Search

AimsDiscontinuation or non-publication of trials may hinder scientific progress and violates the commitment made to research participants. We sought to identify the prevalence of discontinuation and non-publication of heart failure (HF) clinical trials.Methods and resultsWe conducted a cross-sectional search of ClinicalTrials.gov to identify all completed and discontinued HF clinical trials. We limited our search to only include trials that were completed by 31 December 2017. Trials were investigated to identify reasons for discontinuation. Informative termination was defined as trial termination due to safety or efficacy concerns. Data pertaining to the trial phase, funding, intervention, enrolment, and trial completion date were extracted for each trial. A total of 572 trials were included. Of these, 21% (n = 118) were discontinued before completion. Patient accrual was the most frequently cited reason (n = 42; 36%) for trial discontinuation, followed by informative termination (n = 16; 14%) and funding (n = 14; 12%). Overall, 24 780 patients were enrolled in trials that were terminated. Of trials that were completed and not terminated, nearly one-third (n = 131/454; 29%) were not published. Seventy-nine (24%) trials were published within 12 months, 192 (59%) within 24 months, and 252 (78%) trials within 36 months.ConclusionsDiscontinuation and non-publication of HF trials is common. This raises ethical concerns towards participants who volunteer for research and are exposed to potential risks, inconvenience, and discomfort without furthering scientific progress.

AimsEpisodes of acute heart failure (AHF) may lead to end-organ dysfunction. In this post hoc analysis of the Relaxin in Acute Heart Failure trial, we used the MELD-XI (Model of End-Stage Liver Dysfunction) score to examine hepatorenal dysfunction in patients with AHF.Methods and resultsOn admission, the MELD-XI score was elevated (abnormal) in 918 (82%) patients, with 638 (57%) having isolated renal dysfunction (creatinine > 1 mg/dL), 73 (6.5%) isolated liver dysfunction (bilirubin > 1 mg/dL), and 207 (18.5%) coexisting dysfunction of the kidneys and the liver (both creatinine and bilirubin > 1 mg/dL). The percentage of patients with elevated MELD-XI score remained constant through a 60 day follow-up, as we observed a gradual decrease of liver dysfunction prevalence, counterbalanced by an increase in renal dysfunction. Serelaxin treatment was associated with a lower MELD-XI score on Day 2 and Day 5 (both P

Aims: Inflammation has emerged as a potential key pathophysiological mechanism in heart failure (HF) in general and acute HF (AHF) specifically, with inflammatory biomarkers shown to be highly predictive of adverse outcomes in these patients. The CORTAHF study builds on both these data and the fact that steroid burst therapy has been shown to be effective in the treatment of respiratory diseases and COVID‐19. Our hypothesis is that in patients with AHF and elevated C‐reactive protein (CRP) levels without symptoms or signs of infection, a 7‐day course of steroid therapy will lead to reduced inflammation and short‐term improvement in quality of life and a reduced risk of worsening HF (WHF) events. Methods and results: The study, which is currently ongoing, will include 100 patients with AHF ages 18–85, regardless of ejection fraction, screened within 12 h of presentation. Patients will be included who have NT‐proBNP > 1500 pg/mL and CRP > 20 mg/L at screening. Exclusion criteria include haemodynamic instability and symptoms and signs of infection. After signed consent, eligible patients will be randomized according to a central randomization scheme stratified by centre 1:1 to either treatment once daily for 7 days with 40 mg prednisone orally or to standard care. Patients will be assessed at study day 2, day 4 or at discharge if earlier, and at days 7 and 31 at the hospital; and at day 91 through a telephone follow‐up. The primary endpoint is the change in CRP level from baseline to day 7, estimated from a mixed model for repeated measures (MMRM) including all measured timepoints, in patients without a major protocol violation. Secondary endpoints include the time to the first event of WHF adverse event, readmission for HF, or death through day 91; and changes to day 7 in EQ‐5D visual analogue scale score and utility index. Additional clinical and laboratory measures will be assessed. Conclusions: The results of the study will add to the knowledge of the role of inflammation in AHF and potentially inform the design of larger studies with possibly longer duration of anti‐inflammatory therapies in AHF. [ABSTRACT FROM AUTHOR]

Aims: The use of loop diuretics in pulmonary arterial hypertension (PAH) is less frequent compared with heart failure. The clinical and prognostic characteristics of PAH patients according to loop diuretic use remain unexplored. In this study, we retrospectively analysed the characteristics and survival of PAH patients requiring different doses of loop diuretics. Methods and results: Patients diagnosed with PAH between 2001 and 2022 at seven European centres for the management of PAH. According to the median equivalent dose of furosemide in the overall cohort, patients were divided into two subgroups: no/low‐dose loop diuretic and high‐dose loop diuretic. Primary outcome was 5 year all‐cause mortality. Among the 397 patients included, 227 (57%) were treated with loop diuretics. Median daily furosemide equivalent dose was 25 mg, and accordingly patients were divided in no/low dose (i.e. ≤25 mg, n = 257, 65%) vs. high dose (i.e. >25 mg, n = 140, 35%). Patients in the high‐dose group were older, more likely to have comorbidities, and had a more severe disease according to the ESC/ERS risk category. Crude 5 year survival was significantly shorter in patients in the high‐dose group, but after adjustment for age, sex, and risk category, high loop diuretic dose was not significantly associated with the primary outcome. Conclusions: Use of high dose of loop diuretics in PAH is associated with a higher burden of comorbidities, more severe disease, and worse survival. However, in PAH, the need of high loop diuretic dose is a marker of disease severity and not an independent prognostic factor. [ABSTRACT FROM AUTHOR]

Aims: Achieving optimized guideline‐directed medical therapy (GDMT) is recommended prior to transcatheter mitral valve edge‐to‐edge repair (M‐TEER) for secondary mitral regurgitation (SMR). We aimed to propose and validate an easy‐to‐use score for assessing the quality of GDMT in patients with heart failure with reduced ejection fraction (HFrEF) undergoing M‐TEER. Methods and results: Among the 1641 EuroSMR patients enrolled in the EuroSMR Registry who underwent M‐TEER, a total of 1072 patients [median age 74, interquartile range (IQR) 67–79 years, 29% female] had complete data on GDMT and a left ventricular ejection fraction ≤ 40% and were included in the current study. We proposed a GDMT score that considers the dosage levels of three medication classes (angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor‐neprilysin inhibitors, beta‐blockers, and mineralocorticoid receptor antagonists), with a maximum score of 12 points indicating optimal GDMT. The primary outcome was all‐cause mortality. The median GDMT score was 4 points (IQR 3–6). All three domains of the scoring system were associated with all‐cause mortality (P < 0.05 for all). The overall GDMT score was associated with all‐cause mortality (hazard ratio 0.90, 95% confidence interval 0.86–0.95 for each 1‐point increase in the GDMT score). This association remained significant after adjusting for renal function and co‐morbidities. Conclusions: This study demonstrates the utility of a simple GDMT scoring system for assessing the adequacy of GDMT in HFrEF patients with relevant SMR undergoing M‐TEER. The GDMT score has potential applications in guiding the design of future clinical trials and aiding clinical decision‐making processes. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) has a high prevalence, affecting more than 50% of patients with heart failure. HFpEF is associated with multiple comorbidities, and obesity is one of the most common. A distinct phenotype has been proposed for obese patients with HFpEF. Recent data show the beneficial role of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) for weight loss in diabetic and non‐diabetic patients with obesity or overweight when given as adjunctive therapy to diet and exercise. The mechanisms of action are related to paracrine and endocrine signalling pathways within the gastrointestinal tract, pancreas, and central nervous system that delay gastric emptying, decrease appetite, augment pancreatic beta‐cell insulin secretion, and suppress pancreatic glucagon release. These drugs are therefore potentially indicated for treatment of patients with HFpEF and obesity or overweight. Efficacy and safety need to be shown by clinical trials with a first one, Semaglutide Treatment Effect in People with obesity and heart failure with preserved ejection fraction (STEP HFpEF), recently concluded. The aim of the present review is to provide the pathophysiological and pharmacological rationale for GLP‐1 RA administration to obese patients with HFpEF. [ABSTRACT FROM AUTHOR]

Aims: This study aims to explore long‐term clinical outcomes of cardiopoiesis‐guided stem cell therapy for ischaemic heart failure assessed in the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART‐1) trial. Methods and results: CHART‐1 is a multinational, randomized, and double‐blind trial conducted in 39 centres in heart failure patients (n = 315) on standard‐of‐care therapy. The 'active' group received cardiopoietic stem cells delivered intramyocardially using a retention‐enhanced catheter. The 'control' group underwent patient‐level sham procedure. Patients were followed up to 104 weeks. In the entire study population, results of the primary hierarchical composite outcome were maintained neutral at Week 52 [Mann–Whitney estimator 0.52, 95% confidence interval (CI) 0.45–0.59, P = 0.51]. Landmark analyses suggested late clinical benefit in patients with significant left ventricular enlargement receiving adequate dosing. Specifically, beyond 100 days of follow‐up, patients with left ventricular end‐diastolic volume of 200–370 mL treated with ≤19 injections of cardiopoietic stem cells showed reduced risk of death or cardiovascular hospitalization (hazard ratio 0.38, 95% CI 0.16–0.91, P = 0.031) and cardiovascular death or heart failure hospitalization (hazard ratio 0.28, 95% CI 0.09–0.94, P = 0.040). Cardiopoietic stem cell therapy was well tolerated long term with no difference in safety readouts compared with sham at 2 years. Conclusions: Longitudinal follow‐up documents that cardiopoietic stem cell therapy is overall safe, and post hoc analyses suggest benefit in an ischaemic heart failure subpopulation defined by advanced left ventricular enlargement on tolerable stem cell dosing. The long‐term clinical follow‐up thus offers guidance for future targeted trials. [ABSTRACT FROM AUTHOR]

Large clinical data underscore that heart failure is independently associated to an increased risk of negative cognitive outcome and dementia. Emerging evidence suggests that cerebral hypoperfusion, stemming from reduced cardiac output and vascular pathology, may contribute to the largely overlapping vascular dementia and Alzheimer's disease. Despite these insights, cognitive outcomes remain largely overlooked in heart failure management. This narrative review outlines the prevalence and risk of cognitive impairment in heart failure patients, exploring potential shared pathophysiological mechanisms and examining the impact of heart failure therapy on cognitive deficits. Additionally, it discusses clinical implications and suggests future treatment approaches targeting therapeutic outcomes. Cognitive impairment is prevalent among individuals with heart failure, with reported rates varying widely depending on assessment methods. Shared pathological pathways and risk factors, including atrial fibrillation (AF), hypertension, obesity and type 2 diabetes mellitus, suggest a causal link. Mechanisms such as poor perfusion, microembolic events, ischaemic syndromes and cerebral inflammation contribute to this relationship. Moreover, heart failure itself may exacerbate cognitive dysfunction. This emerging understanding posits that vascular dementia and Alzheimer's disease may represent a pathophysiological continuum, driven by both the accumulation of misfolded proteins and cerebrovascular pathology due to cardiovascular dysfunction. Understanding these links is crucial for developing effective treatment strategies. The complex interplay between heart failure and cognitive impairment underscores the necessity for a holistic patient care approach. Both conditions share analogous disease processes, influencing self-management and independence in patients. Prioritizing brain health in heart failure management is essential to enhance patient prognosis and general well-being., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Cardiogenic shock (CS) is linked to high morbidity and mortality rates, posing a challenge for clinicians. Interventions to improve tissue perfusion and blood pressure are crucial to prevent further deterioration. Unfortunately, current inotropes, which act through adrenergic receptor stimulation, are associated with malignant arrhythmias and poorer outcomes. Due to its unique mechanism of action, istaroxime should improve haemodynamics without adrenergic overactivation. The SEISMiC study is designed to examine the safety and efficacy (haemodynamic effect) of istaroxime administrated in pre-CS patients., Methods and Results: The SEISMiC study is a multinational, multicentre, randomized, double-blind, placebo-controlled safety and efficacy study with two parts (A and B). The study enrols patients hospitalized for decompensated heart failure (pre-CS, not related to myocardial ischaemia) with persistent hypotension [systolic blood pressure (SBP) 70-100 mmHg for at least 2 h] and clinically confirmed congestion, NT-proBNP ≥1400 pg/mL, and LVEF≤40%. Subjects must not have taken intravenous (iv) vasopressors, inotropes or digoxin in the past 6 h. Eligible patients are randomized to receive IV infusion of istaroxime (different doses and regimens in Parts A and B) or placebo for up to 60 h. Central haemodynamics, ECG Holter monitoring, cardiac ultrasound and biomarkers are recorded at predefined time points during the trial. The study's primary efficacy endpoint is the SBP area under the curve from baseline curve from baseline to 6 and 24 h in the combined SEISMiC Parts A and B population. Key secondary efficacy endpoints include haemodynamic, laboratory and clinical measures in SEISMiC B alone in the combined SEISMiC A and B studies., Conclusions: The study results will contribute to our understanding of the role of istaroxime in pre-CS patients and potentially provide insight into the drug's haemodynamic effects and safety in this population., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Individual prognostic assessment and disease evolution pathways are undefined in chronic heart failure (HF). The application of unsupervised learning methodologies could help to identify patient phenotypes and the progression in each phenotype as well as to assess adverse event risk., Methods and Results: From a bulk of 7948 HF patients included in the MECKI registry, we selected patients with a minimum 2-year follow-up. We implemented a topological data analysis (TDA), based on 43 variables derived from clinical, biochemical, cardiac ultrasound, and exercise evaluations, to identify several patients' clusters. Thereafter, we used the trajectory analysis to describe the evolution of HF states, which is able to identify bifurcation points, characterized by different follow-up paths, as well as specific end-stages conditions of the disease. Finally, we conducted a 5-year survival analysis (composite of cardiovascular death, left ventricular assist device, or urgent heart transplant). Findings were validated on internal (n = 527) and external (n = 777) populations. We analyzed 4876 patients (age = 63 [53-71], male gender n = 3973 (81.5%), NYHA class I-II n = 3576 (73.3%), III-IV n = 1300 (26.7%), LVEF = 33 [25.5-39.9], atrial fibrillation n = 791 (16.2%), peak VO 2 % pred = 54.8 [43.8-67.2]), with a minimum 2-year follow-up. Nineteen patient clusters were identified by TDA. Trajectory analysis revealed a path characterized by 3 bifurcation and 4 end-stage points. Clusters survival rate varied from 44% to 100% at 2 years and from 20% to 100% at 5 years, respectively. The event frequency at 5-year follow-up for each study cohort cluster was successfully compared with those in the validation cohorts (R = 0.94 and R = 0.84, P < 0.001, for internal and external cohort, respectively). Finally, we conducted a 5-year survival analysis (composite of cardiovascular death, left ventricular assist device, or urgent heart transplant observed in 22% of cases)., Conclusions: Each HF phenotype has a specific disease progression and prognosis. These findings allow to individualize HF patient evolutions and to tailor assessment., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: This survey investigates natriuretic peptide (NP) testing in community and hospital settings, assessing awareness, accessibility, and utilization., Methods and Results: This investigator-initiated survey, conceived within the HFA of the European Society of Cardiology, comprised 14 questions. It underwent validation and pilot testing to ensure question readability and online system functionality. The survey was accessible for 87 days, from 5 April 2023 to 1 July 2023 via a web platform. There were 751 healthcare professionals across 99 countries who responded. Of them, 92.5% had access to NPs testing in hospital whereas 34.3% had no access to NTproBNP in community settings. Access to point of care NP testing was uncommon (9.6%). Public insurance fully covered NPs testing in 31.0% of cases, with private insurance providing coverage in 37.9%. The majority (84.0%) of participants believed that the medical evidence supporting NPs testing was strong, and 54.7% considered it cost-effective. Also, 35.8% found access, awareness, and adoption to be in favour of NPs testing both in hospital and community settings. Strategies to optimize NP testing involved regular guideline updates (57.9%), prioritizing NPs testing for dyspnoea assessment (36.4%), and introducing clinician feedback mechanisms (21.2%). Notably, 40% lacked a community-based HF diagnostic pathway for referring high-NP patients for echocardiography and cardiology evaluation., Conclusions: This survey reveals NP awareness, access, and adoption across several countries. Highlighting the importance of community-based early heart failure diagnosis and optimizing HF diagnostic pathways remains a crucial, unmet opportunity to improve patient outcomes., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Acute heart failure (AHF) classification and management are primarily based on lung congestion and/or hypoperfusion. The quantification of the vascular and tissue lung damage is not standard practice though biomarkers of lung injury may play a relevant role in this context. Haemodynamic stress promotes alveolar and vascular derangement with loss of functional units, impaired lung capillary permeability and fluid swelling. This culminates in a remodelling process with activation of inflammatory and cytokines pathways. Four families of lung surfactant proteins (i.e., SP-A, SP-B, SP-C, and SP-D), essential for the membrane biology and integrity are released by alveolar type II pneumocites. With deregulation of fluid handling and gas exchange pathways, SPs become sensitive markers of lung injury. We report the pathobiology of lung damage; the pathophysiological and clinical implications of alveolar SPs along with the newest evidence for some classical HF biomarkers that have also shown to reflect a vascular and/or a tissue lung-related activity., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Natriuretic peptide (NP) uptake varies in Emergency Departments (EDs) across Europe. The 'Peptide for Life' (P4L) initiative, led by Heart Failure Association, aims to enhance NP utilization for early diagnosis of heart failure (HF). We tested the hypothesis that implementing an educational campaign in Western Balkan countries would significantly increase NP adoption rates in the ED., Methods and Results: This registry examined NP adoption before and after implementing the P4L-ED study across 10 centres in five countries: Bosnia and Herzegovina, Croatia, Montenegro, North Macedonia, and Serbia. A train-the-trainer programme was implemented to enhance awareness of NP testing in the ED, and centres without access received point-of-care instruments. Differences in NP testing between the pre-P4L-ED and post-P4L-ED phases were evaluated. A total of 2519 patients were enrolled in the study: 1224 (48.6%) in the pre-P4L-ED phase and 1295 (51.4%) in the post-P4L-ED phase. NP testing was performed in the ED on 684 patients (55.9%) during the pre-P4L-ED phase and on 1039 patients (80.3%) during the post-P4L-ED phase, indicating a significant absolute difference of 24.4% (95% CI: 20.8% to 27.9%, P < 0.001). The use of both NPs and echocardiography significantly increased from 37.7% in the pre-P4L-ED phase to 61.3% in the post-P4L-ED phase. There was an increased prescription of diuretics and SGLT2 inhibitors during the post-P4L-ED phase., Conclusions: By increasing awareness and providing resources, the utilization of NPs increased in the ED, leading to improved diagnostic accuracy and enhanced patient care., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Patients with heart failure (HF) with reduced ejection fraction (EF) (HFrEF), mildly reduced EF (HFmrEF), and preserved EF (HFpEF) may all progress to advanced HF, but the impact of EF in the advanced setting is not well established. Our aim was to assess the prognostic impact of EF in patients with at least one 'I NEED HELP' marker for advanced HF., Methods and Results: Patients with HF and at least one high-risk 'I NEED HELP' criterion from four centres were included in this analysis. Outcomes were assessed in patients with HFrEF (EF ≤ 40%), HFmrEF (EF 41-49%), and HFpEF (EF ≥ 50%) and with EF analysed as a continuous variable. The prognostic impact of medical therapy for HF in patients with EF < 50% and EF > 50% was also evaluated. All-cause death was the primary endpoint, and cardiovascular death was a secondary endpoint. Among 1149 patients enrolled [mean age 75.1 ± 11.5 years, 67.3% males, 67.6% hospitalized, median follow-up 260 days (inter-quartile range 105-390 days)], HFrEF, HFmrEF, and HFpEF were observed in 699 (60.8%), 122 (10.6%), and 328 (28.6%) patients, and 1 year mortality was 28.3%, 26.2%, and 20.1, respectively (log-rank P = 0.036). As compared with HFrEF patients, HFpEF patients had a lower risk of all-cause death [adjusted hazard ratio (HR adj ) 0.67, 95% confidence interval (CI) 0.48-0.94, P = 0.022], whereas no difference was noted for HFmrEF patients. After multivariable adjustment, a lower risk of all-cause death (HR adj for 5% increase 0.94, 95% CI 0.89-0.99, P = 0.017) and cardiovascular death (HR adj for 5% increase 0.94, 95% CI 0.88-1.00, P = 0.049) was observed at higher EF values. Beta-blockers and renin-angiotensin system inhibitors or sacubitril/valsartan were associated with lower mortality in both EF < 50% and EF ≥ 50% groups., Conclusions: Among patients with HF and at least one 'I NEED HELP' marker for advanced HF, left ventricular EF is still of prognostic value., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Ventilation vs. carbon dioxide production (VE/VCO 2 ) is among the strongest cardiopulmonary exercise testing prognostic parameters in heart failure (HF). It is usually reported as an absolute value. The current definition of normal VE/VCO 2 slope values is inadequate, since it was built from small groups of subjects with a particularly limited number of women and elderly. We aimed to define VE/VCO 2 slope prediction formulas in a sizable population and to test whether the prognostic power of VE/VCO 2 slope in HF was different if expressed as a percentage of the predicted value or as an absolute value., Methods and Results: We calculated the linear regressions between age and VE/VCO 2 slope in 1136 healthy subjects (68% male, age 44.9 ± 14.5, range 13-83 years). We then applied age-adjusted and sex-adjusted formulas to predict VE/VCO 2 slope to HF patients included in the metabolic exercise test data combined with cardiac and kidney indexes score database, which counts 6112 patients (82% male, age 61.4 ± 12.8, left ventricular ejection fraction 33.2 ± 10.5%, peakVO 2 14.8 ± 4.9, mL/min/kg, VE/VCO 2 slope 32.7 ± 7.7) from 24 HF centres. Finally, we evaluated whether the use of absolute values vs. percentages of predicted VE/VCO 2 affected HF prognosis prediction (composite of cardiovascular mortality + urgent transplant or left ventricular assist device). We did so in the entire cardiac and kidney indexes score population and separately in HF patients with severe (peakVO 2 < 14 mL/min/kg, n = 2919, 61.1 events/1000 pts/year) or moderate (peakVO 2 ≥ 14 mL/min/kg, n = 3183, 19.9 events/1000 pts/year) HF. In the healthy population, we obtained the following equations: female, VE/VCO 2 = 0.052 × Age + 23.808 (r = 0.192); male, VE/VCO 2 = 0.095 × Age + 20.227 (r = 0.371) (P = 0.007). We applied these formulas to calculate the percentages of predicted VE/VCO 2 values. The 2-year survival prognostic power of VE/VCO 2 slope was strong, and it was similar if expressed as absolute value or as a percentage of predicted value (AUCs 0.686 and 0.690, respectively). In contrast, in severe HF patients, AUCs significantly differed between absolute values (0.637) and percentages of predicted values (0.650, P = 0.0026). Moreover, VE/VCO 2 slope expressed as a percentage of predicted value allowed to reclassify 6.6% of peakVO 2 < 14 mL/min/kg patients (net reclassification improvement = 0.066, P = 0.0015)., Conclusions: The percentage of predicted VE/VCO 2 slope value strengthens the prognostic power of VE/VCO 2 in severe HF patients, and it should be preferred over the absolute value for HF prognostication. Furthermore, the widespread use of VE/VCO 2 slope expressed as percentage of predicted value can improve our ability to identify HF patients at high risk, which is a goal of utmost clinical relevance., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)