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© 2015 Bentham Science Publishers.Acute decompensated heart failure (ADHF) continues to increase in prevalence and is associated with substantial mortality and morbidity including frequent hospitalizations. The American Heart Association is predicting that

Aims Serelaxin is effective in relieving dyspnoea and improving multiple outcomes in acute heart failure (AHF). Many AHF patients have preserved ejection fraction (HFpEF). Given the lack of evidence-based therapies in this population, we evaluated the effe

© 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

Background: Adenosine exerts actions in multiple organ systems, and adenosine receptors are a therapeutic target in many development programmes.Objective: The aim of this analysis was to evaluate the safety of rolofylline, an adenosine A(1)-receptor antagonist, in patients with acute heart failure.Methods: The effect of rolofylline was investigated in patients hospitalized for acute heart failure with impaired renal function. Intravenous rolofylline 30 mg or placebo was infused over 4 hours daily for up to 3 days. Adverse events (AEs) and serious AEs (SAEs) were recorded from baseline through 7 and 14 days, respectively, and clinical events were adjudicated through 60 days.Results: Of 2033 patients enrolled, 2002 received study drug randomized 2 : 1 to rolofylline or placebo. Rolofylline and placebo were associated with a similar risk of pre-specified groups of AEs or SAEs, other than selected neurological events. Investigator-reported seizures occurred in 11 (0.8%) rolofylline-treated patients and zero patients receiving placebo (p = 0.02). Stroke occurred in 21 (1.6%) patients assigned to rolofylline compared with 3 (0.5%) placebo-treated patients through 60 days with a greater risk for stroke in the rolofylline group (hazard ratio 3.49; 95% CI 1.04, 11.71; p = 0.043). There was no temporal relation to rolofylline administration and no specific stroke subtype or clinical characteristics that predicted stroke in the rolofylline group.Conclusions: Rolofylline treatment was associated with an increased seizure rate, an anticipated complication of A(1)-receptor antagonists. An unanticipated, disproportionate increase in strokes in the rolofylline-treated patients emerged, although no clear temporal relation, aetiology, stroke subtype or interacting factor suggestive of a causal mechanism was identified. Further research into stroke as a potential complication of adenosine-modulating therapies is required. Additionally, this study underscores the value of longer follow-up durations for AEs, even for agents with short treatment periods, such as in acute heart failure. [ABSTRACT FROM AUTHOR]

Cardiac resynchronization therapy (CRT) improves survival, symptoms, quality of life, exercise capacity, and cardiac structure and function in patients with New York Heart Association (NYHA) functional class II or ambulatory class IV heart failure (HF) with wide QRS complex. The totality of evidence supports the use of CRT in patients with less severe HF symptoms. CRT is recommended for patients in sinus rhythm with a widened QRS interval (>=150 ms) not due to right bundle branch block (RBBB) who have severe left ventricular (LV) systolic dysfunction and persistent NYHA functional class II-III symptoms despite optimal medical therapy (strength of evidence A). CRT may be considered for several other patient groups for whom evidence of benefit is clinically significant but less substantial, including patients with a QRS interval of >=120 to <150 ms and severe LV systolic dysfunction who have persistent mild to severe HF despite optimal medical therapy (strength of evidence B), some patients with atrial fibrillation, and some with ambulatory class IV HF. Several evidence gaps remain that need to be addressed, including the ideal threshold for QRS duration, QRS morphology, lead placement, degree of myocardial scarring, and the modality for evaluating dyssynchrony. Recommendations will evolve over time as additional data emerge from completed and ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Treatment with inotropic agents is one of the most controversial topics in heart failure. Initial enthusiasm, based on strong pathophysiological rationale and apparent empirical efficacy, has been progressively limited by results of controlled trials and registries showing poorer outcomes of the patients on inotropic therapy. The use of these agents remains, however, potentially indicated in a significant proportion of patients with low cardiac output, peripheral hypoperfusion and end-organ dysfunction caused by heart failure. Limitations of inotropic therapy seem to be mainly related to their mechanisms of action entailing arrhythmogenesis, peripheral vasodilation, myocardial ischemia and damage, and possibly due to their use in patients without a clear indication, rather than to the general principle of inotropic therapy itself. This review will discuss the characteristics of the patients with a potential indication for inotropic therapy, the main data from registries and controlled trials, the mechanism of the untoward effects of these agents on outcomes and, lastly, perspectives with new agents with novel mechanisms of action. [ABSTRACT FROM AUTHOR]

Decreased systolic function is a central factor in the pathogenesis of heart failure, yet there are no safe medical therapies to improve cardiac function in patients. Currently available inotropes, such as dobutamine and milrinone, increase cardiac contractility at the expense of increased intracellular concentrations of calcium and cAMP, contributing to increased heart rate, hypotension, arrhythmias, and mortality. These adverse effects are inextricably linked to their inotropic mechanism of action. A new class of pharmacologic agents, cardiac myosin activators, directly targets the kinetics of the myosin head. In vitro studies have demonstrated that these agents increase the rate of effective myosin cross-bridge formation, increasing the duration and amount of myocyte contraction, and inhibit non-productive consumption of ATP, potentially improving myocyte energy utilization, with no effect on intracellular calcium or cAMP. Animal models have shown that this novel mechanism increases the systolic ejection time, resulting in improved stroke volume, fractional shortening, and hemodynamics with no effect on myocardial oxygen demand, culminating in significant increases in cardiac efficiency. A first-in-human study in healthy volunteers with the lead cardiac myosin activator, CK-1827452, as well as preliminary results from a study in patients with stable chronic heart failure, have extended these findings to humans, demonstrating significant increases in systolic ejection time, fractional shortening, stroke volume, and cardiac output. These studies suggest that cardiac myosin activators offer the promise of a safe and effective treatment for heart failure. A program of clinical studies are being planned to test whether CK-1827452 will fulfill that promise. [ABSTRACT FROM AUTHOR]

Relaxin is a naturally occurring peptide hormone that plays a central role in the hemodynamic and renovascular adaptive changes that occur during pregnancy. Triggering similar changes could potentially be beneficial in the treatment of patients with heart failure. The effects of relaxin include the production of nitric oxide, inhibition of endothelin, inhibition of angiotensin II, production of VEGF, and production of matrix metalloproteinases. These effects lead to systemic and renal vasodilation, increased arterial compliance, and other vascular changes. The recognition of this has led to the study of relaxin for the treatment of heart failure. An initial pilot study has shown favorable hemodynamic effects in patients with heart failure, including reduction in ventricular filling pressures and increased cardiac output. The ongoing RELAX-AHF clinical program is designed to evaluate the effects of relaxin on the symptoms and outcomes in a large group of patients admitted to hospital for acute heart failure. This review will summarize both the biology of relaxin and the data supporting its potential efficacy in human heart failure. [ABSTRACT FROM AUTHOR]

Although we have recently witnessed substantial progress in management and outcome of patients with chronic heart failure, acute heart failure (AHF) management and outcome have not changed over almost a generation. Vasodilators are one of the cornerstones of AHF management; however, to a large extent, none of those currently used has been examined by large, placebo-controlled, non-hemodynamic monitored, prospective randomized studies powered to assess the effects on outcomes, in addition to symptoms. In this article, we will discuss the role of vasodilators in AHF trying to point out which are the potentially best indications to their administration and which are the pitfalls which may be associated with their use. Unfortunately, most of this discussion is only partially evidence based due to lack of appropriate clinical trials. In general, we believe that vasodilators should be administered early to AHF patients with normal or high blood pressure (BP) at presentation. They should not be administered to patients with low BP since they may cause hypotension and hypoperfusion of vital organs, leading to renal and/or myocardial damage which may further worsen patients' outcome. It is not clear whether vasodilators have a role in either patients with borderline BP at presentation (i.e., low-normal) or beyond the first 1-2 days from presentation. Given the limitations of the currently available clinical trial data, we cannot recommend any specific agent as first line therapy, although nitrates in different formulations are still the most widely used in clinical practice. [ABSTRACT FROM AUTHOR]

BACKGROUND: Heart failure is a major cause of morbidity and mortality and is increasing in prevalence. Treatments for heart failure permit a growing number of persons to live with the illness for many years. The burden of symptoms in persons with advanced heart failure is high. Fatigue, limited exertion, dyspnea, and depression are commonly associated with heart failure, but pain is common as well. METHODS AND RESULTS: Although it is known that underlying comorbidities modify the response to and experience of pain, the interaction between pain and the clinical syndrome of heart failure has not been studied to date. The Pain Assessment, Incidence & Nature in Heart Failure (PAIN-HF) study will evaluate pain in patients with advanced heart failure. Specifically, PAIN-HF will examine the anatomical location of pain, prevalence of pain, its association with aspects of patients' heart failure and comorbid conditions, and its relation to interventions and medications to treat pain. CONCLUSIONS: This study to identify the nature, incidence, and character of pain is an important step in relieving distress and discomfort in persons with heart failure. [ABSTRACT FROM AUTHOR]

Objectives: We sought to investigate the efficacy and safety of tezosentan, a dual endothelin receptor antagonist, in patients hospitalized for acute heart failure (HF).Background: Tezosentan has been previously shown to improve hemodynamics in patients with stable chronic HF.Methods: In a double-blind fashion, 292 patients (cardiac index < or =2.5 l/min per m(2) and pulmonary capillary wedge pressure (PCWP) > or =15 mm Hg) who were admitted to the hospital and in need of intravenous treatment for acute HF and central hemodynamic monitoring were randomized to 24-h intravenous treatment with tezosentan (50 or 100 mg/h) or placebo. Central hemodynamic variables, the dyspnea score, and safety variables were measured.Results: After 6 h of treatment, significantly greater increases in the cardiac index and decreases in PCWP were observed with both tezosentan dosages than with placebo (mean treatment effects at 0.38 and 0.37 l/min per m(2) with 50 and 100 mg/h and -3.9 mm Hg for each dose, respectively; p < 0.0001). This effect was maintained during the remaining infusion and for > or =6 h after treatment cessation. A tendency for an improved dyspnea score and a decreased risk of clinical worsening was observed after 24 h of treatment with each tezosentan dose. Adverse events, more frequent with tezosentan than with placebo (headache, asymptomatic hypotension, early worsening of renal function, nausea, vomiting), were dose-related.Conclusions: Intravenous tezosentan rapidly and effectively improved hemodynamics in these patients. The similar beneficial effects of the two dosages and the increased dose-related adverse events with the higher dosage suggest that the optimal dosing regimen is <50 mg/h. [ABSTRACT FROM AUTHOR]

Perturbations in kidney function are frequently encountered in heart failure (HF) across its spectrum in both chronic and acute settings with distinct implications for patient management and prognosis. Lack of consensus on the threshold for clinically meaningful changes in kidney function has led to heterogeneity in the clinical characteristics and background therapies of individuals enrolled in clinical trials, and in multiple aspects of trial design. A meaningful and collaborative interaction among the disciplines of cardiology and nephrology, clinical trialists, industry sponsors, and regulatory agencies is vital to the development of standardized definitions of changes in kidney function across HF settings. To achieve this critically important objective, the Heart Failure Collaboratory assembled experts in HF and nephrology, including key stakeholders in the U.S. Food and Drug Administration and industry, with the goal of developing initial recommendations for improved standardization of design and conduct of clinical trials in HF. Recommendations included how and when to measure baseline and changes in kidney function, discouraging the use of the term "acute kidney injury," and the consideration of urinary markers in the assessment of kidney function., Competing Interests: Funding Support and Author Disclosures Dr Lala has served as a Speakers Bureau member for Abiomed, Cytokinetics, Novartis, and Zoll; performs contracted research for AstraZeneca, Merck, Bayer, and Novo Nordisk; and serves as Co-Editor-in-Chief of the Journal of Cardiac Failure. Dr Coca has provided consultancy for Renalytix (Scientific Advisor), Takeda (defense for PPI-CKD litigation), Nuwellis (REVERSE-HF trial Steering Committee Member), Vifor (advisor for CKD-associated pruritus and hyperkalemia treatments), Bayer (Cardiorenal Committee), Boehringer Ingelheim (Health Systems CKD Process Improvements Advisory Board), Reprieve Cardiovascular (consultant), Axon Therapies (DSMB for REBALANCE-HF trial), 3ive (RETHINK-HF trial steering committee), and Alexion (advisor for biomarkers in CKD); has ownership interest in Renalytix; has received research funding from Renalytix, ProKidney, Renal Research Institute, and XORTX; has patents or royalties for and serves in an advisory or leadership role for Renalytix; is Associate Editor for Kidney360; and has served on the Editorial Boards of JASN, CJASN, and Kidney International. Dr Abraham has received consulting fees from Boehringer Ingelheim, Cardionomic, Zoll Respicardia, scPharmaceuticals, and Sensible Medical; has received Vectorious Salary support from V-WAVE Medical; and has served as a speaker for Edwards Lifesciences. Dr O’Connor has received grant or research support from Merck; and has received consulting fees from Merck, Bayer, and Abiomed. Dr Januzzi has a board position with Imbria Pharma; is Director at JanaCare; has current/recent grant support from Abbott, Applied Therapeutics, AstraZeneca, Bristol Myers Squibb, and Novartis Pharmaceuticals; has received consulting income from Abbott Diagnostics, Beckman-Coulter, Janssen, Novartis, Prevencio, Quidel, and Roche Diagnostics; and serves on clinical endpoint committees/Data Safety Monitoring Boards for Abbott, AbbVie, Amgen, CVRx, Medtronic, Pfizer, and Roche Diagnostics. Dr Lindenfeld has received consulting fees/honoraria from CVRx, VWAVE, Edwards, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc, Novartis, Abbott, Impulse Dynamics, Alleviant, Boston Scientific, Merck and Co, Inc, and Merck. Dr Teerlink has received research contracts from 3ive Labs, AstraZeneca, Bayer, Boehringer Ingelheim, Cardurion, Cytokinetics, EBR Systems, Edgewise Therapeutics, Edwards, Impulse Dynamics, Kaiser Permanente, LivaNova, Medtronic, Myovant, PCORI, Recardio, and V-Wave; and has served as a consultant for 3ive Labs, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, CorHepta, Cytokinetics, Daiichi-Sankyo, EBR Systems, Edwards, Impulse Dynamics, JuvLabs, Kaiser Permanente, Lilly, LivaNova, Medtronic, Myovant, Novartis, PCORI, Pfizer, RECARDIO, ReCor Medical, Regeneron, Reprieve, Tectonic, V-Wave, Verily, ViCardia, and Windtree Therapeutics. Dr Sarnak has served on a Steering Committee for Trials Funded by Akebia Pharmaceuticals; has attended an Advisory Board for Boehringer Ingelheim; and his spouse is employed by Eli Lilly. Dr Parikh is supported by National Institutes of Health grants U01DK114866, U01DK106962, and R01DK093770; and serves on the scientific advisory board for Alexion and Otsuka pharmaceuticals. Dr Konstam is a consultant for FIRE1, Pfizer, Luitpold, Cardurion, Cytogenetics, and Boehringer Ingelheim. Dr Costanzo has served as a Board of Directors member for Nuwellis; has received research grants from Nuwellis, Bayer, Alleviant, and V-WAVE to the Midwest Cardiovascular Institute; has served as a consultant to Sequana, Nuwellis, WhiteSwell, and Boehringer Ingelheim; and serves as Executive Managing Editor of the Journal of Heart and Lung Transplantation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Empagliflozin improves outcomes in acute heart failure (AHF). Patients with AHF and low blood pressure (BP) have poor prognosis. Whether empagliflozin is effective and safe in patients with AHF and low BP is currently unknown. The aim of this study was to assess the efficacy and safety of empagliflozin (vs. placebo) in patients with low BP - either systolic BP (SBP) <110 mmHg or diastolic BP (DBP) <70 mmHg - at randomization., Methods and Results: EMPULSE included 530 patients with AHF followed for 90 days. The primary outcome was a hierarchical composite of all-cause mortality, HF events, and Kansas City Cardiomyopathy Questionnaire total symptom score changes at 90 days tested using the win ratio (WR). Patients were required to have SBP ≥100 mmHg for randomization. A total of 131 (25%) patients had SBP <110 mmHg and 190 (36%) DBP <70 mmHg. In placebo, low BP was associated with more clinical and adverse events. Compared to placebo, BP changes with empagliflozin were of small magnitude (-2 to 2 mmHg), not reaching statistical significance. Patients presenting with low BP increased their BP, on average, throughout the 90-day follow-up, regardless of treatment group. Empagliflozin (vs. placebo) improved clinical outcomes regardless of BP at randomization, potentially with a larger magnitude of effect in patients presenting with low DBP at randomization: primary outcome WR = 1.48, 95% confidence interval (CI) 1.15-1.90, p = 0.0025; WR = 1.23, 95% CI 0.94-1.60 in DBP ≥70 mmHg and WR = 2.11, 95% CI 1.46-3.04 in DBP < 70 mmHg (interaction p = 0.02)., Conclusions: Patients admitted for AHF with low BP had a higher risk of clinical events. Empagliflozin did not lower BP more than placebo and was effective and safe irrespective of BP. Empagliflozin should be considered for the treatment of AHF patients even when presenting with low BP., (© 2025 European Society of Cardiology.)

Background: There is limited published information on outcome adjudication in heart failure (HF) trials, particularly in heart failure with preserved ejection fraction (HFpEF)., Objectives: The study sought to compare investigator reports with clinical events committee (CEC) adjudication and assess the impact of the SCTI (Standardized Data Collection for Cardiovascular Trials) criteria., Methods: In the EMPEROR-Preserved (EMPagliflozin outcome tRial in Patients with chronic heart Failure With Preserved Ejection Fraction) trial, we compared investigator reports with CEC for concordance, treatment effect on primary composite outcome events and components (first event primary heart failure hospitalization [HHF] or cardiovascular [CV] mortality), prognosis after first HHF, total HHF, and trial duration with and without SCTI criteria., Results: The CEC confirmed 67.4% investigator-reported events for the primary outcome (CV mortality 82.7%, HHF 66.3%). The HR for treatment effect did not differ between adjudication methods for the primary outcome: investigator reports (HR: 0.77; 95% CI: 0.69-0.87), CEC (HR: 0.79; 95% CI: 0.69-0.90), its components, or total HHFs. The prognosis after the first HHF for all-cause mortality and CV mortality also did not differ between investigator reports and the CEC, nor did investigator reports and HHFs with a different CEC cause. SCTI criteria were present in 92% of CEC HHFs with a similar treatment effect to non-SCTI criteria. The investigator-reported primary events reached the protocol target number 6 months earlier than the CEC (7 months with full SCTI criteria)., Conclusions: Investigator adjudication is an alternative to a CEC with similar accuracy and faster event accumulation in HFpEF. The use of granular (SCTI) criteria did not improve trial performance. Our data suggest that a broader definition of an HHF event could be particularly beneficial in HFpEF clinical trials. (EMPagliflozin outcome tRial in Patients with chronic heart Failure With Preserved Ejection Fraction; NCT03057951)., Competing Interests: Funding Support and Author Disclosures The EMPEROR-Preserved trial was funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance. Dr Carson has received consulting fees from Boehringer Ingelheim and IQVIA related to work on a clinical events committee during the conduct of the study. Dr Teerlink has received research support from and/or served as a consultant for Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics. Dr Komajda has received consulting fees from Boehringer Ingelheim related to work on a clinical events committee during the conduct of the study; and personal fees from Novartis, Servier, Amgen, Sanofi, Bayer, AstraZeneca, Lilly, and Torrent. Dr Anand has received consulting fees from Boehringer Ingelheim related to work on a clinical events committee during the conduct of the study; and personal fees from Novartis, Servier, Amgen, Sanofi, Bayer, AstraZeneca, Lilly, and Torrent. Dr Packer has received consulting fees from AbbVie, Actavis, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson and Johnson, Eli Lilly and Company, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, and Theravance; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Butler has received consulting fees from Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, VWave, and Vifor; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Doehner has received consulting fees from Boehringer Ingelheim related to work on the clinical events committee during the conduct of the study; personal fees from Aimediq, Bayer, Boehringer Ingelheim, Medtronic, Pfizer, Sanofi, Sphingotec, and Vifor Pharma; and research support from the European Union (Horizon2020), the German Ministry of Education and Research, the German Center for Cardiovascular Research, Vifor Pharma, and ZS Pharma. Dr Ferreira has received consulting fees from Boehringer Ingelheim; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Filippatos has received lecture fees from and/or committee member contributions from clinical trials sponsored by Bayer, Medtronic, Vifor, Servier, Novartis, and Amgen; research support from the European Union; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Haass has received consulting fees from Boehringer Ingelheim related to work on the clinical events committee during the conduct of the study. Dr Miller has received consulting fees from Abbott, Boehringer Ingelheim, Respicardia, CVRx, Pfizer, and AbbVie. Dr Pehrson has received consulting fees and/or lecture fees from Boehringer Ingelheim, GlaxoSmithKline, Celgene, Bristol Myers Squibb, Bayer, and Johnson and Johnson. Dr Pocock has received consulting fees and payment or honoraria for lectures, presentations, Speakers Bureau service, manuscript writing, or educational events from Boehringer Ingelheim; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Drs Iwata, Brueckmann, and Gasior are employees of Boehringer Ingelheim. Dr Zannad has received steering committee or advisory board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, Livanova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor). Dr Anker has received grants and personal fees from Vifor International and Abbott Vascular; personal fees from AstraZeneca, Bayer, Brahms, Boehringer Ingelheim, Cardiac Dimensions, Novartis, Occlutech, Servier, and Vifor International; and served on the Trial Executive Committee for the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance (trial sponsor)., (Copyright © 2025 American College of Cardiology Foundation. All rights reserved.)

Aims: Serelaxin is recombinant human relaxin-2, a hormone responsible for haemodynamic adaptations and organ protection in pregnancy. In the RELAX-AHF trial, serelaxin demonstrated reductions in cardiac, renal and hepatic damage. In RELAX-AHF-2, organ damage-related biomarkers were assessed in a biomarker substudy., Methods and Results: Patients enrolled within 16 h of presentation for heart failure hospitalization were randomized to 48-h infusions of either serelaxin (30 μg/kg/day) or placebo, and plasma samples were obtained at baseline, 2, 5, and 14 days in patients participating in the biomarker substudy. Of the 6545 patients analysed in RELAX-AHF-2, 1020 (15.6%) patients (mean age 72 ± 12 years; 61% male) were enrolled in the biomarker substudy. Compared to placebo, serelaxin decreased percentage change from baseline in troponin T through day 14 (serelaxin +0.2% vs. placebo +40.3%; p = 0.042), as well as creatinine (-0.8% vs. +5.8%; p = 0.002), cystatin C (+3.8% vs. +8.3%; p = 0.016), and uric acid (+0.8% vs. +7.2%; p = 0.0014) at day 2. The decrease of N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to day 2 was greater in serelaxin-treated patients (-39.8% vs. -27.6%; p = 0.002). Early changes in NT-proBNP and troponin, but not creatinine, cystatin C and uric acid, were associated with 180-day mortality. In this substudy population, serelaxin did not reduce 180-day cardiovascular death (hazard ratio [HR] 0.78; 95% confidence interval [CI] 0.49-1.25; p = 0.30), but significantly reduced worsening heart failure through day 5 (HR 0.55; 95% CI 0.33-0.93; p = 0.027)., Conclusion: In this substudy, serelaxin decreased plasma concentrations of cardiac, renal and hepatic injury markers. Changes of most of these markers were associated with cardiovascular mortality. In this pre-specified biomarker subgroup, serelaxin did not reduce 180-day cardiovascular mortality but significantly reduced worsening heart failure through day 5., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

In the past decade, our understanding of heart failure pathophysiology has advanced significantly, resulting in the development of new medications such as angiotensin-neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors and oral soluble guanylate cyclase stimulators. Backed by positive findings from large randomized controlled trials, recommendations for their use were recently included in the 2022 AHA/ACC/HFSA guidelines and 2023 ESC guidelines for management of heart failure. Promising drugs for future heart failure treatment include agents that modulate the neurohormonal system, vasodilators, anti-inflammatory drugs, mitotropes, which improve deranged energy metabolism of the failing heart, and myotropes, which increase cardiac contractility by affecting cardiac sarcomere function. Here, we discuss these new and future heart failure drugs. We explain their mechanisms of action, critically evaluate their performance in clinical trials and summarize the clinical scenarios in which the latest guidelines recommend their use. This Review aims to offer clinicians and researchers a comprehensive overview of novel therapeutic classes in heart failure treatment., Competing Interests: Competing interests: C.D.’s spouse is employed by and holds stock in iRhythm Technologies. J.R.T. has received research support and/or has been a consultant for 3ive Labs, Angitia, AskBio, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimensions, Cardurion, CorHepta, Cytokinetics, Daiichi-Sankyo, EBR Systems, Edgewise Therapeutics, Edwards, Endotronix, Impulse Dynamics, JuvLabs, Kaiser Permanente, Lilly, LivaNova, Medtronic, Myovant, Novartis, PCORI, Pfizer, RECARDIO, ReCor Medical, Regeneron, Reprieve, Stealth, Tectonic, V-Wave, Verily, ViCardia and Windtree Therapeutics. L.H. has no competing interests to disclose., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Competing Interests: Declarations of Competing Interest All authors declare that they have no conflicts of interest.

Background: The prognostic importance of residual congestion after acute heart failure (AHF) hospitalization is still debated., Objectives: The authors aimed to assess the impact of residual congestion in a large cohort of patients with AHF enrolled in the RELAX-AHF-2 (Relaxin in Acute Heart Failure 2) trial., Methods: Residual congestion was assessed at day 5 after admission among hospitalized patients using an established composite congestion score (CCS) based on the presence of orthopnea, peripheral edema, and increased jugular venous pressure, ranging from 0 to 8 points. The primary endpoint was a composite of cardiovascular death or rehospitalization for heart failure or renal failure at 180 days., Results: Among the 5,900 AHF patients included in this analysis, 3,380 (57.3%) had at least 1 sign of congestion (ie, CCS ≥1) and 1,066 (18.1%) had a CCS ≥3 at day 5 after admission. Patients with residual congestion at day 5 were more symptomatic, had more comorbidities, received higher doses of loop diuretic agents in-hospital, albeit with lower diuretic response, were less likely to have hemoconcentration, and were more likely to have worsening renal function at day 5. After multivariable adjustment for clinically meaningful variables, any sign of residual congestion and CCS ≥3 at day 5 were both independently associated with a higher risk of the primary endpoint (adjusted HR: 1.32 [95% CI: 1.15-1.51]; P < 0.001 and adjusted HR: 1.62 [95% CI: 1.39-1.88]; both P < 0.001)., Conclusions: Among patients with AHF who were still hospitalized at day 5, residual congestion was common and independently associated with worse outcome. (Efficacy, Safety and Tolerability of Serelaxin When Added to Standard Therapy in AHF [RELAX-AHF-2]; NCT01870778)., Competing Interests: Funding Support and Author Disclosures The RELAX-AHF-2 trial was funded by Novartis. Dr Pagnesi has received personal fees from Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Novartis, Roche Diagnostics, and Vifor Pharma. Drs Cotter and Davison have received research grants and personal fees from Novartis during the trials’ conduct; and have received grants from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics, Roche Diagnostics, Sanofi and Windtree Therapeutics. Dr Jongs has received a travel grant from AstraZeneca. Dr Felker has received research grants from the National Institutes of Health (NIH), Bayer, BMS, Novartis, Daxor, Merck, Cytokinetics, and CSL-Behring; has been a consultant to Novartis, BMS, Cytokinetics, Innolife, Boehringer-Ingelheim, Abbott, Sanofi, Regeneron, Myovant, Sequana, Windtree Therapeutics, and Whiteswell, and has served on clinical endpoint committees/data safety monitoring boards for Merck, Medtronic, EBR Systems, Rocket Pharma, V-Wave, and LivaNova. Dr Filippatos has participated in committees for trials and registries sponsored by Novartis, Servier, Medtronic, Vifor, Boehringer Ingelheim, and Bayer. Dr Greenberg has received research support from the American Heart Association, the NIH, and Rocket Pharma; and has served as a consultant for ACI, Actelion, Akcea, Amgen, Bayer, EBR Systems, Ionis, Janssen, Merck, MyoKardia, Novartis, Relypsa, Rocket, Sanofi, Vifor Pharma, Viking, Zensun, and Zoll. Dr Pang has served as a consultant for Baxter, Bristol Myers Squibb, and Merck; and has received research or other support from Bristol Myers Squibb, Roche, Novartis, the Patient-Centered Outcomes Research Institute, the American Heart Association, the National Heart, Lung, and Blood Institute, the Agency for Healthcare Research and Quality, OrthoDiagnostics, and Abbott. Dr Ponikowski has received consulting fees and speaker honoraria from Vifor Pharma, Amgen, Servier, Novartis, Berlin Chemie, Bayer, Pfizer, Cibiem, Impulse Dynamics, Renal Guard Solutions, Boehringer Ingelheim, and AstraZeneca; and has received research grants from Vifor Pharma. Dr Adamo has received speaker fees from Abbott Vascular and Medtronic. Drs Severin and Gimpelewicz are employees of Novartis Pharma. Dr Voors has received consultancy fees and/or grant support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, MyoKardia, Novartis, Novo Nordisk, Roche Diagnostics, Servier, and Vifor Pharma. Dr Teerlink has received research grants and/or consulting fees from Abbott, AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, EBR Systems, Medtronic, Merck, and Novartis. Dr Metra has received consulting honoraria as a member of trial committees or advisory boards for Abbott Vascular, Actelion, Amgen, Bayer, Edwards Therapeutics, Servier, Vifor Pharma, and Windtree Therapeutics. 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: Multimorbidity frequently occurs in patients with acute heart failure (AHF). The co-occurrence of comorbidities often follows specific patterns., Objectives: This study investigated multimorbidity subtypes and their associations with clinical outcomes., Methods: From the prospective RELAX-AHF-2 (Relaxin for the Treatment of Acute Heart Failure-2) trial, 6,545 patients (26% with HF with preserved ejection fraction, defined as LVEF ≥50%) were classified into multimorbidity groups using latent class analysis. The association between subgroups and clinical outcomes was examined. Validation of these findings was conducted in the RELAX-AHF trial, which comprised 1,161 patients., Results: Five distinct multimorbidity groups emerged: 1) diabetes and chronic kidney disease (CKD) (often male, high prevalence of CKD and diabetes mellitus); 2) ischemic (ischemic HF); 3) elderly/atrial fibrillation (AF) (oldest, high prevalence of AF); 4) metabolic (obese, hypertensive, more often HF with preserved ejection fraction); and 5) young (fewest comorbidities). After adjusting for confounders, patients in the diabetes and CKD (HR: 1.80; 95% CI: 1.50-2.20), elderly/AF (HR: 1.42; 95% CI: 1.20-1.70), and metabolic (HR: 1.40; 95% CI: 1.20-1.80) groups had higher rates of the composite outcome than patients in the young group, primarily driven by differences in rehospitalization. Treatment allocation (placebo or serelaxin) modified these associations (P interaction  <0.001). Serelaxin-treated patients in the young group were associated with a lower risk for all-cause mortality (HR: 0.59; 95% CI: 0.40-0.90). Similarly, patients from the RELAX-AHF trial clustered in 5 multimorbidity groups. The clinical characteristics and associations with outcomes could also be validated., Conclusions: Comorbidities naturally clustered into 5 mutually exclusive groups in RELAX-AHF-2, showing variations in clinical outcomes. These data emphasize that the specific combination of comorbidities can influence adverse outcomes and treatment responses in patients with AHF., Competing Interests: Funding Support and Author Disclosures This study was funded by the PROMINENT project (funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement number 754425). Dr Tromp is supported by the National University of Singapore Start-up grant, the tier 1 grant from the ministry of education, and the CS-IRG New Investigator Grant from the National Medical Research Council; has received consulting or speaker fees from Daiichi Sankyo, Boehringer Ingelheim, Roche Diagnostics, and Us2.ai; and owns patent US-10702247-B2 unrelated to the present work. Drs Cotter and Davison are employees of Momentum Research, Inc, which has received grants from Abbott Laboratories, Amgen, Celyad, Cirius Therapeutics Inc, Corteria Pharmaceuticals, Roche Diagnostics Inc, Sanofi, Windtree Therapeutics Inc, and XyloCor Therapeutics. Dr Felker has received research grants from the National Heart, Lung, and Blood Institute, the American Heart Association, Amgen, Bayer, BMS, Merck, Cytokinetics, and CSL-Behring; has acted as a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Boehringer Ingelheim, American Regent, Abbott, AstraZeneca, Reprieve, Myovant, Sequana, Windtree Therapeutics, and Whiteswell; and has served on clinical endpoint committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. Dr Gimpelewicz is an employee of Novartis. Dr Greenberg is a consultant for or on the advisory board of AstraZeneca, Bayer, Ionis, Merck, Mesoblast, and Tenaya; and has been on the Data Safety Monitoring Board of ACI, Axon, AstraZeneca, Bayer, Cytokinetics, Boehringer Ingelheim, EBR Systems, Faraday, Inventiva, Impulse Dynamics, Ionis, Salubris, Vifor, Viking, and Windtree. 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, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, ProSciento Inc, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as co-founder and nonexecutive director of Us2.ai. Dr Voors has received research support and/or has been a consultant for Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Cytokinetics, Merck, MyoKardia, Novo Nordisk, Novartis, and Roche Diagnostics. Dr Metra received personal fees of minimal amounts in the last 3 years from Actelion, Amgen, LivaNova, and Vifor pharma as a member of Executive or Data Monitoring Committees of sponsored clinical trials; and from AstraZeneca, Abbott Vascular, Bayer, Boehringer Ingelheim, and Edwards Therapeutics for participation on advisory boards and/or speeches at sponsored meetings. Dr Teerlink has received research support and/or has been a consultant for Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim, Bristol Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, Servier, and Windtree Therapeutics. Dr van der Meer received grant support and/or consultancy fees from Novartis, Pharma Nord, Pfizer, Ionis, Astra Zeneca, Vifor Pharma, Pharmacosmos, BridgeBio, and Novo Nordisk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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

Background: Inadequate inclusion in clinical trial enrollment may contribute to health inequities by evaluating interventions in cohorts that do not fully represent target populations., Objectives: The aim of this study was to determine if characteristics of patients with heart failure (HF) enrolled in a pivotal trial are associated with who receives an intervention after approval., Methods: Demographics from 2,017,107 Medicare patients hospitalized for HF were compared with those of the first 10,631 Medicare beneficiaries who received implantable pulmonary artery pressure sensors. Characteristics of the population studied in the pivotal CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) clinical trial (n = 550) were compared with those of both groups. All demographic data were analyzed nationally and in 4 U.S. regions., Results: The Medicare HF cohort included 80.9% White, 13.3% African American, 1.9% Hispanic, 1.3% Asian, and 51.5% female patients. Medicare patients <65 years of age were more likely to be African American (33%) and male (58%), whereas older patients were mostly White (84%) and female (53%). Forty-one percent of U.S. HF hospitalizations occurred in the South; demographic characteristics varied significantly across all U.S. regions. The CHAMPION trial adequately represented African Americans (23% overall, 35% <65 years of age), Hispanic Americans (2%), and Asian Americans (1%) but underrepresented women (27%). The trial's population characteristics were similar to those of the first patients who received pulmonary artery sensors (82% White, 13% African American, 1% Asian, 1% Hispanic, and 29% female)., Conclusions: Demographics of Centers for Medicare and Medicaid Services beneficiaries hospitalized with HF vary regionally and by age, which should be considered when defining "adequate" representation in clinical studies. Enrollment diversity in clinical trials may affect who receives early application of recently approved innovations., Competing Interests: Funding Support and Author Disclosures Abbott provided resources for access and analyses of CMS claims data and demographic information from the CHAMPION trial. Dr Adamson is an employee of Abbott. Dr Echols is a consultant to Abbott. Dr DeFilippis serves on a clinical trial committee for Abiomed. Dr Morris has received research funding from the Agency for Healthcare Research and Quality (HS026081), the American Heart Association, Google, and Merck; and has received consulting fees from Abbott, Acorai, Boehringer Ingelheim, Eli Lilly, Cytokinetics, Edwards Lifesciences, Ionis, Merck, and Regeneron. Dr Bennett has received consulting fees and speaker honoraria from Abbott. Dr Abraham has received consulting fees from Abbott Vascular, AquaPass, Boehringer Ingelheim, Impulse Dynamics, Sensible Medical Innovations, V-Wave, and Zoll Respicardia. Dr Lindenfeld has received consulting and/or research support from Abbott, AstraZeneca, Boehringer Ingelheim, Boston Scientific, CVRx, Edwards Lifesciences, Impulse Dynamics, Merck, Medtronic, V-Wave, Vifor, and Volumetrix. Dr Teerlink has received research support from 3ive Labs, AstraZeneca, Bayer, Boehringer Ingelheim, Cardurion, Cytokinetics, EBR Systems, Edwards Lifesciences, Impulse Dynamics, Kaiser Permanente, LivaNova, Medtronic, Myovant Sciences, the Patient-Centered Outcomes Research Institute, RECARDIO, and V-Wave; and is a consultant for 3ive Labs, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardurion, CorHepta, Cytokinetics, Daiichi-Sankyo, EBR Systems, Edwards Lifesciences, Eli Lilly Impulse Dynamics, JuvLabs, Kaiser Permanente, LivaNova, Medtronic, Myovant Sciences, Novartis, the Patient-Centered Outcomes Research Institute, Pfizer, ReCor Medical, Regeneron, Reprieve, Tectonic, V-Wave, Verily, ViCardia, and Windtree Therapeutics. Dr O’Connor has received research funding from Merck; and has received consulting fees from Bayer and Dey. Dr Connolly is an employee of Abbott. Dr Li is an employee of Abbott. Dr. Vaduganathan has received research grant support from, served on advisory boards for, or has had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer, Baxter Healthcare, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer, Occlutech, and Impulse Dynamics. Dr Batchelor has received consulting fees from Boston Scientific, Medtronic, Edwards Lifesciences, V-Wave, Chiesi, Abbott, and Idorsia; and has received research support from Abbott and Boston Scientific. Dr McCants has received consulting fees and speaker honoraria from Abbott. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)