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

Aims Methods and results Conclusions The effects of initiating sacubitril/valsartan in patients with stable heart failure with reduced ejection fraction (HFrEF) on response to fluid and sodium expansion are unknown.We have explored changes in natriuresis, diuresis, and congestion in response to the administration of intravenous fluid/sodium load in patients with HFrEF before as compared to after the initiation of sacubitril/valsartan. At baseline (before sacubitril/valsartan initiation) and 2 and 3 months after the initiation, patients underwent an evaluation that consisted of three phases of 3 h: the rest phase (0–3 h), the load phase (3–6 h) in which 1 L of intravenous Ringer solution was administered, and the diuretic phase (6–9 h) at the beginning of which furosemide was administered. Overall, 216 patients completed the study. In comparison to baseline values, at 2 and 3 months after sacubitril/valsartan initiation, patients' diuresis and natriuresis in response to Ringer administration significantly increased (mean difference: 38.8 [17.38] ml, p = 0.0040, and 9.6 [2.02] mmol, p < 0.0001, respectively). Symptoms and signs of congestion after the fluid/sodium challenge were significantly decreased at months 2 and 3 compared to baseline. Compared to baseline, there was also an increment of natriuresis after furosemide administration on sacubitril/valsartan (9.8 [5.13] mmol, p = 0.0167). There was a significant decrease in body weight in subsequent visits when compared to baseline values (−0.50 [−12.7, 7.4] kg at 2 months, and −0.75 [−15.9, 7.5] kg at 3 months; both p < 0.0001).The initiation of sacubitril/valsartan in HFrEF patients was associated with improvements in natriuresis, diuresis, and weight loss and better clinical adaptation to potentially decongestive stressors. [ABSTRACT FROM AUTHOR]

Because signs of congestion are associated with adverse outcomes in patients with acute heart failure (AHF), attempts were made to decongest patients as much as possible with diuretic agents (loop diuretic agents, thiazides, acetazolamide) or mechanical devices. Those interventions improved signs of congestion but failed to meaningfully improve patients' symptoms, improve quality of life, or reduce early readmissions or deaths. Recent studies have shown that implementation of guideline-directed medical therapies after an AHF admission led to both more decongestion and improved symptoms, quality of life, and outcomes. Therefore, for most patients with AHF whose symptoms and congestion can be controlled with loop diuretic agents, the main focus should be rapid guideline-directed medical therapy uptitration. Enhanced decongestion, ie, adding a second-line diuretic agent to a loop diuretic agent, should be reserved for those patients who do not respond to loop diuretic agents. [Display omitted] • Congestion in patients with AHF is associated with poor outcomes and frequent hospital readmissions. • Enhanced decongestion leads to minimal improvement in symptoms or outcomes in patients with AHF. • Greater focus on GDMT after discharge can improve outcomes for patients hospitalized with AHF. [ABSTRACT FROM AUTHOR]

Acute heart failure (AHF) is a common cause of hospitalization, particularly among older individuals, and has high mortality and readmission rates. Adherence to guideline-directed medical therapy (GDMT) is crucial for improving outcomes in heart failure (HF) patients, as non-adherence can lead to exacerbations and adverse outcomes. However, studies have shown that medication non-adherence rates among HF patients can be as high as 70%. Various factors contribute to non-adherence, including patient circumstances, treatment-related factors, and healthcare system and payer factors. Adherence interventions, such as patient education, medication regimen management, and reminders, have been shown to improve medication adherence and reduce mortality and hospital readmissions in HF patients. Improving adherence to GDMT is essential for improving AHF outcomes, and further research is needed to identify effective approaches to enhance medication adherence. [Extracted from the article]

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

Background: This study aimed to assess the value of blood and urine biomarkers in addition to routine clinical variables in risk stratification of patients admitted to ICU. Methods: Multivariable prognostic models were developed in this post hoc analysis of the French and EuRopean Outcome ReGistry in Intensive Care Units study, a prospective observational study of patients admitted to ICUs. The study included 2087 patients consecutively admitted to the ICU who required invasive mechanical ventilation or a vasoactive agent for more than 24 h. The main outcome measures were in-ICU, in-hospital, and 1 year mortality. Results: Models including only SAPS II or APACHE II scores had c-indexes for in-hospital and 1 year mortality of 0.64 and 0.65, and 0.63 and 0.61, respectively. The c-indexes for a model including age and estimated glomerular filtration rate were higher at 0.69 and 0.67, respectively. Models utilizing available clinical variables increased the c-index for in-hospital and 1 year mortality to 0.80 and 0.76, respectively. The addition of biomarkers and urine proteomic markers increased c-indexes to 0.83 and 0.78. Conclusions: The commonly used scores for risk stratification in ICU patients did not perform well in this study. Models including clinical variables and biomarkers had significantly higher predictive values. [ABSTRACT FROM AUTHOR]

Acute heart failure (AHF) has been seen throughout the last decades of research as an inevitable step on the way to advanced heart failure (HF), as is evident from the graph presented in I Figure i 1, which is adapted from the 2022 AHA/ACC/HFSA guideline for the management of HF[1] and has been presented in different shapes and forms over the last 20 plus years. Acute heart failure is a remitting-relapsing disorder and not a step towards advanced heart failure: Implications for decongestion therapy In these advanced HF patients, AHF is the culmination of progression of chronic advanced HF,[16] possibly characterizing the trajectory towards stage C/D HF. First, if patients with AHF are in a precursor stage towards advanced HF, they should have the same characteristics as patients with advanced HF, with the main difference being a younger age. [Extracted from the article]

Conclusions The prognosis of patients with AHF can be improved, but to do so physicians' and patients' mindsets must be changed. Lastly, intravenous iron therapy, in patients in whom it is indicated, was examined in the AFFIRM-HF study,[15] suggesting a relative reduction in 6-month risk of HF hospitalizations or CV death of approximately 18% in patients with EF <50% ( I Figure i 1C). Patients were enrolled in STRONG-HF regardless of ejection fraction (EF) and no interaction was found between treatment intensification and EF, with numerically higher treatment effects seen in patients with higher EF. Research into acute heart failure (AHF) therapy at and after discharge has progressed significantly in recent years.[1] Despite this progress, patients' outcomes and quality of life remain dismal, leaving much room for improvement.[[2], [4]] Acute heart failure is a severe disease with dire prognosis during the first 3-6 months after... Although any manuscript on AHF starts with this comment in both introduction and discussion, the severity of the disease does not seem to be fully appreciated. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Aims: This retrospective analysis sought to identify markers that might distinguish between acute heart failure (HF) and worsening HF in chronic outpatients. Methods and results: The BIOSTAT‐CHF index cohort included 2516 patients with new or worsening HF symptoms: 1694 enrolled as inpatients (acute HF) and 822 as outpatients (worsening HF in chronic outpatients). A validation cohort included 935 inpatients and 803 outpatients. Multivariable models were developed in the index cohort using clinical characteristics, routine laboratory values, and proteomics data to examine which factors predict adverse outcomes in both conditions and to determine which factors differ between acute HF and worsening HF in chronic outpatients, validated in the validation cohort. Patients with acute HF had substantially higher morbidity and mortality (6‐month mortality was 12.3% for acute HF and 4.7% for worsening HF in chronic outpatients). Multivariable models predicting 180‐day mortality and 180‐day HF readmission differed substantially between acute HF and worsening HF in chronic outpatients. Carbohydrate antigen 125 was the strongest single biomarker to distinguish acute HF from worsening HF in chronic outpatients, but only yielded a C‐index of 0.71. A model including multiple biomarkers and clinical variables achieved a high degree of discrimination with a C‐index of 0.913 in the index cohort and 0.901 in the validation cohort. Conclusions: This study identifies different characteristics and predictors of outcome in acute HF patients as compared to outpatients with chronic HF developing worsening HF. The markers identified may be useful in better diagnosing acute HF and may become targets for treatment development. [ABSTRACT FROM AUTHOR]

Liver biopsies are a critical component of pivotal studies in non-alcoholic steatohepatitis (NASH), constituting inclusion criteria, risk stratification factors and endpoints. We evaluated the reliability of NASH Clinical Research Network scoring of liver biopsies in a NASH clinical trial. Digitized slides of 678 biopsies from 339 patients with paired biopsies randomized into the EMMINENCE study – examining a novel insulin sensitizer (MSDC-0602K) in NASH – were read independently by 3 hepatopathologists blinded to treatment code and scored using the NASH CRN histological scoring system. Various endpoints were computed from these scores. Inter-reader linearly weighted kappas were 0.609, 0.484, 0.328, and 0.517 for steatosis, fibrosis, lobular inflammation, and ballooning, respectively. Inter-reader unweighted kappas were 0.400 for the diagnosis of NASH, 0.396 for NASH resolution without worsening fibrosis, and 0.366 for fibrosis improvement without worsening NASH. In the current study, 46.3% of the patients included in the study based on 1 hepatopathologist's qualifying reading were deemed not to meet the study's histologic inclusion criteria by at least 1 of the 3 hepatopathologists. The MSDC-0602K treatment effect was lowest for those histologic features with lower inter-reader reliability. Simulations show that the lack of reliability of endpoints and inclusion criteria can drastically reduce study power – from >90% in a well-powered study to as low as 40%. The reliability of hepatopathologists' liver biopsy evaluation using currently accepted criteria is suboptimal. This lack of reliability may affect NASH pivotal studies by introducing patients who do not meet NASH study entry criteria, misclassifying fibrosis subgroups, and attenuating apparent treatment effects. Since liver biopsy analysis plays such an important role in clinical studies of non-alcoholic steatohepatitis, it is important to understand the reliability of hepato-pathologist readings. We examined both inter- and intra-reader variability in a large data set of paired liver biopsies from a clinical trial. We found very poor inter-reader and modest intra-reader variability. This result has important implications for entry criteria, fibrosis stratification, and the ability to measure a treatment effect in clinical trials. • Liver biopsy is a critical inclusion criteria and outcome measure in NASH studies. • Reader variability was tested in 678 biopsies from a NASH study of MSDC-0602K. • Kappas were poor for the diagnosis of NASH, its resolution and fibrosis improvement. • Almost half of the patients would have been excluded from entry by 1 of the readers. • Poor reliability allows improper entry, misclassification, and diminishes treatment effect. [ABSTRACT FROM AUTHOR]

Aims: Over the last 30 years, many medicine development programmes in acute and chronic heart failure (HF) with preserved ejection fraction (HFpEF) have failed, in contrast to those in HF with reduced ejection fraction (HFrEF). We explore how the neutral results in larger HF trials may be attributable to chance and/or the dilution of statistical power.Methods and Results: Using simulations, we examined the probability that a positive finding in a Phase 2 trial would result in the study of a truly effective medicine in a Phase 3 trial. We assessed the similarity of clinical trial and registry patient populations. We conducted a meta-analysis of paired Phase 2 and 3 trials in HFrEF and acute HF examining the associations of trial phase and size with placebo event rates and treatment effects for HF events and death. We estimated loss in trial power attributable to dilution with increasing trial size. Appropriately powered Phase 3 trials should have yielded ∼35% positive results. Patient populations in Phase 3 trials are similar to those in Phase 2 trials but both differ substantially from the populations of 'real-life' registries. We observed decreasing placebo event rates and smaller treatment effects with increasing trial size, especially for HF events (and less so for mortality). This was more pronounced in trials in acute HF patients.Conclusions: The selection of more positive Phase 2 trials for further development does not explain the failure of HFpEF and acute HF medicine development. Increasing sample size may lead to reduced event rates and smaller treatment effects, resulting in a high rate of neutral Phase 3 trials. [ABSTRACT FROM AUTHOR]

Aims: The effectiveness and safety of 48 h intravenous 30 μg/kg/day serelaxin infusion in acute heart failure (AHF) has been studied in six randomized, controlled clinical trials.Methods and Results: We conducted a fixed-effect meta-analysis including all studies of intravenous serelaxin initiated within the first 16 h of admission for AHF. Endpoints considered were the primary and secondary endpoints examined in the serelaxin phase III studies. In six randomized controlled trials, 6105 total patients were randomized to receive intravenous serelaxin 30 μg/kg/day and 5254 patients to control. Worsening heart failure to day 5 occurred in 6.0% and 8.1% of patients randomized to serelaxin and control, respectively (hazard ratio 0.77, 95% confidence interval 0.67-0.89; P = 0.0002). Serelaxin had no statistically significant effect on length of stay, or cardiovascular death, or heart or renal failure rehospitalization. Serelaxin administration resulted in statistically significant improvement in markers of renal function and reductions in both N-terminal pro-B-type natriuretic peptide and troponin. No significant adverse outcomes were noted with serelaxin. Through the last follow-up, which occurred at an average of 4.5 months (1-6 months), serelaxin administration was associated with a reduction in all-cause mortality, with an estimated hazard ratio of 0.87 (95% confidence interval 0.77-0.98; P = 0.0261).Conclusions: Administration of intravenous serelaxin to patients admitted for AHF was associated with a highly significant reduction in the risk of 5-day worsening heart failure and in changes in renal function markers, but not length of stay, or cardiovascular death, or heart or renal failure rehospitalization. Serelaxin administration was safe and associated with a significant reduction in all-cause mortality. [ABSTRACT FROM AUTHOR]

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

Background Site selection is critical in acute heart failure trials. We assessed whether the enrollment rate per site affects patients' characteristics, outcomes and treatment response. Methods and results A total of 1161 patients enrolled at 96 sites in the RELAX-AHF trial (serelaxin vs placebo) were included. Annualized enrollment rate was calculated as the total number of patients enrolled at each site divided by time that the site was open (patients per year). Sites were classified in low (< 10), medium (10–20) and high enrolling sites (> 20 patients per site/year) and were compared for prognosis and serelaxin effect. High enrolling sites were more prevalent in Eastern Europe and Israel. Time from hospital admission to randomization was shorter in high enrolling sites (6.3 ± 4.4 h > 20 patients sites versus 8.7 ± 4.5 h for < 10 patients sites; p < 0.0001). Patients had slightly fewer comorbidities, lower levels of natriuretic peptides and creatinine and more severe pulmonary congestion in high enrolling sites. Use of evidence-based therapies was higher in high enrolling sites. The rates of worsening heart failure to day 5, 180-day cardiovascular and all-cause mortality and 60-day heart failure/renal failure rehospitalization or cardiovascular death, were similar across study groups even after adjustment for covariates. The effects of serelaxin on these outcomes did not differ by enrollment rate. Conclusions Characteristics of RELAX-AHF study patients enrolled in high versus low enrolling sites differed only slightly and there were no differences in outcomes. Differences in serelaxin effects by enrollment rate were not discernible. [ABSTRACT FROM AUTHOR]

Aims: The course of patients following admission for acute heart failure (AHF) is of major importance to patients and healthcare providers. We examined predictors and associations of length of stay (LOS), 30-day post-discharge readmission and 90-day post-discharge mortality in 1990 patients enrolled in the PROTECT study.Methods and Results: PROTECT was a randomized study that examined the effect of the adenosine blocker rolofylline in patients within 24 h of admission for AHF with mild to moderate renal impairment. Geographic-region-adjusted multivariable models showed that LOS was only partly explained by the severity of heart failure (HF), comorbidities (diabetes mellitus, renal impairment, ischaemic heart disease) and degree of metabolic dysfunction (cholesterol and albumin) at baseline (adjusted R(2) 0.27). Addition of in-hospital worsening heart failure (WHF) and changes in metabolic markers contributed significantly to prediction of LOS [R(2) difference 0.050, 95% confidence interval (CI) 0.0282-0.072]. Thirty-day HF readmission was associated with more severe HF and previous HF admission but not with LOS (odds ratios 1.00, 95% CI 0.97-1.04). Death within 90 days after discharge was associated with older age, more severe HF, worse renal function, and lower sodium and bicarbonate at admission; LOS was a strong predictor of 90-day post-discharge mortality.Conclusions: In patients admitted for AHF, LOS is not well-predicted by traditional markers of disease severity, but strongly associated with the occurrence of in-hospital WHF. Longer LOS is a strong predictor of early mortality after discharge but not of readmission. These findings may help focus efforts to reduce LOS and post-discharge outcomes on patients' subgroups at increased risk. [ABSTRACT FROM AUTHOR]

Thus, efficacy and safety analyses will be conducted in only the analysis set comprising randomized patients, excluding only patients randomized erroneously, and placing patients in their assigned treatment groups for analysis. Patients are not adequately treated in the vulnerable period following discharge from a hospital admission for acute heart failure (AHF).1,2 The Safety, Tolerability and efficacy of Rapid Optimization, helped by NT-proBNP and GDF-15, of Heart Failure therapies (STRONG-HF) study (ClinicalTrials.gov NCT03412201) was designed to assess whether rapid optimization of oral heart failure therapies, using frequent visits and biomarkers to monitor congestion, within a short time following discharge from a hospitalization for AHF can improve clinical outcomes.3 A total of 900 patients were to be randomized 1:1 to either "high-intensity" or "usual" care and followed for 90 days. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). [Extracted from the article]

Aims: Cardiopoiesis is a conditioning programme that aims to upgrade the cardioregenerative aptitude of patient-derived stem cells through lineage specification. Cardiopoietic stem cells tested initially for feasibility and safety exhibited signs of clinical benefit in patients with ischaemic heart failure (HF) warranting definitive evaluation. Accordingly, CHART-1 is designed as a large randomized, sham-controlled multicentre study aimed to validate cardiopoietic stem cell therapy.Methods: Patients (n = 240) with chronic HF secondary to ischaemic heart disease, reduced LVEF (<35%), and at high risk for recurrent HF-related events, despite optimal medical therapy, will be randomized 1:1 to receive 600 × 10(6) bone marrow-derived and lineage-directed autologous cardiopoietic stem cells administered via a retention-enhanced intramyocardial injection catheter or a sham procedure. The primary efficacy endpoint is a hierarchical composite of mortality, worsening HF, Minnesota Living with Heart Failure Questionnaire score, 6 min walk test, LV end-systolic volume, and LVEF at 9 months. The secondary efficacy endpoint is the time to cardiovascular death or worsening HF at 12 months. Safety endpoints include mortality, readmissions, aborted sudden deaths, and serious adverse events at 12 and 24 months.Conclusion: The CHART-1 clinical trial is powered to examine the therapeutic impact of lineage-directed stem cells as a strategy to achieve cardiac regeneration in HF populations. On completion, CHART-1 will offer a definitive evaluation of the efficacy and safety of cardiopoietic stem cells in the treatment of chronic ischaemic HF.Trial Registration: NCT01768702. [ABSTRACT FROM AUTHOR]

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 a double-blind, placebo-controlled trial, enrolling 1161 patients admitted to hospital for AHF who were randomized to 48 h i.v infusions of placebo or serelaxin (30 µg/kg per day) within 16 h from presentation. Diuretic response was defined as Δ weight kg/[(total i.v. dose)/40 mg] + [(total oral dose)/80 mg)] furosemide (or equivalent loop diuretic dose) up to day 5. Median diuretic response was -0.42 (-1.00, -0.14) kg/40 mg. A poor diuretic response was independently associated with Western-like region (Western Europe, North America, Israel, and Poland), lower diastolic blood pressure, the absence of oedema, higher blood urea nitrogen, and lower levels of aspartate aminotransferase and potassium (all P < 0.01). Randomization to serelaxin was associated with lower doses of i.v. loop diuretics and slightly less weight loss, resulting in a neutral effect on diuretic response. Worse diuretic response was independently associated both with less relief of dyspnoea, measured with a visual analogue scale (VAS) at day 5 (primary endpoint; P = 0.0002), and with a higher risk of cardiovascular death or rehospitalization for heart failure or renal failure through day 60 (secondary endpoint, P < 0.0001), but not with increased 180-day cardiovascular mortality (P = 0.507).Conclusions: In patients hospitalized for AHF, a poor diuretic response was associated with a poor in-hospital and early post-discharge clinical outcome. Serelaxin had a neutral effect on diuretic response.Trial Registration: NCT00520806. [ABSTRACT FROM AUTHOR]

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 a double-blind, placebo-controlled trial, enrolling 1161 patients admitted to hospital for AHF who were randomized to 48 h i.v infusions of placebo or serelaxin (30 µg/kg per day) within 16 h from presentation. Diuretic response was defined as Δ weight kg/[(total i.v. dose)/40 mg] + [(total oral dose)/80 mg)] furosemide (or equivalent loop diuretic dose) up to day 5. Median diuretic response was −0.42 (−1.00, −0.14) kg/40 mg. A poor diuretic response was independently associated with Western-like region (Western Europe, North America, Israel, and Poland), lower diastolic blood pressure, the absence of oedema, higher blood urea nitrogen, and lower levels of aspartate aminotransferase and potassium (all P < 0.01). Randomization to serelaxin was associated with lower doses of i.v. loop diuretics and slightly less weight loss, resulting in a neutral effect on diuretic response. Worse diuretic response was independently associated both with less relief of dyspnoea, measured with a visual analogue scale ( VAS) at day 5 (primary endpoint; P = 0.0002), and with a higher risk of cardiovascular death or rehospitalization for heart failure or renal failure through day 60 (secondary endpoint, P < 0.0001), but not with increased 180-day cardiovascular mortality ( P = 0.507). Conclusions In patients hospitalized for AHF, a poor diuretic response was associated with a poor in-hospital and early post-discharge clinical outcome. Serelaxin had a neutral effect on diuretic response. Trial registration: NCT00520806 [ABSTRACT FROM AUTHOR]

Aims In Western countries with typically elderly ischaemic acute heart failure patients, predictors and clinical outcome of renal dysfunction and worsening renal function are well described. However, the prevalence, predictors and clinical outcome of renal dysfunction in younger, mainly hypertensive acute heart failure patients from Africa, have not been described. Methods and results From 1006 patients enrolled in the sub-Saharan Africa Survey of Heart Failure ( THESUS-HF), renal function was determined by the estimated glomerular filtration rate using the Modification of Diet in Renal Disease ( MDRD) formula. Worsening renal function was defined as an increase in creatinine ≤0.3 mg/ dL (26.5 µmol/L) from baseline to day 7/discharge. The mean ( SD) age of the patients was 52.4 (18.2) years, 481 (50.8%) were women and the predominant race was black African [932 of 946 (98.5%)]. Heart failure was most commonly a result of hypertension ( n = 363, 39.5%) and only 7.8% had ischaemic heart failure. At hospital admission, 289 patients (30.6%) had an estimated glomerular filtration rate ≤60 ml/min.1.73m2. Worsening renal function during hospitalization was detected in 53 (9.8 %) of 543 patients with a follow-up creatinine value, and was independently associated with the Western sub-Saharan region, body mass index, and the presence of rales. Worsening renal function was an independent predictor of death or readmission over 60 days [multivariable hazard ratio = 2.06 (1.10, 3.38); P = 0.023] and all-cause death over 180 days [multivariable hazard ratio =1.92 (1.08, 3.38); P = 0.025]. Conclusions Renal dysfunction is also prevalent in younger non-ischaemic acute heart failure patients in Africa, but worsening renal function is less prevalent and has different predictors compared with Western cohorts. Nevertheless, worsening renal function is strongly and independently related with clinical outcome. [ABSTRACT FROM AUTHOR]

Aims We aimed to determine the relation between baseline systolic blood pressure (SBP), change in SBP, and worsening renal function (WRF) in acute heart failure (AHF) patients enrolled in the Pre-RELAX-AHF trial. Methods and results The Pre-RELAX-AHF study enrolled 234 patients within 16 h of admission (median 7 h) for AHF and randomized them to relaxin given intravenous (i.v.) for 48 h or placebo. Blood pressure was measured at baseline, at 3, 6, 9, 12, 24, 36, and 48 h and at 3, 4, and 5 days after enrolment. Worsening renal function was defined as a serum creatinine increase of ≥0.3 mg/dL by Day 5. Worsening renal function was found in 68 of the 225 evaluable patients (30%). Patients with WRF were older (73.5 ± 9.4 vs. 69.1 ± 10.6 years; P= 0.003), had a higher baseline SBP (147.3 ± 19.9 vs. 140.8 ± 16.7 mmHg; P= 0.01), and had a greater early drop in SBP (37.9 ± 16.0 vs. 31.4 ± 12.2 mmHg; P= 0.004). In a multivariable model, higher age, higher baseline creatinine, and a greater early drop in SBP, but not baseline SBP, remained independent predictors of WRF. Furthermore, WRF was associated with a higher Day 60 (P= 0.01), and Day 180 (P= 0.003) mortality. Conclusions Worsening renal function in hospitalized AHF patients is related to a poor clinical outcome and is predicted by a greater early drop in SBP. [ABSTRACT FROM AUTHOR]

Objectives: Recent heart failure studies have suggested that inflammatory and immune system activation are associated with increased levels of cytokines, chemokines and inflammatory proteins during acutely decompensated heart failure. The objectives of this substudy were to evaluate the role of neurohormonal and inflammatory activation in the pathogenesis and outcome of acute heart failure (AHF) and the correlation between biomarker levels and clinical outcomes. Methods: Serum levels of B-type natriuretic peptide-32 (BNP-32), endothelin-1 (ET-1), norepinephrine, troponins I and T, C-reactive protein (CRP), von Willebrand factor, plasminogen activator inhibitor-1, interleukin-6 (IL-6) and tissue plasminogen activator (TPA) were measured at baseline, 24 and 48 h and 7 and 30 days in 112 patients with AHF recruited to the Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Study neurohormonal substudy. Results: On univariable analysis, CRP, BNP and ET-1 were predictive of worsening heart failure by day 30; when considered together, only CRP and BNP were significantly associated with this outcome. On adjustment for age, baseline blood pressure, serum sodium and serum creatinine, only age and BNP remained significant. CRP, IL-6 and TPA levels were significantly correlated with 180-day mortality on univariable analysis. Conclusion: Circulating markers of inflammation may be useful in gauging prognosis in patients with AHF. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The armamentarium of therapies for patients with heart failure and reduced ejection fraction (HFREF) has increase substantially with the introduction of Angiotensin Receptor Neprilysin Inhibitor (ARNi), sodium glucose cotransport inhibitors (SGLTis), ivabradine, and Vericinguat, bringing to seven the number of potential therapies for HFREF. In the current review we highlight available data on the different classes of medications. Renin angiotensin blockers (RAASbs) and beta blockers (BBs) were shown to have very substantial effects in patients with HFREF. These medications are generic and hence relatively inexpensive. They have a 30-year track record of relatively benign short- and long-term safety profiles and should remain the cornerstone of therapy for patients with HFREF. ARNis are effective in further reducing adverse effects and should replace RAASbs in symptomatic HFREF patients, despite their relatively high prices. The addition of SGLTis (congested patients), Ivabradine (tachycardic patients), and Vericinguat (hypertensive patients) should be considered in patients who remain symptomatic despite optimal doses of RAASbs/ARNis, MRAs, and BBs. Comparative studies examining the efficacy of these medications, and strategies and prioritizing some over others should be considered as, given their similar side effects on heart rate, blood pressure, and renal function, it is highly unlikely that all can be given to the same patient. [ABSTRACT FROM AUTHOR]

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

Background: Neurohormonal (NH) activation characterizes the heart failure (HF) syndrome and is a well-established therapeutic target. Acute HF (AHF) presumably results from or is due to even greater NH activation, contributing to the high post-discharge morbidity and mortality. Objective: To describe the association between plasma renin activity (PRA) and 3 separate AHF outcomes a) worsening HF (WHF) or death through day 5; b) HF hospitalization or all-cause death through day 30; c) all-cause death through day 30. Methods: A secondary analysis of the BLAST-AHF (Biased Ligand of the Angiotensin II Type 1 Receptor) Trial, a Phase II, global, dose-finding, randomized, controlled study of TRV027 that enrolled 621 patients. Eligible patients had a history of HF, elevated natriuretic peptide level, signs and symptoms of HF, a SBP > 120mmHg, and an eGFR between 20-75ml/min/1.73m2. The primary trial was neutral, with no differential effect of TRV027 by PRA level. PRA was measured at baseline and divided into tertiles to compare baseline characteristics. Cox-proportional hazard modelling considered PRA as a continuous variable using well-established prognostic co-variates, with α set at p<0.05. Results: Of 621 randomized patients, 578 (93.1%) had a baseline PRA. See Table for several key baseline characteristics. Using doubling of PRA to determine the effect size, PRA was significantly, but modestly, associated with each outcome by univariable association (WHF or death through day 5 (HR 1.11 (95%CI 1.01-1.23, p=0.04)); HF hospitalization or death through day 30 (HR 1.13 (95% CI 1.02-1.26, p=0.02)), all-cause death through day 30 (1.18 (95% CI 1.02-1.37, p=0.03). After multivariable adjustment, PRA was no longer significantly associated with any outcome. Conclusion: In this retrospective analysis from BLAST-AHF, baseline PRA levels were not associated with worse outcomes, suggesting acute neurohormonal blockade may be less beneficial in AHF vs chronic HF. [ABSTRACT FROM AUTHOR]

• A new insulin sensitizer can be dosed to full effect without dose-limiting side effects. • MSDC-0602K improved glucose metabolism and liver enzyme levels in patients with NASH, with or without T2D. • Dose-dependent improvements were seen for all categories of liver histology. • Aspartate aminotransferase and glycated hemoglobin cut-offs defined patients who benefitted most from treatment. MSDC-0602K is a novel insulin sensitizer designed to preferentially target the mitochondrial pyruvate carrier while minimizing direct binding to the transcriptional factor PPARγ. Herein, we aimed to assess the efficacy and safety of MSDC-0602K in patients with non-alcoholic steatohepatitis. Patients with biopsy-confirmed NASH and fibrosis (F1-F3) were randomized to daily oral placebo, or 1 of 3 MSDC-0602K doses in a 52-week double-blind study. The primary efficacy endpoint was hepatic histological improvement of ≥2 points in non-alcoholic fatty liver disease activity score (NAS) with a ≥1-point reduction in either ballooning or lobular inflammation and no increase in fibrosis stage at 12 months. Secondary endpoints included NAS improvement without worsening fibrosis, NASH resolution, and fibrosis reduction. Exploratory endpoints included changes in insulin sensitivity, liver injury and liver fibrosis markers. Patients were randomly assigned to placebo (n = 94), or 62.5 mg (n = 99), 125 mg (n = 98), or 250 mg (n = 101) of MSDC-0602K. At baseline, glycated hemoglobin was 6.4 ± 1.0%, 61.5% of patients had fibrosis F2/F3 and the average NAS was 5.3. The primary endpoint was reached in 29.7%, 29.8%, 32.9% and 39.5% of patients in the placebo, 62.5 mg, 125 mg and 250 mg dose arms, respectively, with adjusted odds ratios relative to placebo of 0.89 (95% CI 0.44–1.81), 1.22 (95% CI 0.60–2.48), and 1.64 (95% CI 0.83–3.27). The 2 highest doses of MSDC-0602K led to significant reductions in glucose, glycated hemoglobin, insulin, liver enzymes and NAS compared to placebo. The incidence of hypoglycemia and PPARγ-agonist-associated events such as edema and fractures were similar in the placebo and MSDC-0602K groups. MSDC-0602K did not demonstrate statistically significant effects on primary and secondary liver histology endpoints. However, effects on non-invasive measures of liver cell injury and glucose metabolism support further exploration of MSDC-0602K's safety and potential efficacy in patients with type 2 diabetes and liver injury. [ClinicalTrials.gov Identifier: NCT02784444]. First-generation insulin sensitizers are used to treat type 2 diabetes, but are associated with side effects including edema, bone fractures, and hypoglycemia. MSDC-0602K is a second-generation insulin sensitizer designed to reduce these side effects. We hypothesized that insulin sensitization could improve non-alcoholic steatohepatitis. In the current study of patients with non-alcoholic steatohepatitis, MSDC-0602K did not demonstrate significant effects on liver histology with the biopsy techniques used. However, useful information was gained for the design of future studies and MSDC-0602K significantly decreased fasting glucose, insulin, glycated hemoglobin, and markers of liver injury without dose-limiting side effects. [ABSTRACT FROM AUTHOR]

Aims: Patients admitted for acute heart failure (HF) are at high risk of readmission and death, especially in the 90 days following discharge. We aimed to assess the safety and efficacy of early optimization of oral HF therapy with beta-blockers (BB), angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) or angiotensin receptor-neprilysin inhibitors (ARNi), and mineralocorticoid receptor antagonists (MRA) on 90-day clinical outcomes in patients admitted for acute HF.Methods: In a multicentre, randomized, open-label, parallel-group study, a total of 900 patients will be randomized in a 1:1 ratio to either 'usual care' or 'high-intensity care'. Patients enrolled in the usual care arm will be discharged and managed according to usual clinical practice at the site. In the high-intensity care arm, doses of oral HF medications - including a BB, ACEi or ARB, and MRA - will be up-titrated to 50% of recommended doses before discharge and to 100% of recommended doses within 2 weeks of discharge. Up-titration will be delayed if the patients develop worsening symptoms and signs of congestion, hyperkalaemia, hypotension, bradycardia, worsening of renal function or significant increase in N-terminal pro-B-type natriuretic peptide between visits. The primary endpoint is 90-day all-cause mortality or HF readmission.Conclusions: STRONG-HF is the first study to assess whether rapid up-titration of evidence-based guideline-recommended therapies with close follow-up in a large cohort of patients discharged from an acute HF admission is safe and can affect adverse outcomes during the first 90 days after discharge.Clinical Trial Registration: ClinicalTrials.gov Identifier NCT03412201. [ABSTRACT FROM AUTHOR]

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

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

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

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

Aims: Changes in systolic blood pressure (SBP) during an admission for acute heart failure (AHF), especially those leading to hypotension, have been suggested to increase the risk for adverse outcomes.Methods and Results: We analysed associations of SBP decrease during the first 24 h from randomization with serum creatinine changes at the last time-point available (72 h), using linear regression, and with 30- and 180-day outcomes, using Cox regression, in 1257 patients in the VERITAS study. After multivariable adjustment for baseline SBP, greater SBP decrease at 24 h from randomization was associated with greater creatinine increase at 72 h and greater risk for 30-day all-cause death, worsening heart failure (HF) or HF readmission. The hazard ratio (HR) for each 1 mmHg decrease in SBP at 24 h for 30-day death, worsening HF or HF rehospitalization was 1.01 [95% confidence interval (CI) 1.00-1.02; P = 0.021]. Similarly, the HR for each 1 mmHg decrease in SBP at 24 h for 180-day all-cause mortality was 1.01 (95% CI 1.00-1.03; P = 0.038). The associations between SBP decrease and outcomes did not differ by tezosentan treatment group, although tezosentan treatment was associated with a greater SBP decrease at 24 h.Conclusions: In the current post hoc analysis, SBP decrease during the first 24 h was associated with increased renal impairment and adverse outcomes at 30 and 180 days. Caution, with special attention to blood pressure monitoring, should be exercised when vasodilating agents are given to AHF patients. [ABSTRACT FROM AUTHOR]

Aims Changes in systolic blood pressure (SBP) during an admission for acute heart failure (AHF), especially those leading to hypotension, have been suggested to increase the risk for adverse outcomes. Methods and results We analysed associations of SBP decrease during the first 24 h from randomization with serum creatinine changes at the last time-point available (72 h), using linear regression, and with 30- and 180-day outcomes, using Cox regression, in 1257 patients in the VERITAS study. After multivariable adjustment for baseline SBP, greater SBP decrease at 24 h from randomization was associated with greater creatinine increase at 72 h and greater risk for 30-day all-cause death, worsening heart failure (HF) or HF readmission. The hazard ratio (HR) for each 1mmHg decrease in SBP at 24 h for 30-day death, worsening HF or HF rehospitalization was 1.01 [95% confidence interval (CI) 1.00-1.02; P =0.021]. Similarly, the HR for each 1mmHg decrease in SBP at 24h for 180-day all-cause mortality was 1.01 (95% CI 1.00-1.03; P =0.038). The associations between SBP decrease and outcomes did not differ by tezosentan treatment group, although tezosentan treatment was associated with a greater SBP decrease at 24 h. Conclusions In the current post hoc analysis, SBP decrease during the first 24 h was associated with increased renal impairment and adverse outcomes at 30 and 180 days. Caution, with special attention to blood pressure monitoring, should be exercised when vasodilating agents are given to AHF patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Plasma concentrations of B-type natriuretic peptide (BNP) and troponin are often measured for diagnostic purposes when patients are admitted with heart failure, but their prognostic value when measured soon after admission is uncertain. We aimed to investigate the added prognostic value of admission measurements of BNP and troponins in patients with acute heart failure.Methods and Results: Multivariable prognostic models for death or any worsening heart failure (WHF) or rehospitalization for WHF by 30 days, 30-day death or rehospitalization for WHF, and 90-day mortality were constructed using baseline data from the Value of Endothelin Receptor Inhibition with Tezosentan in Acute heart failure Studies (VERITAS) including BNP and troponin I. Of 1347 patients, the median (interquartile range) value of BNP was 422 (156-945) pg/mL and 855 (63%) had measurable troponin I. By 30 days, 432 patients had died or experienced WHF. Clinical variables had only moderate predictive performance that was not substantially improved by BNP or troponin I (c-indices 0.6528 and 0.6595, respectively). By 30 days, 150 patients died or were rehospitalized for WHF. The c-index using clinical variables (0.6855) was not improved by adding biomarkers. By 90 days, 135 patients had died. The c-index for mortality was somewhat better than for composite outcomes (0.7394) but improved little with biomarkers (0.7461).Conclusion: Routine clinical data recorded at the time of admission in patients with acute heart failure are poor at predicting recurrent admissions but somewhat better at predicting mortality. Neither BNP nor troponin measured at admission improved predictions; measurement closer to discharge, or of other novel biomarkers, might perform differently. [ABSTRACT FROM AUTHOR]

Objective Plasma concentrations of B-type natriuretic peptide (BNP) and troponin are often measured for diagnostic purposes when patients are admitted with heart failure, but their prognostic value when measured soon after admission is uncertain. We aimed to investigate the added prognostic value of admission measurements of BNP and troponins in patients with acute heart failure. Methods and results Multivariable prognostic models for death or any worsening heart failure (WHF) or rehospitalization for WHF by 30 days, 30-day death or rehospitalization for WHF, and 90-day mortality were constructed using baseline data from the Value of Endothelin Receptor Inhibition with Tezosentan in Acute heart failure Studies (VERITAS) including BNP and troponin I. Of 1347 patients, the median (interquartile range) value of BNP was 422 (156-945) pg/mL and 855 (63%) had measurable troponin I. By 30 days, 432 patients had died or experienced WHF. Clinical variables had only moderate predictive performance that was not substantially improved by BNP or troponin I (c-indices 0.6528 and 0.6595, respectively). By 30 days, 150 patients died or were rehospitalized for WHF. The c-index using clinical variables (0.6855) was not improved by adding biomarkers. By 90 days, 135 patients had died. The c-index for mortality was somewhat better than for composite outcomes (0.7394) but improved little with biomarkers (0.7461). Conclusion Routine clinical data recorded at the time of admission in patients with acute heart failure are poor at predicting recurrent admissions but somewhat better at predicting mortality. Neither BNP nor troponin measured at admission improved predictions; measurement closer to discharge, or of other novel biomarkers, might perform differently. [ABSTRACT FROM AUTHOR]

Background In-hospital worsening heart failure (WHF) is predictive of worse post-discharge outcomes and has been recently used as an endpoint in clinical trials in acute heart failure (AHF). Methods We described the clinical and prognostic significance of WHF in consecutive patients hospitalized for AHF at our institute. WHF was defined as worsening signs and symptoms of HF requiring treatment intensification. We compared WHF events by day 7 (early WHF) with WHF occurring at any time during admission. The primary endpoint was cardiovascular (CV) death and HF rehospitalizations through day 60. Results We included 387 consecutive patients. Median length of stay was 11 days (interquartile range 8–18 days). Forty-five patients (11.6%) had WHF, HF rehospitalization, or death through day 7 whereas 90 (23.3%) had WHF or died at any time during initial hospitalization. Patients with WHF occurring any time during admission were more symptomatic, had lower systolic blood pressure, worse renal function, and higher troponins at baseline. Both early WHF and WHF at any time during hospitalization were associated with a longer length of stay and higher CV death and HF rehospitalization rates at day 60, but only WHF at any time was associated with all-cause death at day 180 (adjusted HR 2.42 95% CI 1.30, 4.52; p = 0.0055) and with all-cause death any time during the follow-up period (adjusted HR 1.60 95% CI 1.02, 2.53; p = 0.0425). Conclusions Our study confirms the prognostic significance of WHF and shows the independent prognostic value of WHF also for long-term mortality when assessed throughout hospitalization. [ABSTRACT FROM AUTHOR]

Aims: Patients with acute heart failure (HF) in Africa are rarely being treated with a hydralazine/nitrates combination. Therefore the effect of this treatment was studied here.Methods and Results: The study was planned to enrol 500 patients during an acute HF admission, from nine sub-Saharan African countries. Patients were randomized in a double-blind manner to receive 50 mg hydralazine/20 mg isosorbide dinitrate (HYIS) t.i.d. or matching placebo for 24 weeks followed by open label HYIS for all patients. The study was terminated after 147 patients were enrolled due mostly to issues with recruitment into a prospective, placebo-controlled study. Most patients were recruited from Mozambique, South Africa, Kenya, and Uganda. The primary endpoint of death or HF readmission through 24 weeks was neutral [hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.48-2.27, P = 0.90] in the 133 randomized patients included in the analyses. There were non-signficant effects in favour of HYIS in secondary endpoints including change in dyspnoea severity at day 7 or discharge, decrease in systolic blood pressure, greater decrease in weight, and increase in 6-min walk test distance at week 24. There were also small changes in echocardiographic indices of cardiac size and function in favour or HYIS, but none was significant.Conclusion: The BA-HEF trial demonstrated challenges in recruiting the expected number of patients with acute HF in a number of African countries, which highlights the need for strategic logistic support.Trial Registration: NCT01822808. [ABSTRACT FROM AUTHOR]

Aims: We examined the effects of istaroxime in patients hospitalized for acute heart failure (AHF) related Society for Cardiovascular Angiography and Interventions (SCAI) stage B pre‐cardiogenic shock (CS). Methods and results: Sixty patients with AHF without acute myocardial infarction with pre‐CS, defined as systolic blood pressure (SBP) <90 mmHg without hypoperfusion, venous lactate ≥2 mmol/L and/or mechanical or inotropic support, were randomized to istaroxime 1.0–1.5 μg/kg/min or placebo for 24 h. The primary endpoint, the adjusted area under the curve (AUC) change in SBP from time of treatment to 6 h, was 53.1 (standard error [SE] 6.88) mmHg × hour versus 30.9 (SE 6.76) mmHg × hour with istaroxime versus placebo (p = 0.017). Adjusted SBP AUC at 24 h was 291.2 (SE 27.5) versus 208.7 (SE 27.0) mmHg × hour (p = 0.025). At 24 h, some echocardiographic measurements improved with istaroxime versus placebo including cardiac index (+0.21 L/min/m2; p = 0.016), left atrial area (−1.8 cm2; p = 0.008), and left ventricular end‐systolic volume (−12.0 ml; p = 0.034). There were no significant differences in pulse pressure, laboratory measurements, serious adverse events or adverse events between the treatment groups except for more nausea, vomiting and infusion site pain in the istaroxime‐treated patients. In a post‐hoc analysis, patients receiving ≤1.0 μg/kg/min versus 1.5 μg/kg/min had similar increase in blood pressure, but a trend towards less adverse events. Conclusion: In a phase 2a study of patients with AHF related pre‐CS, istaroxime improved blood pressure and some echocardiography measures related to heart failure and was well tolerated. [ABSTRACT FROM AUTHOR]