP vs. 2.2% and 4.0% in those with decreased NT-proBNP (P = 0.039 and P = 0.045, respectively). However, no difference in outcome was found at 180 days (13.5% vs. 13.2%; P = 0.93)., Conclusion: Among patients with acute HF enrolled in STRONG-HF, HIC reduced 180-day HF readmission or death regardless of baseline NT-proBNP. GRMT up-titration early post-discharge, utilizing increased NT-proBNP as guidance to increase diuretic therapy and reduce the GRMT up-titration rate, resulted in the same 180-day outcomes regardless of early post-discharge NT-proBNP change., Competing Interests: Conflict of interest: A.M. has received grants from Roche Diagnostics, Abbott Laboratories, 4TEEN4, and Windtree Therapeutics; honoraria for lectures from Roche Diagnostics, Bayer, and MSD; is a consultant for Corteria Pharmaceuticals, S-form Pharma, FIRE-1, Implicity, 4TEEN4, and Adrenomed; and is coinventor of a patent on combination therapy for patients having acute or persistent dyspnoea. G.C. is employee of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. .G.C. is director of Heart Initiative, a non-profit organization. B.D. is employee of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. B.D. is director of Heart Initiative, a non-profit organization. A.C.S. has received honoraria for lectures or consultancy from AstraZeneca, Novartis, Vifor, Bayer, Merck, Sanofi, Abbott, and Boehringer Ingelheim. M.M. has received personal fees from Amgen, Livanova, and Vifor Pharma as a member of executive committees of sponsored clinical trials and from AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, and Roche Diagnostics for participation to advisory boards or for speaking at sponsored meetings. C.E. is employee of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. O.C. received grants from Servier. R.D. has received supporting fees for coordination of STRONG-HF trial activities. G.F. has received lecture fees or was a committee member for trials and registries sponsored by Bayer, Vifor, Boehringer Ingelheim, Medtronic, Servier, and Amgen. K.S. has received grants from Medtronic, Servier, and Amylam and honoraria from MSD, Novartis, and Sanofi. A.A.V. has received consultancy fees or research support from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cytokinetics, Myocardia, Merck, Novartis, Novo Nordisk, and Roche Diagnostics. MN is employee of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. KT is employee of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. A.D. works for the Faculty of Medicine, Eduardo Mondlane University (Maputo, Mozambique), which received research grants from the Heart Initiative for their participation in this study. P.S.P. has received grants or research contracts from American Heart Association, Roche, Siemens, Ortho Diagnostics, Abbott, Beckman Coulter, and Siemens; consulting fees from Roche; honoraria from WebMD; and he has financial interest in The Heart Course. J.C. has received personal fees from Novartis, AstraZeneca, Boehringer Ingelheim, Roche Diagnostics, and Pfizer. C.S.P.L. 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/Executive Committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc., EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd., Redcardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and serves as co-founder and non-executive director of Us2.ai. M.P. has received personal fees from Abbott Laboratories, AstraZeneca, Boehringer Ingelheim and Vifor Pharma. MA has received speaker fees from Abbott Vascular and Medtronic. M.B. is employee of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. The other authors have no conflicts to report., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Convenient administration of coronavirus disease 2019 (COVID-19) treatment in community settings is desirable. Sotrovimab is a pan-sarbecovirus dual-action monoclonal antibody formulated for intravenous (IV) or intramuscular (IM) administration for early treatment of mild/moderate COVID-19., Method: This multicenter phase 3 study based on a randomized open-label design tested the noninferiority of IM to IV administration according to an absolute noninferiority margin of 3.5%. From June to August 2021, patients aged ≥12 years with COVID-19, who were neither hospitalized nor receiving supplemental oxygen but were at high risk for progression, were randomized 1:1:1 to receive sotrovimab as a single 500-mg IV infusion or a 500- or 250-mg IM injection. The primary composite endpoint was progression to (1) all-cause hospitalization for >24 hours for acute management of illness or (2) all-cause death through day 29., Results: Sotrovimab 500 mg IM was noninferior to 500 mg IV: 10 (2.7%) of 376 participants vs 5 (1.3%) of 378 met the primary endpoint, respectively (absolute adjusted risk difference, 1.06%; 95% CI, -1.15% to 3.26%). The 95% CI upper limit was lower than the prespecified noninferiority margin of 3.5%. The 250-mg IM group was discontinued early because of the greater proportion of hospitalizations vs the 500-mg groups. Serious adverse events occurred in <1% to 2% of participants across groups. Four participants experienced serious disease-related events and died (500 mg IM, 2/393, <1%; 250 mg IM, 2/195, 1%)., Conclusions: Sotrovimab 500-mg IM injection was well tolerated and noninferior to IV administration. IM administration could expand outpatient treatment access for COVID-19., Clinical Trials Registration: ClinicalTrials.gov: NCT04913675., Competing Interests: Potential conflicts of interest. A. E. S., J. A., A. F., Y. G.-R., R. H., E. J., J. M., and N. P. report acting as trial investigators for Vir Biotechnology and receiving nonfinancial support from Vir Biotechnology during the conduct of the study. A. K. reports acting as a trial investigator for Vir Biotechnology and receiving nonfinancial support from Vir Biotechnology during the conduct of the study; grants and consulting fees from Gilead Biosciences; and clinical trial payments from Regeneron, Vir Biotechnology, GSK, and Gilead Biosciences. A. K. also reports serving on data safety monitoring or advisory boards for Gilead Biosciences. E. S. reports acting as a trial investigator for Vir Biotechnology and receiving nonfinancial support from Vir Biotechnology during the conduct of the study and research support from AbbVie, Eli Lilly, Otsuka, Eisai, and Ironshore. E. S. also reports serving on speaker bureaus for Janssen, Teva, and AbbVie. D. C., M. L. A., S. P., S. C., E. M., J. E. S., W. W. Y., E. L. A., and L. A. G. are employees of Vir Biotechnology and report stock ownership in Vir Biotechnology and third-party funding from GSK to Vir Biotechnology for the submitted work. P. S. P. is an employee of Vir Biotechnology and reports stock ownership in Vir Biotechnology, third-party funding from GSK to Vir Biotechnology for the submitted work, and patents pending for sotrovimab for the treatment of COVID-19. D. K. H. was an employee of Vir Biotechnology and held stock in Vir Biotechnology at the time of the study; he is currently an employee of Janssen Pharmaceutical Companies of Johnson & Johnson and reports stock ownership in Johnson & Johnson. D. I., A. S., D. A., A. P., A. N., N. N., and Q. W. are employees of GSK and report stock ownership in GSK., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: We aimed to study whether improvement in renal function by serelaxin in patients who were hospitalized for acute heart failure (HF) might explain any potential effect on clinical outcomes., Methods: We included 6318 patients from the RELAXin in AHF-2 (RELAX-AHF2) study. Improvement in renal function was defined as a decrease in serum creatinine of ≥ 0.3 mg/dL and ≥ 25%, or increase in estimated glomerular filtration rate of ≥ 25% between baseline and day 2. Worsening renal function (WRF) was defined as the reverse. We performed causal mediation analyses regarding 180-day all-cause mortality (ACM), cardiovascular death (CVD), and hospitalization for HF/renal failure., Results: Improvement in renal function was more frequently observed with serelaxin when compared with placebo [OR 1.88 (95% CI 1.64-2.15, p < 0.0001)], but was not associated with subsequent clinical outcomes. WRF occurred less frequent with serelaxin [OR 0.70 (95% CI 0.60-0.83, p < 0.0001)] and was associated with increased risk of ACM, worsening HF and the composite of CVD and HF or renal failure hospitalization. Improvement in renal function did not mediate the treatment effect of serelaxin [CVD HR 1.01 (0.99-1.04), ACM HR 1.01 (0.99-1.03), HF/renal failure hospitalization HR 0.99 (0.97-1.00)]., Conclusions: Despite the significant improvement in renal function by serelaxin in patients with acute HF, the potential beneficial treatment effect was not mediated by improvement in renal function. These data suggest that improvement in renal function might not be a suitable surrogate marker for potential treatment efficacy in future studies with novel relaxin agents in acute HF. Central illustration. Conceptual model explaining mediation analysis; treatment efficacy of heart failure therapies mediated by renal function., (© 2023. The Author(s).)

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

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

Background: Acute heart failure (AHF) is associated with a poor prognosis regardless of left ventricular ejection fraction (LVEF). STRONG-HF showed the efficacy and safety of a strategy of rapid uptitration of oral treatment for heart failure (HF) and close follow-up (high-intensity care), compared with usual care, in patients recently hospitalized for AHF and enrolled independently from their LVEF., Objectives: In this study, we sought to assess the impact of baseline LVEF on the effects of high-intensity care vs usual care in STRONG-HF., Methods: The STRONG-HF trial enrolled patients hospitalized for AHF with any LVEF and not treated with full doses of renin-angiotensin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. High-intensity care with uptitration of oral medications was performed independently from LVEF. The primary endpoint was the composite of HF rehospitalization or all-cause death at day 180., Results: Among the 1,078 patients randomized, 731 (68%) had LVEF ≤40% and 347 (32%) had LVEF >40%. The treatment benefit of high-intensity care vs usual care on the primary endpoint was consistent across the whole LVEF spectrum (interaction P with LVEF as a continuous variable = 0.372). Mean difference in the EQ-5D visual analog scale change from baseline to day 90 between treatment arms was slightly greater at higher LVEF values, but with no interaction between LVEF as a continuous variable and the treatment strategy (interaction P = 0.358). Serious adverse events were also independent from LVEF., Conclusions: Rapid uptitration of oral medications for HF and close follow-up reduce 180-day death and HF rehospitalization after AHF hospitalization independently from LVEF. (Safety, Tolerability and Efficacy of Rapid Optimization, Helped by NT-ProBNP Testing, of Heart Failure Therapies [STRONG-HF]; NCT03412201)., Competing Interests: Funding Support and Author Disclosures Funding for this study was provided by a grant to the Heart Initiative from Roche Diagnostics International. Dr Pagnesi has received personal fees from Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, and Vifor Pharma. Dr Metra has received personal fees from Actelion, Amgen, Livanova, and Vifor Pharma as a member of executive or data monitoring committees of sponsored clinical trials; and has received personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, and Roche Diagnostics for participation in advisory boards or for speaking at sponsored meetings. Dr Cohen-Solal has received honoraria for lectures or consultancy from AstraZeneca, Novartis, Vifor, Bayer, Merck, Sanofi, Abbott, and Boehringer Ingelheim. Drs Edwards, Novosadova, Takagi, Barros, Cotter, and Davison are employees of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. Drs Cotter and Davison are directors of the Heart Initiative, a nonprofit organization. Dr Adamo has received speaker fees from Abbott Vascular and Medtronic. Dr Lam 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 to 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, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development, Medscape/WebMD Global, Merck, Novartis, Novo Nordisk, Prosciento, Radcliffe Group, Redcardio, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as cofounder and nonexecutive director of Us2.ai. Dr Chioncel has received grants from Servier. Dr Diaz has received supporting fees for coordination of STRONG-HF trial activities. Dr Filippatos has received lecture fees or was a committee member for trials and registries sponsored by Bayer, Vifor, Boehringer Ingelheim, Medtronic, Servier, and Amgen. Dr Sliwa has received grants from Medtronic, Servier, and Amylam; and has received honoraria from MSD, Novartis, and Sanofi. Dr Voors has received consultancy fees or research support from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cytokinetics, Myocardia, Merck, Novartis, Novo Nordisk, and Roche Diagnostics. Dr Damasceno’s institute received research grants from the Heart Initiative for their participation in this study. Dr Pang has received grants or research contracts from the American Heart Association, Roche, Siemens, Ortho Diagnostics, Abbott, Beckman Coulter, and Siemens; has received consulting fees from Roche; has received honoraria from WebMD; and has financial interest in The Heart Course. Dr Celutkiene has received personal fees from Novartis, AstraZeneca, Boehringer Ingelheim, Roche Diagnostics, and Pfizer. Dr Mebazaa has received grants from Roche Diagnostics, Abbott Laboratories, 4TEEN4, and Windtree Therapeutics; has received honoraria for lectures from Roche Diagnostics, Bayer, and MSD; is a consultant for Corteria Pharmaceuticals, S-form Pharma, FIRE-1, Implicity, 4TEEN4, and Adrenomed; and is coinventor of a patent on combination therapy for patients having acute or persistent dyspnea. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023. Published by Elsevier Inc.)

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

Background: We investigated the role of the dynamic changes of pulmonary congestion, as assessed by sonographic B-lines, as a tool to stratify prognosis in patients admitted for acute heart failure with reduced and preserved ejection fraction (HFrEF, HFpEF)., Methods: In this multicenter, prospective study, lung ultrasound was performed at admission and before discharge by trained investigators, blinded to clinical findings., Results: We enrolled 208 consecutive patients (mean age 76 [95% confidence interval, 70-84] years), 125 with HFrEF, 83 with HFpEF (mean ejection fraction 32% and 57%, respectively). The primary composite endpoint of cardiovascular death or HF re-hospitalization occurred in 18% of patients within 6 months. In the overall population, independent predictors of the occurrence of the primary endpoint were the number of B-lines at discharge, NT-proBNP levels, moderate-to-severe mitral regurgitation, and inferior vena cava diameter on admission. B-lines at discharge were the only independent predictor in both HFrEF and HFpEF subgroups. A cut-off of B-lines > 15 at discharge displayed the highest accuracy in predicting the primary endpoint (AUC = 0.80, p < 0.0001). Halving B-lines during hospitalization further improved event classification (continuous net reclassification improvement = 22.8%, p = 0.04)., Conclusions: The presence of residual subclinical sonographic pulmonary congestion at discharge predicts 6-month clinical outcomes across the whole spectrum of acute HF patients, independent of conventional biohumoral and echocardiographic parameters. Achieving effective pulmonary decongestion during hospitalization is associated with better outcomes.

Aim: Recent data suggest that guideline-directed medical therapy of patients with heart failure (HF) with reduced ejection fraction (HFrEF) might improve clinical outcomes in patients with HF up to a left ventricular ejection fraction (LVEF) of 55-65%, whereas patients with higher LVEF do not seem to benefit. Recent data have shown that LVEF may have a U-shaped relation with outcome, with poorer outcome also in patients with supranormal values. This suggests that patients with supranormal LVEF may be a distinctive group of patients., Methods and Results: RELAX-AHF-2 was a multicentre, placebo-controlled trial on the effects of serelaxin on 180-day cardiovascular (CV) mortality and worsening HF at day 5 in patients with acute HF. Echocardiograms were performed at hospital admission in 6128 patients: 155 (2.5%) patients were classified as HF with supranormal ejection fraction (HFsnEF; LVEF >65%), 1440 (23.5%) as HF with preserved ejection fraction (HFpEF; LVEF 50-65%), 1353 (22.1%) as HF with mildly reduced ejection fraction (HFmrEF; LVEF 41-49%) and 3180 (51.9%) as HFrEF (LVEF <40%). Patients with HFsnEF compared to HFpEF were more often women, had higher prevalence of non-ischaemic HF, had lower levels of natriuretic peptides, were less likely to be treated with beta-blockers and had higher blood urea nitrogen plasma levels. All-cause mortality was not statistically different between groups, although patients with HFsnEF had the highest numerical rate. A declining trend was seen in the proportion of 180-day deaths due to CV causes from HFrEF (290/359, 80.8%) to HFsnEF (14/24, 58.3%). The reverse was observed with death from non-CV causes. No treatment effect of serelaxin was observed in any of the subgroups., Conclusions: In this study, only 2.5% of patients were classified as HFsnEF. HFsnEF was primarily characterized by female sex, lower natriuretic peptides and a higher risk of non-CV death., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: There is a paucity of evidence for dose and pace of up-titration of guideline-directed medical therapies after admission to hospital for acute heart failure., Methods: In this multinational, open-label, randomised, parallel-group trial (STRONG-HF), patients aged 18-85 years admitted to hospital with acute heart failure, not treated with full doses of guideline-directed drug treatment, were recruited from 87 hospitals in 14 countries. Before discharge, eligible patients were randomly assigned (1:1), stratified by left ventricular ejection fraction (≤40% vs >40%) and country, with blocks of size 30 within strata and randomly ordered sub-blocks of 2, 4, and 6, to either usual care or high-intensity care. Usual care followed usual local practice, and high-intensity care involved the up-titration of treatments to 100% of recommended doses within 2 weeks of discharge and four scheduled outpatient visits over the 2 months after discharge that closely monitored clinical status, laboratory values, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations. The primary endpoint was 180-day readmission to hospital due to heart failure or all-cause death. Efficacy and safety were assessed in the intention-to-treat (ITT) population (ie, all patients validly randomly assigned to treatment). The primary endpoint was assessed in all patients enrolled at hospitals that followed up patients to day 180. Because of a protocol amendment to the primary endpoint, the results of patients enrolled on or before this amendment were down-weighted. This study is registered with ClinicalTrials.gov, NCT03412201, and is now complete., Findings: Between May 10, 2018, and Sept 23, 2022, 1641 patients were screened and 1078 were successfully randomly assigned to high-intensity care (n=542) or usual care (n=536; ITT population). Mean age was 63·0 years (SD 13·6), 416 (39%) of 1078 patients were female, 662 (61%) were male, 832 (77%) were White or Caucasian, 230 (21%) were Black, 12 (1%) were other races, one (<1%) was Native American, and one (<1%) was Pacific Islander (two [<1%] had missing data on race). The study was stopped early per the data and safety monitoring board's recommendation because of greater than expected between-group differences. As of data cutoff (Oct 13, 2022), by day 90, a higher proportion of patients in the high-intensity care group had been up-titrated to full doses of prescribed drugs (renin-angiotensin blockers 278 [55%] of 505 vs 11 [2%] of 497; β blockers 249 [49%] vs 20 [4%]; and mineralocorticoid receptor antagonists 423 [84%] vs 231 [46%]). By day 90, blood pressure, pulse, New York Heart Association class, bodyweight, and NT-proBNP concentration had decreased more in the high-intensity care group than in the usual care group. Heart failure readmission or all-cause death up to day 180 occurred in 74 (15·2% down-weighted adjusted Kaplan-Meier estimate) of 506 patients in the high-intensity care group and 109 (23·3%) of 502 patients in the usual care group (adjusted risk difference 8·1% [95% CI 2·9-13·2]; p=0·0021; risk ratio 0·66 [95% CI 0·50-0·86]). More adverse events by 90 days occurred in the high-intensity care group (223 [41%] of 542) than in the usual care group (158 [29%] of 536) but similar incidences of serious adverse events (88 [16%] vs 92 [17%]) and fatal adverse events (25 [5%] vs 32 [6%]) were reported in each group., Interpretation: An intensive treatment strategy of rapid up-titration of guideline-directed medication and close follow-up after an acute heart failure admission was readily accepted by patients because it reduced symptoms, improved quality of life, and reduced the risk of 180-day all-cause death or heart failure readmission compared with usual care., Funding: Roche Diagnostics., Competing Interests: Declaration of interests AM has received grants from Roche Diagnostics, Abbott Laboratories, 4TEEN4, and Windtree Therapeutics; honoraria for lectures from Roche Diagnostics, Bayer, and MSD; is a consultant for Corteria Pharmaceuticals, S-form Pharma, FIRE-1, Implicity, 4TEEN4, and Adrenomed; and is coinventor of a patent on combination therapy for patients having acute or persistent dyspnoea. BD and GC are directors of Heart Initiative, a non-profit organisation. BD, CE, MN, KT, and GC are employees of Momentum Research, which has received grants for research from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Corteria Pharmaceuticals, Heart Initiative, Sanofi, Windtree Therapeutics, and XyloCor Therapeutics. OC serves on an advisory board for Boehringer Ingelheim. KS has received grants from Medtronic, Servier, and Amylam and honoraria from MSD, Novartis, and Sanofi. AC-S has received honoraria for lectures or consultancy from AstraZeneca, Novartis, Vifor, Bayer, Merck, Sanofi, Abbott, and Boehringer Ingelheim. RD has received supporting fees for coordination of STRONG-HF trial activities. GF has received lecture fees or was a committee member for trials and registries sponsored by Bayer, Vifor, Boehringer Ingelheim, Medtronic, and Amgen. MM has received personal fees since January, 2021, from Actelion, Amgen, Livanova, and Vifor Pharma as a member of executive or data monitoring committees of sponsored clinical trials and from AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, and Novartis for participation in advisory boards or for speaking at sponsored meetings. AAV has received consultancy fees or research support from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cytokinetics, Myocardia, Merck, Novartis, Novo Nordisk, and Roche Diagnostics. AD works for the Faculty of Medicine, Eduardo Mondlane University (Maputo, Mozambique), which received research grants from the Heart Initiative for their participation in this study. PSP has received grants or research contracts from American Heart Association, Roche, Siemens, Ortho Diagnostics, Abbott, Beckman Coulter, and Siemens; consulting fees from Roche; honoraria from WebMD; and he has financial interest in The Heart Course. JC has received personal fees from Novartis, AstraZeneca, Boehringer Ingelheim, Roche Diagnostics, and Pfizer. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Emergency department (ED) providers play a critical role in the stabilization and diagnostic evaluation of patients presenting with acute heart failure (AHF), and EDs are key areas for establishing current best practices and future considerations for the disposition of and decision making for patients with AHF. These elements include accurate risk assessment; response to initial treatment and shared decision making concerning optimal venue of care; reframing of physicians' risk perceptions for patients presenting with AHF; exploration of alternative venues of care beyond hospitalization; population-level changes in demographics, management and outcomes of HF patients; development and testing of data-driven pathways to assist with disposition decisions in the ED; and suggested outcomes for measuring success., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Previous studies have suggested that the neutrophil-to-lymphocyte ratio (NLR) is a novel yet readily evaluable inflammatory biomarker that may be useful for determining cardiovascular prognosis during acute episodes. The study investigated the role of NLR in predicting cardiovascular (CV) outcomes in patients with acute heart failure (HF). Individual patient data from the BLAST-AHF (phase 2b study of the biased ligand of the angiotensin 2 type 1 receptor, TRV027), Pre-RELAX-AHF (phase 2b study of recombinant human relaxin-2, serelaxin), and RELAX-AHF (phase 3 study of serelaxin) randomized, placebo-controlled studies for patients with acute HF were pooled for analysis. Dyspnea visual analog scale area under the curve through day 5, worsening HF through day 5, 30-day all-cause mortality, 60-day HF/renal failure rehospitalizations or CV death, 180-day all-cause mortality, and 180-day CV death were assessed. There were several differences in the baseline characteristics of the patients divided by NLR tertile, with patients in the higher NLR having worse clinical characteristics. NLR was an independent predictor of 30-day all-cause mortality (adjusted hazard ratio [HR] per log 2 NLR increment: 1.66 [1.22 to 2.25], p = 0.001), 60-day HF/renal failure rehospitalizations or CV death: 1.33 [1.12 to 1.57], p = 0.001), 180-day all-cause mortality (adjusted HR 1.27 [1.08 to 1.50], p = 0.003), and 180-day CV death (adjusted HR 1.24 [1.04 to 1.49], p = 0.018). NLR, a readily available inflammatory biomarker, was associated with independent risk for short- and long-term adverse outcomes in acute HF, surpassing traditional markers, such as natriuretic peptides., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Heart failure (HF) is a common condition leading to activation of emergency medical services (EMS)., Objective: The aim of this study was to describe reasons given by persons with HF, family members, or other caregivers for requesting EMS activation during 911 calls., Methods: In this descriptive qualitative study, a content analysis was performed on transcribed audio files of 383 EMS requests involving 383 persons with HF in the community., Results: One hundred forty-seven calls (38.4%) were placed by the family members, 75 (19.6%) were placed by the patients, 56 (14.6%) were placed by healthcare workers or personnel from living facilities, and the remaining calls (n = 105, 27.4%) were placed by others (eg, friends, neighbors, officers). Three broad categories of symptoms, signs, and events were identified as the reasons for an EMS request. Frequently reported symptoms were breathing problems (55.4%), chest pain (18.3%), and other pain (eg, head, extremities) (16.7%). Signs included decreased consciousness (15.4%), swelling (5.7%), and bleeding (5.0%). The reported events involved falls (8.1%), heart attack (6.3%), hypoxic episodes (6.0%), stroke (5.2%), and post-hospital-discharge complications (4.7%). In most calls (74.9%), multiple reasons were reported and a combination of symptoms, signs, and events were identified. Heart failure diagnosis was mentioned in fewer than 10% of the calls., Conclusions: Overall, symptoms and signs of HF exacerbation were common reasons to activate 911 calls. Falls were frequently reported. Under the duress of the emergent situations surrounding the 911 call, callers rarely mentioned the existence of HF. Interventions are needed to guide patients with HF and their family members to promote the management of HF to reduce EMS activation as well as to activate EMS quickly for acute changes in HF conditions., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Influenza A virus's (IAV's) frequent genetic changes challenge vaccine strategies and engender resistance to current drugs. We sought to identify conserved and essential RNA secondary structures within IAV's genome that are predicted to have greater constraints on mutation in response to therapeutic targeting. We identified and genetically validated an RNA structure (packaging stem-loop 2 (PSL2)) that mediates in vitro packaging and in vivo disease and is conserved across all known IAV isolates. A PSL2-targeting locked nucleic acid (LNA), administered 3 d after, or 14 d before, a lethal IAV inoculum provided 100% survival in mice, led to the development of strong immunity to rechallenge with a tenfold lethal inoculum, evaded attempts to select for resistance and retained full potency against neuraminidase inhibitor-resistant virus. Use of an analogous approach to target SARS-CoV-2, prophylactic administration of LNAs specific for highly conserved RNA structures in the viral genome, protected hamsters from efficient transmission of the SARS-CoV-2 USA&#95;WA1/2020 variant. These findings highlight the potential applicability of this approach to any virus of interest via a process we term 'programmable antivirals', with implications for antiviral prophylaxis and post-exposure therapy., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)