Search

Aims: Burst steroid therapy, effective in acute respiratory diseases, may benefit patients with acute heart failure (AHF) in whom inflammatory activation is associated with adverse outcomes. Methods and results: CORTAHF assessed whether burst steroid therapy reduces inflammation and results in better quality of life and clinical outcomes in AHF. Patients with AHF, N‐terminal pro‐B‐type natriuretic peptide >1500 pg/ml, and high‐sensitivity C‐reactive protein (hsCRP) >20 mg/L were randomized 1:1 to oral, once daily 40 mg prednisone for 7 days or usual care, without blinding. Patients were followed for 90 days. A total of 101 patients were randomized. At day 7 the primary endpoint, hsCRP decreased in both arms – adjusted geometric mean ratios (GMRs) were 0.30 and 0.40 in the prednisone and usual care arms (ratio of GMRs 0.75, 95% confidence interval [CI] 0.56–1.00, p = 0.0498). The 90‐day risk of worsening heart failure (HF), HF readmission or death as reported by the unblinded investigators was significantly lower in the prednisone group (10.4%) than in usual care (30.8%) (hazard ratio 0.31, 95% CI 0.11–0.86, p = 0.016). The EQ‐5D visual analogue scale score as reported by the unblinded patients increased more in the prednisone group on day 7 (least squares mean difference 2.57, 95% CI 0.12–5.01 points, p = 0.040). All effects were statistically significant in the pre‐specified subgroup with centrally‐measured interleukin‐6 >13 pg/ml. Adverse events, particularly hyperglycaemia, occurred more in the prednisone group with no difference in infection rate. Conclusion: In this small open‐label study of patients with AHF, burst steroid therapy was associated with reduced inflammation as measured by hsCRP levels at day 7 (primary endpoint). Secondary endpoints showed improved quality of life at day 7 and reduced 90‐day risk of death or worsening HF. Large prospective studies are needed to evaluate these findings. [ABSTRACT FROM AUTHOR]

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: 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. Methods and results: 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. Conclusions: 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: 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. Methods and results: 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). Conclusions: 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]

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]

This article discusses the association between C-reactive protein (CRP) and heart failure (HF). CRP is a marker of inflammation and has been found to be elevated in patients with HF. The article highlights a study that shows the addition of CRP to a risk score improves the prediction of 30-day mortality in patients with acute HF. The study suggests that inflammation may play a stronger role in acute HF compared to chronic HF. The findings of this study may lead to further research on anti-inflammatory therapies for acute HF. [Extracted from the article]

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]

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]

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]

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: Acute heart failure (AHF) has an impact on human health worldwide. Despite guidelines for treatment and management of AHF, mortality rates remain high. The main objective of this study was to compare standard in‐hospital treatment and management of AHF against current clinical guidelines and variations across regions. Methods: Between February 2018 and May 2021, investigators were approached to participate in the STRONG‐HF study. The lead investigator at 158 sites in 20 countries completed a site feasibility questionnaire. Sites were grouped by country into five different regions: Africa and the Middle East, Eastern Europe, Russia, South America, and Western Europe. Results: According to the questionnaires, there are large differences in how patients present due to AHF and where in the hospital they are treated. There were significant differences in reported percentage of AHF patients receiving angiotensin converting enzymes inhibitors across the regions (P < 0.001), mostly due to prescription of more angiotensin II receptor blockers and angiotensin receptor‐neprilysin inhibitors in South America and Western Europe. Reported beta‐blocker use was high across all of the regions. Device therapy and percutaneous interventions were more common in Europe. Sites reported a 5 to 8 day length of stay, while in Russia most have a 10 to 12 day length of stay. Regions reported that AHF patients follow up with a community cardiologist or general practitioner post‐discharge, although follow‐up was commonly more than 1 month post discharge, and not all sites had the capability to measure natriuretic peptides post discharge. Conclusions: In this analysis of feasibility questionnaires, most sites reported general adherence to ESC guidelines for treatment and management of AHF patients although percutaneous and device therapy was less common outside Europe and follow‐up after discharge took place late and was not as extensive as recommended. There were wide variations seen within and across regions in some areas. [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]

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]

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]

The article "Reply to 'Is it possible to establish a threshold to define the inflammatory risk of acute heart failure patients?' Letter regarding the article 'Burst steroid therapy for acute heart failure: The CORTAHF randomized, open-label, pilot trial'" discusses the challenges in defining inflammatory activation in acute heart failure (AHF) patients. The study aimed to enroll patients with interleukin-6 (IL-6) levels >13 pg/ml to capture those with greater inflammatory activation, but logistical issues led to the use of C-reactive protein (CRP) levels >20 mg/L as a threshold instead. The results suggest that patients with CRP >20 mg/L and IL-6 >13 pg/ml had better outcomes, supporting the use of high CRP and IL-6 levels as targets for anti-inflammatory therapies in AHF studies. [Extracted from the article]

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]

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]

Aims: The current study explores whether degree of inflammation, reflected by C‐reactive protein (CRP) level, modifies the effect of intravenous (IV) corticosteroid administered in the emergency department (ED) on clinical outcomes in patients with acute heart failure (AHF). Methods and results: We selected patients diagnosed with AHF in the ED, with confirmed N‐terminal pro‐B‐type natriuretic peptide > 300 pg/mL and CRP > 5 mg/L in the ED from the Epidemiology of Acute Heart Failure in the Emergency Departments (EAHFE) registry. In these 1109 patients, 121 were treated by corticosteroid. The corticosteroid therapy hazard ratio (HR) for 30 day all‐cause mortality was 1.26 [95% confidence interval (CI) 0.75–2.09, P = 0.38]. Although not statistically significant, HRs tended to decrease with increasing CRP level, with point estimates favouring corticosteroid at CRP levels above 20. In patients with CRP > 40 mg/L, with adjusted HRs of 0.56 (95% CI 0.20–1.55, P = 0.27) for 30 day all‐cause mortality, 0.92 (95% CI 0.52–1.62, P = 0.78) for 30 day post‐discharge ED revisit, hospitalization, or death, and adjusted odds ratio of 0.61 (95% CI 0.17–2.14, P = 0.44) for in‐hospital all‐cause mortality. Conclusions: The present analysis suggests that corticosteroids might have the potential to improve outcomes in AHF patients with inflammatory activation. Larger, prospective studies of anti‐inflammatory therapy should be considered to assess potential benefit in patients with the highest degree of inflammation. [ABSTRACT FROM AUTHOR]

Aims: Limited data are available on clinical characteristics and prognosis of heart failure (HF) in black African populations especially with respect to current classifications and HF management guidelines. Methods and results: In this post hoc analysis, African patients admitted with acute HF and enrolled in the THESUS‐HF registry in one of 12 hospitals in 9 countries were classified as having preserved left ventricular ejection fraction (LVEF) (HFpEF), mid‐range LVEF (HFmrEF), and reduced LVEF (HFrEF) based on echocardiography performed close to the time of admission. Sociodemographic and clinical characteristics, management, and 60 and 180 day outcomes were compared between the groups. Of 888 patients with LVEF available, there were 472 (53.2%) with HFrEF, 174 (19.6%) with HFmrEF, and 243 (27.3%) with HFpEF. History of atrial fibrillation was higher in patients with HFmrEF (28.5%) than in patients with HFrEF (14.5%). Patients with HFrEF had a larger mean LV systolic diameter (54.1 ± 9.67 mm) than patients with HFmrEF (42.9 ± 8.47 mm), who had a larger mean LV diameter than patients with HFpEF (32.6 ± 8.64 mm); a similar pattern with LV diastolic diameter was observed. The mean posterior diastolic wall thickness (10.2 ± 2.94 mm) was lower in patients with HFrEF than in those with HFmrEF (11.1 ± 2.59 mm) and HFpEF (11.2 ± 2.90 mm). Patients with HFpEF were less likely to use angiotensin‐converting enzyme inhibitor/angiotensin receptor blockers, and aldosterone inhibitors, and more likely to use beta‐blockers than those with HFrEF at either admission or discharge/Day 7. Death or readmission rates through Day 60 and 180 day death rates did not differ significantly among the groups; unadjusted hazard ratios relative to patients with HFrEF were 1.32 [95% confidence interval (CI) 0.84–2.08] and 1.24 (95% CI 0.82–1.89) for 60 day death or readmission and 0.92 (95% CI 0.59–1.43) and 0.78 (95% CI 0.51–1.20) for 180 day death in patients with HFmrEF and HFpEF, respectively. Conclusions: Classification by LVEF according to European Society of Cardiology guidelines revealed some differences in clinical presentation but similar mortality and rehospitalization rates across all EF groups in Africans admitted for HF. [ABSTRACT FROM AUTHOR]

Background: For patients with acute heart failure (AHF), substantial diuresis after administration of loop diuretics is generally associated with better clinical outcomes but may cause creatinine to rise, suggesting renal function decline. We investigated the interaction between diuretic response and worsening renal function (WRF) on clinical outcomes in patients with AHF. Methods and results: In two AHF cohorts (PROTECT, n = 1698 and RELAX‐AHF‐2, n = 5586 in current analysis), the prognostic impact of WRF (creatinine ≥0.3 mg/dl increase baseline—day 4; sensitivity analyses incorporated baseline renal function) by diuretic response (kg weight loss/40 mg furosemide equivalent baseline—day 4) was investigated with regard to (cardiovascular) death or cardiovascular/renal hospitalization using subpopulation treatment effect pattern plots (STEPP) and survival analyses. WRF occurred in 286 (16.8%) and 1031 (18.5%) patients in PROTECT and RELAX‐AHF‐2, respectively. Patients with WRF had higher left ventricular ejection fraction and lower estimated glomerular filtration rate at baseline (p < 0.05), and received higher doses of loop diuretics and had a worse diuretic response (p < 0.001). In patients with a poor diuretic response (≤0.35 kg weight loss/40 mg furosemide equivalent as identified by STEPP), WRF was associated with higher risk of (cardiovascular) death or cardiovascular/renal hospitalization (p < 0.001 both cohorts), but this was not the case for patients with a good diuretic response (p = 0.900 both cohorts). Conclusion: In two large cohorts of patients with AHF, WRF in the first 4 days was not associated with worse outcomes when patients had a good diuretic response. The occurrence of WRF in patients with AHF should therefore be considered in the context of diuretic response. [ABSTRACT FROM AUTHOR]

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

Background and Aim: Liver histology changes are the current gold standard for evaluating non‐alcoholic steatohepatitis (NASH), but are limited by their invasiveness and variability for sampling and interpretation. We evaluated noninvasive biomarkers as an indication of histologic changes in NASH. Methods: Associations between 12‐month biomarker and NASH Clinical Research Network histologic score changes in 339 patients with NASH in the EMMINENCE trial was examined with multivariable models and partial canonical correlation. A meta‐analysis of 17 NASH trials including 3717 patients examined associations between these same changes and histologic response within treatment groups, and treatment effects on biomarkers and on liver histology. Biopsy measures assessed were changes in ballooning, steatosis, inflammation, and fibrosis, NASH improvement without worsening of fibrosis, and fibrosis improvement without worsening of NASH. All analytic methods suggest that a combination of aspartate aminotransferase (AST), cytokeratin‐18 (CK‐18 [M30 or M65]), and hemoglobin A1C (HbA1c) changes best predicts overall liver biopsy changes in response to interventions. Results: The weighted average of standardized mean changes (0.403 × AST, 0.314 × CK‐18, 0.283 × HbA1c) facilitated comparisons of within‐group responses and treatment effects among studies included in the meta‐analysis. This composite in EMMINENCE discriminated between patients with and without NASH resolution without worsening fibrosis with area under the receiver‐operator characteristic curve of 0.7880, and for fibrosis improvement without NASH worsening of 0.7553. Conclusion: A composite score based on changes in AST, HbA1c, and CK‐18 could serve as a surrogate for liver histologic improvement and an effective objective, noninvasive tool for comparative assessment of treatment effects of novel interventions. [ABSTRACT FROM AUTHOR]

Aims: The relationship between N‐terminal pro‐brain natriuretic peptide (NT‐pro‐BNP) and galectin‐3 and outcomes has not been studied in African patients with acute heart failure (AHF). The current analysis sought to describe the association between plasma levels of NT‐pro‐BNP and galectin‐3 and cardiovascular (CV) death or heart failure (HF) hospitalization, as well as their associations with symptoms and echocardiography markers of left and right ventricular remodelling among AHF patientsv in sub‐Saharan Africa. Methods and results: In a subset of 80 patients with complete data in a study assessing the effects of hydralazine and nitrates in patients with AHF (BAHEF trial; NCT01822808), NT‐pro‐BNP and galectin‐3 analyses were performed, and the association with various characteristics and outcome measures assessed. The mean age of the patients for whom the aforementioned biomarkers were measured was 52.6 years, with 52.5% women. Galectin‐3 at baseline predicted changes (Week 24 to baseline) in left ventricular ejection fraction, left ventricular end‐systolic diameter, left ventricular end‐diastolic diameter, and tricuspid annular plane systolic excursion. Biomarkers and their changes were not associated with changes in 6 min walk test at 24 weeks. Baseline galectin‐3 and change in NT‐pro‐BNP were associated with improvements in dyspnoea at 24 weeks. Nine patients had an HF readmission or died of CV causes through 24 weeks (11.6%). Both biomarkers at baseline predicted combined CV death or HF hospitalization through Week 24 (P‐values = 0.0328 and 0.0001, respectively). Conclusions: In a cohort of patients with AHF from sub‐Saharan Africa, NT‐pro‐BNP and galectin‐3 at baseline and their changes were associated with some changes in dyspnoea, echocardiographic remodelling, and CV death or HF hospitalization through Week 24. These tests have potential of being used for risk stratification of AHF patients in sub‐Saharan Africa where resources are scarce. [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]

Aims: Whether risk of worsening renal function (WRF) during acute heart failure (AHF) hospitalization or the association between in‐hospital WRF and post‐discharge outcomes vary according to left ventricular ejection fraction (LVEF) is uncertain. We assessed incidence of WRF, factors related to its development and impact of WRF on post‐discharge outcomes across the spectrum of LVEF in patients enrolled in RELAX‐AHF‐2. Methods and results: A total of 6112 patients who had LVEF measured on admission and renal function determined prospectively during hospitalization were included. WRF, defined as a rise in serum creatinine ≥0.3 mg/dL from baseline through day 5, occurred in 1722 patients (28.2%). Incidence increased progressively from lowest to highest LVEF quartile (P < 0.001). After baseline adjustment, WRF risk in Q4 (LVEF >50%) remained significantly greater than in Q1 (LVEF ≤29%; hazard ratio 1.2, 95% confidence interval 1–1.43; P = 0.050). Age and comorbidity burden including chronic kidney disease increased as LVEF increased. Neither admission haemodynamic abnormalities, extent of diuresis during hospitalization nor residual congestion explained the increased incidence of WRF in patients with higher LVEF. Serelaxin treatment and diuretic responsiveness were associated with reduced risk of WRF in all LVEF quartiles. WRF in patients in the upper three LVEF quartiles increased risk of post‐discharge events. Conclusions: Worsening renal function incidence during AHF hospitalization increases progressively with LVEF. Greater susceptibility of patients with higher LVEF to WRF appears more related to their advanced age and worse underlying kidney function rather than haemodynamic or treatment effects. WRF is associated with increased risk of post‐discharge events except in patients in the lowest LVEF quartile. [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]

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: Recently, bio-adrenomedullin (bio-ADM) was proposed as a congestion marker in heart failure (HF). In the present study, we aimed to study whether bio-ADM levels at discharge from a hospital admission for worsening HF could provide additional information on (residual) congestion status, diuretic dose titration and clinical outcomes.Methods and Results: Plasma bio-ADM was measured in 1236 acute HF patients in the PROTECT trial at day 7 or discharge. Median discharge bio-ADM was 33.7 [21.5-61.5] pg/mL. Patients with higher discharge bio-ADM levels were hospitalised longer, had higher brain natriuretic peptide levels, and poorer diuretic response (all P < 0.001). Bio-ADM was the strongest predictor of discharge residual congestion (clinical congestion score > 3) (odds ratio 4.35, 95% confidence interval 3.37-5.62; P < 0.001). Oedema at discharge was one of the strongest predictors of discharge bio-ADM (β = 0.218; P < 0.001). Higher discharge loop diuretic doses were associated with a poorer diuretic response during hospitalisation (β = 0.187; P < 0.001) and higher bio-ADM levels (β = 0.084; P = 0.020). High discharge bio-ADM levels combined with higher use of loop diuretics were independently associated with a greater risk of 60-day HF rehospitalisation (hazard ratio 4.02, 95% confidence interval 2.23-7.26; P < 0.001).Conclusion: In hospitalised HF patients, elevated pre-discharge bio-ADM levels were associated with higher discharge loop diuretic doses and reflected residual congestion. Patients with combined higher bio-ADM levels and higher loop diuretic use at discharge had an increased risk of rehospitalisation. Assessment of discharge bio-ADM levels may be a readily applicable marker to identify patients with residual congestion at higher risk of early hospital readmission. [ABSTRACT FROM AUTHOR]

Aims: Although left ventricular ejection fraction (LVEF) is routinely used to categorize patients with heart failure (HF), whether it predicts outcomes after hospitalization for acute heart failure (AHF) is uncertain. Consequently, we assessed the relationship between LVEF and cardiovascular (CV) outcomes in a large, well characterized cohort of patients hospitalized for AHF.Methods and Results: The 6128 patients from the RELAX-AHF-2 trial who had LVEF measured during AHF hospitalization were separated into LVEF quartiles and the relationship between LVEF and a composite of CV mortality and rehospitalization for HF or renal failure through 180 days was assessed. We found progressively lower risk for this composite outcome as LVEF increased (hazard ratio 0.95, 95% confidence interval 0.93-0.98 per 5% LVEF increase, P < 0.001) that was driven predominantly by decreased risk for rehospitalization. The smoothed spline curve depicting risk remained stable as LVEF decreased until reaching approximately 40%, at which point risk increased progressively with further reductions in LVEF. Significant differences between LVEF quartiles for post-discharge CV risk were seen in patients with an ischaemic aetiology or with a history of HF preceding index hospitalization, but were less robust in patients with non-ischaemic aetiology and absent in those with de novo HF.Conclusion: In patients hospitalized with AHF, CV events over 180 days were more frequent in patients with lower LVEF. This was due predominantly to a significant increase in risk for HF/renal failure rehospitalization but not in either CV or all-cause mortality. LVEF had greater prognostic value in patients with ischaemic aetiology or pre-existing HF. [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]

Aims: Neurohormonal activation characterizes chronic heart failure (HF) and is a well-established therapeutic target. Neurohormonal activation may also play a key role in acute HF (AHF). We aim to describe the association between plasma renin activity (PRA) and three AHF outcomes: (i) worsening HF or death through day 5 of hospitalization; (ii) HF rehospitalization or death through day 30; and (iii) all-cause death through day 30.Methods and Results: A secondary analysis of the BLAST-AHF trial was performed. Eligible patients had a history of HF, elevated natriuretic peptides, signs and symptoms of HF, systolic blood pressure >120 mmHg, and an estimated glomerular filtration rate between 20-75 mL/min/1.73 m2 . The primary trial was neutral, with no differential effect of study drug by PRA levels. Baseline PRA levels were grouped into tertiles. Adjusted Cox proportional hazard model determined the association of PRA levels with outcomes (α set at P < 0.05). Of 618 randomized patients, 578 (93.5%) had a baseline PRA. PRA was modestly, but significantly, associated with each outcome without adjustment [worsening HF or death through day 5: hazard ratio (HR) 1.11, 95% confidence interval (CI) 1.01-1.23, P = 0.04; HF rehospitalization or death through day 30: HR 1.13, 95% CI 1.02-1.26, P = 0.02; all-cause death through day 30: HR 1.18, 95% CI 1.02-1.37, P = 0.03]. After multivariable adjustment, PRA was only significantly associated with HF rehospitalization or death through day 30 (HR 1.15, 95% CI 1.01-1.32, P = 0.04).Conclusion: Baseline PRA levels are associated with increased risk for the composite of 30-day HF rehospitalization or death in patients with AHF. [ABSTRACT FROM AUTHOR]

Aims: Episodes 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 results: On 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 < 0.05), but this difference vs. placebo disappeared during longer follow‐up. In the multivariable model, an elevated MELD‐XI score on admission was associated with higher 180 day mortality: hazard ratios (95% confidence interval) for cardiovascular death were 3.10 (1.22–7.87), and for all‐cause death 2.47 (1.19–5.15); both P < 0.05. The addition of the MELD‐XI score to a prespecified prognostic model increased the discrimination of the model for all‐cause death, but the increment in the C‐index was only modest: 0.013 (P = 0.02). Conclusions: In patients with AHF, hepatorenal dysfunction is prevalent and related to poor outcome. The MELD‐XI score is a useful prognosticator in AHF. [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: 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: Left ventricular (LV) reverse remodelling is an important marker of improved outcomes in patients with advanced heart failure (HF). We examined the impact of the intramyocardial administration of bone-marrow-derived, lineage-directed, autologous cardiopoietic mesenchymal stem cells (C3BS-CQR-1) on LV remodelling in patients with advanced HF enrolled in the CHART-1 study.Methods and Results: Patients (n=351) with symptomatic advanced HF secondary to ischaemic heart disease, and reduced LV ejection fraction (LVEF <35%) were randomized to receive C3BS-CQR-1 or a sham procedure. In a post hoc analysis we examined the effect of C3BS-CQR-1 on LV reverse remodelling within 1 year of the procedure and the influence of C3BS-CQR-1 dosing in the 271 patients treated as randomized. Delivery of C3BS-CQR-1 was associated with a progressive decrease in both LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV) within 52 weeks after treatment. At 1 year, the LVEDV and LVESV of treated patients decreased by 17.0 mL and 12.8 mL greater than controls (P=0.006 and P=0.017, respectively). The effect on LVEDV was maintained after multivariable adjustment for baseline age, systolic blood pressure, LVEDV, LVEF and history of myocardial infarction. The largest reverse remodelling was evident in the patients receiving a moderate number of injections (<20).Conclusion: In CHART-1, intramyocardial administration of cardiopoietic stem cells led to reverse remodelling as evidenced by significant progressive decreases in LVEDV and LVESV through the 52 weeks of follow-up. Further studies are needed to explore the dose response with regard to cell number and injected volume, and reverse remodelling. [ABSTRACT FROM AUTHOR]

Aims: It is unclear whether distinct pathophysiological processes are present among patients with acute heart failure (AHF), with and without diabetes. Network analysis of biomarkers may identify correlative associations that reflect different pathophysiological pathways.Methods and Results: We analysed a panel of 48 circulating biomarkers measured within 24 h of admission for AHF in a subset of patients enrolled in the PROTECT trial. In patients with and without diabetes, we performed a network analysis to identify correlations between measured biomarkers. Compared with patients without diabetes (n = 1111), those with diabetes (n = 922) had a higher prevalence of ischaemic heart disease and traditional coronary risk factors. After multivariable adjustment, patients with and without diabetes had significantly different levels of biomarkers across a spectrum of pathophysiological domains, including inflammation (TNFR-1a, periostin), cardiomyocyte stretch (BNP), angiogenesis (VEGFR, angiogenin), and renal function (NGAL, KIM-1) (adjusted P-value <0.05). Among patients with diabetes, network analysis revealed that periostin strongly clustered with C-reactive protein and interleukin-6. Furthermore, renal markers (creatinine and NGAL) closely associated with potassium and glucose. These findings were not seen among patients without diabetes.Conclusion: Patients with AHF and diabetes, compared with those without diabetes, have distinct biomarker profiles. Network analysis suggests that cardiac remodelling, inflammation, and fibrosis are closely associated with each other in patients with diabetes. Furthermore, potassium levels may be sensitive to changes in renal function as reflected by the strong renal-potassium-glucose correlation. These findings were not seen among patients without diabetes and may suggest distinct pathophysiological processes among AHF patients with diabetes. [ABSTRACT FROM AUTHOR]

Aims We evaluated the added prognostic value of a multi-time point-based multimarker panel of biomarkers in patients with acute heart failure ( AHF). Methods and results Seven circulating biomarkers [ NT-proBNP, high sensitivity cardiac troponin T (hs-c TnT), soluble ST2 (sST2), growth differentiation factor 15 ( GDF-15), cystatin-C, galectin-3, and high sensitivity C-reactive protein (hs- CRP)] were measured at baseline and on days 2, 5, 14, and 60 in 1161 patients enrolled in the RELAX-AHF trial. Patients with BNP ≥350 ng/L or NT-proBNP ≥1400 ng/L, mild to moderate renal impairment, and systolic blood pressure >125 mmHg were included in the trial. Time-dependent Cox regression analysis was utilized to evaluate the incremental value of serial measurement of biomarkers. Added value of individual biomarkers and their combination, on top of a pre-specified baseline model, was quantified with the gain in the C-index. Serial biomarker evaluation showed incremental predictive value over baseline measurements alone for the prediction of 180-day cardiovascular mortality except for galectin-3. While a repeat measurement as early as day 2 was adequate for NT-proBNP and cystatin-C in terms of maximizing discriminatory accuracy, further measurements on days 14 and 60 provided added value for hs-c TnT, GDF-15, sST2, and hs- CRP. Individual biomarker additions on top of the baseline model showed additional prognostic value. The greatest prognostic gain was, however, attained with the combination of NT-proBNP, hs-c TnT, GDF-15, and sST2, which yielded 0.08 unit absolute increment in the C-index to 0.87 (95% confidence interval 0.83-0.91]. Conclusion In patients with AHF and mild to moderate renal impairment, a multimarker approach based on a panel of serially evaluated biomarkers provides the greatest prognostic improvement unmatched by a single time point-based single marker strategy. [ABSTRACT FROM AUTHOR]

Aim Improved prediction of early post-discharge death or rehospitalization after admission for acute heart failure is a major unmet need. We evaluated the value of biomarkers to predict either low or high risk for early post-discharge events. Methods and results A total of 1653 patients enrolled in the PROTECT trial who were discharged alive and with available blood samples were included. Forty-seven biomarkers were serially evaluated in these patients. Measurement closest to discharge was used to evaluate the predictive value of biomarkers for low and high post-discharge risk. Patients were classified as 'low risk' if post-discharge 30-day risk of death or heart failure rehospitalization was <5% while risk >20% was used to define 'high risk'. Cut-off values that yielded a 95% negative predictive value and a 20% positive predictive value were identified for each biomarker. Partial area under the receiver operating characteristic curve ( pAUC) in the high-sensitivity and high-specificity regions was calculated to compare low-risk and high-risk predictive values. Of patients analysed, 193 (11.7%) patients reached the 30-day death or heart failure rehospitalization outcome. We found marked differences between low-risk and high-risk predictors. Cardiac-specific troponin I was the strongest biomarker for low-risk prediction ( pAUC = 0.552, 95% confidence interval 0.52-0.58) while endothelin-1 showed better performance for high-risk prediction ( pAUC = 0.560, 95% confidence interval 0.53-0.59). Several biomarkers (individually and in combination) provided added predictive value, on top of a clinical model, in both low-risk and high-risk regions. Conclusion Different biomarkers predicted low risk vs. high risk of early post-discharge death or heart failure readmission in patients hospitalized for acute heart failure. [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]

Patients admitted for acute heart failure (AHF) experience high rates of in-hospital and post-discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin-2, a hormone with vasodilatory and end-organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX-AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all-cause and cardiovascular mortality by 37% through day 180. RELAX-AHF-2 ( ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX-AHF-2 is a multicentre, randomized, double-blind, placebo-controlled, event-driven, phase 3 trial enrolling ∼6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild-to-moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all-cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in-hospital length of stay during index AHF. The results from RELAX-AHF-2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF. [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: 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]

Aims: Episodes of acute heart failure (AHF) unfavourably affect multiple organs, which may have an adverse impact on the outcomes. We investigated the prevalence and clinical consequences of abnormal liver function tests (LFTs) in AHF patients enrolled in the PROTECT study.Methods and Results: The LFTs comprised serial assessment of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and albumin at baseline and during follow-up (daily until discharge, on days 7 and 14). The prevalence of abnormal LFTs (above upper limit of normal for AST and ALT or below lower limit of normal for albumin) was: at baseline AST 20%, ALT 12%, albumin 40%; and at day 14: AST 15%, ALT 9%, albumin 26%. Abnormal LFTs at baseline were associated with a higher risk of in-hospital death with odds ratios [95% confidence interval (CI)] of 3.5 (1.7-7.3) for AST, 3.9 (1.8-8.4) for ALT, and 2.8 (1.3-5.9) for albumin (all P < 0.01). Abnormal baseline and discharge LFTs had an unfavourable impact on 180-day mortality with hazard ratios (95% CI) for baseline AST, ALT, and albumin of 1.3 (1.0-1.7), 1.1 (1.0-1.2), 1.4 (1.1-1.8), respectively, and 1.5 (1.1-2.0), 1.5 (1.0-2.2), and 1.6 (1.2-2.1), for discharge AST, ALT, albumin, respectively (all P < 0.05). Analysis of LFTs trajectories (calculated as changes in LFTs over time) revealed that increasing AST and ALT on day 3 as well as decreasing albumin on day 4 were independent prognosticators of 180-day outcome (all P < 0.05).Conclusions: Abnormal LFTs are frequent in AHF at baseline and during hospital stay and predict worse outcomes. Whether this association is causal and what are the underlying mechanisms involved require further study. [ABSTRACT FROM AUTHOR]

Aims: Urinary kidney injury molecule-1 (KIM-1) is a marker of tubular damage and associated with worse outcome in heart failure (HF). Plasma KIM-1 has not been described in HF.Methods and Results: In a renal mechanistic cohort of 120 chronic HF patients, we established the association between plasma KIM-1, renal invasive haemodynamic parameters {renal blood flow ([(131) I]hippuran clearance) and measured glomerular filtration rate (GFR; [(125) I]iothalamate)} and urinary tubular damage markers. The association between plasma KIM-1, plasma creatinine, and clinical outcome was further explored in a cohort of 2033 acute HF patients. Median plasma KIM-1 was 171.5 pg/mL (122.8-325.7) in chronic (n = 99) and 295.1 pg/mL (182.2-484.2) in acute HF (n = 1588). In chronic HF, plasma KIM-1 was associated with GFR (P < 0.001), creatinine, and cystatin C. Plasma KIM-1 was associated with urinary N-acetyl-β-d-glucosaminidase (NAG), but not with other urinary tubular damage markers. Log plasma KIM-1 predicted adverse clinical outcome after adjustment for age, gender, and GFR [hazard ratio (HR) 1.94, 95% confidence interval (CI) 1.07-3.53, P = 0.030]. Statistical significance was lost after correction for NT-proBNP (HR 1.61, 95% CI 0.81-3.20, P = 0.175). In acute HF, higher plasma KIM-1 levels were associated with higher creatinine, lower albumin, and presence of diabetes. Log plasma KIM-1 predicted 60-day HF rehospitalization (HR 1.27, 95% CI 1.03-1.55, P = 0.024), but not 180-day mortality or 60-day death or renal or cardiovascular rehospitalization.Conclusions: Plasma KIM-1 is associated with glomerular filtration and urinary NAG, but not with other urinary tubular damage markers. Plasma KIM-1 does not predict outcome in chronic HF after correction for NT-proBNP. In acute HF, plasma KIM-1 predicts HF rehospitalization in multivariable analysis. [ABSTRACT FROM AUTHOR]

Aims: Our aim was to identify circulating microRNAs (miRNAs) associated with acute heart failure (AHF).Methods and Results: Plasma miRNA profiling included 137 patients with AHF from 3 different cohorts, 20 with chronic heart failure (CHF), 8 with acute exacerbation of COPD, and 41 healthy controls. Levels of circulating miRNAs were measured using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Plasma levels of miRNAs in patients with AHF were decreased compared with CHF patients or healthy subjects, whereas no significant changes were observed between acute COPD patients and controls. Fifteen miRNAs found in the discovery phase to differ most significantly between healthy controls and patients with AHF were further investigated in an extended cohort of 100 AHF patients at admission and a separate cohort of 18 AHF patients at different time points. Out of these 15 miRNAs, 12 could be confirmed in an additional AHF validation cohort and 7 passed the Bonferroni correction threshold (miR-18a-5p, miR-26b-5p, miR-27a-3p, miR-30e-5p, miR-106a-5p, miR-199a-3p, and miR-652-3p, all P < 0.00005). A further drop in miRNA levels within 48 h after AHF admission was associated with an increased risk of 180-day mortality in a subset of the identified miRNAs.Conclusions: Declining levels of circulating miRNAs were associated with increasing acuity of heart failure. Early in-hospital decreasing miRNA levels were predictive for mortality in a subset of miRNAs in patients with AHF. The discovered miRNA panel may serve as a launch-pad for molecular pathway studies to identify new pharmacological targets and miRNA-based therapies. [ABSTRACT FROM AUTHOR]