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

Despite the progress in the care of individuals with heart failure (HF), important sex disparities in knowledge and management remain, covering all the aspects of the syndrome, from aetiology and pathophysiology to treatment. Important distinctions in phenotypic presentation are widely known, but the mechanisms behind these differences are only partially defined. The impact of sex‐specific conditions in the predisposition to HF has gained progressive interest in the HF community. Under‐recruitment of women in large randomized clinical trials has continued in the more recent studies despite epidemiological data no longer reporting any substantial difference in the lifetime risk and prognosis between sexes. Target dose of medications and criteria for device eligibility are derived from studies with a large predominance of men, whereas specific information in women is lacking. The present scientific statement encompasses the whole scenario of available evidence on sex‐disparities in HF and aims to define the most challenging and urgent residual gaps in the evidence for the scientific and clinical HF communities. [ABSTRACT FROM AUTHOR]

AimsWomen with heart failure are typically older, and more often have hypertension and a preserved left ventricular ejection fraction as compared with men. We sought to analyze if these sex differences influence the course and outcome of acute heart failure.Methods and resultsWe analyzed sex differences in acute heart failure in 1161 patients enrolled in the RELAX-AHF study. The pre-specified study endpoints were used. At baseline, women (436/1161 patients) were older, had a higher left ventricular ejection fraction, a higher rate of hypertension, and were treated differently from men. Early dyspnea improvement (moderate or marked dyspnea improvement measured by Likert scale during the first 24 h) was greater in women. However, dyspnea improvement over the first 5 days (change from baseline in the visual analog scale area under the curve (VAS AUC) to day 5) was similar between men and women. Women reported greater improvements in general wellbeing by Likert, but no such benefits were evident with the VAS score. Multi-variable predictors of moderate or marked dyspnea improvement were female sex (p = 0.0011), lower age (p = 0.0026) and lower diuretic dose (p = 0.0067). The additional efficacy endpoints of RELAX-AHF were similar between men and women and serelaxin was equally effective in men and women.ConclusionsWomen exhibit better earlier dyspnea relief and improvement in general wellbeing compared with men, even adjusted for age and left ventricular ejection fraction. However, in-hospital and post-discharge clinical outcomes were similar between men and women. This trial is registered at ClinicalTrials.gov, NCT00520806.

A new study published in the European Heart Journal explores the bidirectional relationship between atrial fibrillation (AF) and cancer. The study, based on a Dutch database of nearly 800,000 patients, confirms that both conditions are associated with increased mortality. The coexistence of AF and cancer presents clinical challenges, including the management of cancer therapy-related cardiovascular disease and the complications of anticoagulation therapy. The study suggests that baseline cardiovascular risk stratification and periodic assessment of thrombosis and bleeding risks should guide treatment decisions. The management of AF should consider the prognosis of cancer and potential drug interactions. [Extracted from the article]

BackgroundAccording to the 2004 Surgeon General's Report on Health Consequences of Smoking, after >15 years of abstinence, the cardiovascular risk of former smokers becomes similar to that of never-smokers. Whether this health benefit of smoking cessation varies by amount and duration of prior smoking remains unclear.Methods and resultsOf the 4482 adults ≥65 years without prevalent heart failure (HF) in the Cardiovascular Health Study, 2556 were never-smokers, 629 current smokers, and 1297 former smokers with >15 years of cessation, of whom 312 were heavy smokers (highest quartile; ≥32 pack-years). Age-sex-race-adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for centrally adjudicated incident HF and mortality during 13 years of follow-up were estimated using Cox regression models. Compared with never-smokers, former smokers as a group had similar risk for incident HF (aHR, 0.99; 95% CI, 0.85-1.16) and all-cause mortality (aHR, 1.08; 95% CI, 0.96-1.20), but former heavy smokers had higher risk for both HF (aHR, 1.45; 95% CI, 1.15-1.83) and mortality (aHR, 1.38; 95% CI, 1.17-1.64). However, when compared with current smokers, former heavy smokers had lower risk of death (aHR, 0.64; 95% CI, 0.53-0.77), but not of HF (aHR, 0.97; 95% CI, 0.74-1.28).ConclusionsAfter >15 years of smoking cessation, the risk of HF and death for most former smokers becomes similar to that of never-smokers. Although this benefit of smoking cessation is not extended to those with ≥32 pack-years of prior smoking, they have lower risk of death relative to current smokers.

The burden of heart failure with preserved ejection fraction (HFpEF) is considerable and is projected to worsen. To date, there are no approved therapies available for reducing mortality or hospitalizations for these patients. The pathophysiology of HFpEF is complex and includes alterations in cardiac structure and function, systemic and pulmonary vascular abnormalities, end-organ involvement, and comorbidities. There remain major gaps in our understanding of HFpEF pathophysiology. To facilitate a discussion of how to proceed effectively in future with development of therapies for HFpEF, a meeting was facilitated by the Food and Drug Administration and included representatives from academia, industry, and regulatory agencies. This document summarizes the proceedings from this meeting.

AimsAlthough dyspnoea is the most common cause of admission for acute heart failure (AHF), more needs to be known about its clinical course and prognostic significance.Methods and resultsThe Pre-RELAX-AHF study randomized 232 subjects with AHF to placebo or four doses of relaxin and evaluated early (6-24 h Likert scale) and persistent [change in visual analogue scale area under the curve (VAS AUC) through Day 5] dyspnoea relief. Worsening heart failure (WHF) was defined as worsening AHF signs and symptoms requiring additional therapy. Patients were followed until Day 180. Early dyspnoea relief was observed in only 25% of all patients, and VAS AUC at 5 days was 45% over baseline values in all patients (32% placebo; 50% all relaxin-treated patients). Worsening heart failure to Day 5 was observed in 16% of all patients (21% placebo; 14% relaxin). Lack of persistent dyspnoea relief and WHF were associated with a longer length of initial hospital stay and worse 60-day outcomes.ConclusionDyspnoea relief in patients admitted with AHF is often incomplete, and many may show WHF after the initial stabilization. Both lack of persistent dyspnoea relief and in-hospital WHF predict a longer length of stay and worse outcome.

Aims: Hospital admission during nighttime and off hours may affect the outcome of patients with various cardiovascular conditions due to suboptimal resources and personnel availability, but data for acute heart failure remain controversial. Therefore, we studied outcomes of acute heart failure patients according to their time of admission from the global International Registry to assess medical practice with lOngitudinal obseRvation for Treatment of Heart Failure. Methods and results: Overall, 18 553 acute heart failure patients were divided according to time of admission into 'morning' (7:00–14:59), 'evening' (15:00–22:59), and 'night' (23:00–06:59) shift groups. Patients were also dichotomized to admission during 'working hours' (9:00–16:59 during standard working days) and 'non‐working hours' (any other time). Clinical characteristics, treatments, and outcomes were compared across groups. The hospital length of stay was longer for morning (odds ratio: 1.08; 95% confidence interval: 1.06–1.10, P < 0.001) and evening shift (odds ratio: 1.10; 95% confidence interval: 1.07–1.12, P < 0.001) as compared with night shift. The length of stay was also longer for working vs. non‐working hours (odds ratio: 1.03; 95% confidence interval: 1.02–1.05, P < 0.001). There were no significant differences in in‐hospital mortality among the groups. Admission during working hours, compared with non‐working hours, was associated with significantly lower mortality at 1 year (hazard ratio: 0.88; 95% confidence interval: 0.80–0.96, P = 0.003). Conclusions: Acute heart failure patients admitted during the night shift and non‐working hours had shorter length of stay but similar in‐hospital mortality. However, patients admitted during non‐working hours were at a higher risk for 1 year mortality. These findings may have implications for the health policies and heart failure trials. [ABSTRACT FROM AUTHOR]

Aims: Atrial fibrillation/flutter (AF) is common in heart failure (HF) with preserved left ventricular ejection fraction (LVEF) and associated with worse outcomes. Empagliflozin reduces cardiovascular death or HF hospitalizations and slows estimated glomerular filtration rate (eGFR) decline in patients with HF and LVEF >40%. We aimed to assess the efficacy and safety of empagliflozin in improving outcomes in patients with HF and LVEF >40% with and without AF. Methods and results: In this pre‐defined secondary analysis of EMPEROR‐Preserved, we compared the effects of empagliflozin versus placebo on the primary and secondary endpoints and safety outcomes, stratified by baseline AF, defined as AF reported in any electrocardiogram before empagliflozin initiation or in medical history. Among 5988 patients randomized, 3135 (52%) had baseline AF; these patients were older, with worse functional class, more previous HF hospitalizations and higher natriuretic peptides compared to those without AF (all p < 0.001). After a median of 26 months, empagliflozin reduced cardiovascular death or HF hospitalization compared to placebo to a similar extent in patients with and without AF (hazard ratio [HR] 0.78 [95% confidence interval 0.66–0.93] vs. 0.78 [0.64–0.95], interaction p = 0.96). Empagliflozin also reduced total HF hospitalizations (HR 0.73 [0.57–0.94] vs. 0.72 [0.54–0.95], interaction p = 0.94) and annual eGFR decline (difference = 1.368 vs. 1.372 ml/min/1.73 m2/year, interaction p = 0.99) consistently in patients with and without AF. There was no increase in serious adverse events with empagliflozin versus placebo in patients with and without AF. Conclusions: In patients with HF and ejection fraction >40%, empagliflozin reduced the risk of serious HF events and slowed the eGFR decline regardless of baseline AF. [ABSTRACT FROM AUTHOR]

Acute heart failure is a major cause of urgent hospitalizations. These are followed by marked increases in death and rehospitalization rates, which then decline exponentially though they remain higher than in patients without a recent hospitalization. Therefore, optimal management of patients with acute heart failure before discharge and in the early post‐discharge phase is critical. First, it may prevent rehospitalizations through the early detection and effective treatment of residual or recurrent congestion, the main manifestation of decompensation. Second, initiation at pre‐discharge and titration to target doses in the early post‐discharge period, of guideline‐directed medical therapy may improve both short‐ and long‐term outcomes. Third, in chronic heart failure, medical treatment is often left unchanged, so the acute heart failure hospitalization presents an opportunity for implementation of therapy. The aim of this scientific statement by the Heart Failure Association of the European Society of Cardiology is to summarize recent findings that have implications for clinical management both in the pre‐discharge and the early post‐discharge phase after a hospitalization for acute heart failure. [ABSTRACT FROM AUTHOR]

Aim: Evidence on healthcare resource utilization (HCRU) for hospitalized patients with heart failure (HF) and reduced (HFrEF), mildly reduced (HFmrEF) and preserved (HFpEF) ejection fraction is limited. Methods and results: We analysed HCRU in relation to left ventricular ejection fraction (LVEF) phenotypes, clinical features and in‐hospital and 12‐month outcomes in 16 943 patients hospitalized for HF in a worldwide registry. HFrEF was more prevalent (53%) than HFmrEF (17%) or HFpEF (30%). Patients with HFmrEF and HFpEF were older, more often women, with milder symptoms and more comorbidities, but differences were not pronounced. HCRU was high in all three groups; two or more in‐ and out‐of‐hospital services were required by 51%, 49% and 52% of patients with HFrEF, HFmrEF and HFpEF, respectively, and intensive care unit by 41%, 41% and 37%, respectively. Hospitalization length was similar (median, 8 days). Discharge prescription of neurohormonal inhibitors was <80% for each agent in HFrEF and only slightly lower in HFmrEF and HFpEF (74% and 67%, respectively, for beta‐blockers). Compared to HFrEF, 12‐month all‐cause and cardiovascular mortality were lower for HFmrEF (adjusted hazard ratios 0.78 [95% confidence interval 0.59–0.71] and 0.80 [0.70–0.92]) and HFpEF (0.64 [0.59–0.87] and 0.63 [0.56–0.71]); 12‐month HF hospitalization was also lower for HFpEF and HFmrEF (21% and 20% vs. 25% for HFrEF). In‐hospital mortality, 12‐month non‐cardiovascular mortality and 12‐month all‐cause hospitalization were similar among groups. Conclusions: In patients hospitalized for HF, overall HCRU was similarly high across LVEF spectrum, reflecting the subtle clinical differences among LVEF phenotypes during hospitalization. Discharge prescription of neurohormonal inhibitors was suboptimal in HFrEF and lower but significant in patients with HFpEF and HFmrEF, who had better long‐term cardiovascular outcomes than HFrEF, but similar risk for non‐cardiovascular events. [ABSTRACT FROM AUTHOR]

Natriuretic peptides, brain (B‐type) natriuretic peptide (BNP) and N‐terminal prohormone of brain natriuretic peptide (NT‐proBNP) are globally and most often used for the diagnosis of heart failure (HF). In addition, they can have an important complementary role in the risk stratification of its prognosis. Since the development of angiotensin receptor–neprilysin inhibitors (ARNIs), the use of natriuretic peptides as therapeutic agents has grown in importance. The present document is the result of the Trilateral Cooperation Project among the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America and the Japanese Heart Failure Society. It represents an expert consensus that aims to provide a comprehensive, up‐to‐date perspective on natriuretic peptides in the diagnosis and management of HF, with a focus on the following main issues: (1) history and basic research: discovery, production and cardiovascular protection; (2) diagnostic and prognostic biomarkers: acute HF, chronic HF, inclusion/endpoint in clinical trials, and natriuretic peptide‐guided therapy; (3) therapeutic use: nesiritide (BNP), carperitide (ANP) and ARNIs; and (4) gaps in knowledge and future directions. [ABSTRACT FROM AUTHOR]

Background: Galectin-3, a biomarker of inflammation and fibrosis, can be associated with renal and myocardial damage and dysfunction in patients with acute heart failure (AHF).Methods and Results: We retrospectively analyzed 790 AHF patients enrolled in the AKINESIS study. During hospitalization, patients with galectin-3 elevation (> 25.9 ng/ml) on admission more frequently had acute kidney injury (assessed by KDIGO criteria), renal tubular damage (peak urine neutrophil gelatinase-associated lipocalin [uNGAL] >150 ng/dl) and myocardial injury (≥ 20% increase in the peak high sensitivity cardiac troponin I [hs-cTnI] value compared to admission). They less frequently had ≥ 30% reduction in B-type natriuretic peptide from admission to last measured value. In multivariable linear regression analysis, galectin-3 was negatively associated with estimated glomerular filtration rate and positively associated with uNGAL and hs-cTnI. Higher galectin-3 was associated with renal replacement therapy, inotrope use and mortality during hospitalization. In univariable Cox regression analysis, higher galectin-3 was associated with increased risk for the composite of death or HF rehospitalization and death alone at one-year. After multivariable adjustment, higher galectin-3 was only associated with death.Conclusions: In patients with AHF, higher galectin-3 values were associated with renal dysfunction, renal tubular damage and myocardial injury, and predicted worse outcomes. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a long‐term clinical syndrome, with increasing prevalence and considerable healthcare costs that are further expected to increase dramatically. Despite significant advances in therapy and prevention, mortality and morbidity remain high and quality of life poor. Epidemiological data, that is, prevalence, incidence, mortality, and morbidity, show geographical variations across the European countries, depending on differences in aetiology, clinical characteristics, and treatment. However, data on the prevalence of the disease are scarce, as are those on quality of life. For these reasons, the ESC‐HFA has developed a position paper to comprehensively assess our understanding of the burden of HF in Europe, in order to guide future policies for this syndrome. This manuscript will discuss the available epidemiological data on HF prevalence, outcomes, and human costs—in terms of quality of life—in European countries. [ABSTRACT FROM AUTHOR]

Background: Empagliflozin improves outcomes in patients with heart failure with a preserved ejection fraction, but whether the effects are consistent in patients with and without diabetes remains to be elucidated.Methods: Patients with class II through IV heart failure and a left ventricular ejection fraction >40% were randomized to receive empagliflozin 10 mg or placebo in addition to usual therapy. We undertook a prespecified analysis comparing the effects of empagliflozin versus placebo in patients with and without diabetes.Results: Of the 5988 patients enrolled, 2938 (49%) had diabetes. The risk of the primary outcome (first hospitalization for heart failure or cardiovascular death), total hospitalizations for heart failure, and estimated glomerular filtration rate decline was higher in patients with diabetes. Empagliflozin reduced the rate of the primary outcome irrespective of diabetes status (hazard ratio, 0.79 [95% CI, 0.67, 0.94] for patients with diabetes versus hazard ratio, 0.78 [95% CI, 0.64, 0.95] in patients without diabetes; Pinteraction=0.92). The effect of empagliflozin to reduce total hospitalizations for heart failure was also consistent in patients with and without diabetes. The effect of empagliflozin to attenuate estimated glomerular filtration rate decline during double-blind treatment was also present in patients with and without diabetes, although more pronounced in patients with diabetes (1.77 in diabetes versus 0.98 mL/min/1.73m2 in patients without diabetes; Pinteraction=0.01). Across these 3 end points, the effect of empagliflozin did not differ in patients with prediabetes or normoglycemia (33% and 18% of the patient population, respectively). When investigated as a continuous variable, baseline hemoglobin A1c did not modify the effects on the primary outcome (Pinteraction=0.26). There was no increased risk of hypoglycemic events in either subgroup as compared with placebo.Conclusions: In patients with heart failure and a preserved ejection fraction enrolled in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), empagliflozin significantly reduced the risk of heart failure outcomes irrespective of diabetes status at baseline.Registration: URL: https://www.Clinicaltrials: gov; Unique identifier: NCT03057951. [ABSTRACT FROM AUTHOR]

Aims: To perform a comprehensive characterization of acute heart failure (AHF) with preserved (HFpEF), versus mildly reduced (HFmrEF) versus reduced ejection fraction (HFrEF). Methods and results: Of 5951 participants in the ESC HF Long‐Term Registry hospitalized for AHF (acute coronary syndromes excluded), 29% had HFpEF, 18% HFmrEF, and 53% HFrEF. Hospitalization reasons were most commonly atrial fibrillation (more in HFmrEF and HFpEF), followed by ischaemia (HFmrEF), infection (HFmrEF and HFpEF), worsening renal function (HFrEF), and uncontrolled hypertension (HFmrEF and HFpEF). Hospitalization characteristics included lower blood pressure, more oedema and higher natriuretic peptides with lower ejection fraction, similar pulmonary congestion, more mitral regurgitation in HFrEF and HFmrEF and more tricuspid regurgitation in HFrEF. In‐hospital mortality was 3.4% in HFrEF, 2.1% in HFmrEF and 2.2% in HFpEF. Intravenous diuretic (∼80%) and nitrate (∼15%) use was similar but inotrope use greater in HFrEF (16%, vs. HFmrEF 7.4% vs. HFpEF 5.3%). Weight loss and estimated glomerular filtration rate improvement were greater in HFrEF, whereas reduction in natriuretic peptides was similar. Over 1 year post‐discharge, events per 100 patient‐years (95% confidence interval) in HFrEF versus HFmrEF versus HFpEF were: all‐cause death 22 (20–24) versus 17 (14–20) versus 17 (15–20); cardiovascular (CV) death 12 (10–13) versus 8.6 (6.6–11) versus 8.4 (6.9–10); non‐CV death 2.4 (1.8–3.1) versus 3.3 (2.1–4.8) versus 4.5 (3.5–5.9); all‐cause hospitalization 48 (45–51) versus 35 (31–40) versus 42 (39–46); HF hospitalization 29 (27–32) versus 19 (16–22) versus 17 (15–20); and non‐CV hospitalization 7.7 (6.6–8.9) versus 9.6 (7.5–12) versus 15 (13–17). Conclusion: In AHF, HFrEF is more severe and has greater in‐hospital mortality. Post‐discharge, HFrEF has greater CV risk, HFpEF greater non‐CV risk, and HFmrEF lower overall risk. [ABSTRACT FROM AUTHOR]

Aims: Improving renal function (IRF) is paradoxically associated with worse outcomes in acute heart failure (AHF), but outcomes may differ based on response to decongestion. We explored if the relationship of IRF with mortality in hospitalized AHF patients differs based on successful decongestion. Methods and results: We evaluated 760 AHF patients from AKINESIS for the relationship between IRF, change in B‐type natriuretic peptide (BNP), and 1‐year mortality. IRF was defined as a ≥20% increase in estimated glomerular filtration rate (eGFR) relative to admission. Adequate decongestion was defined as a ≥40% decrease in last measured BNP relative to admission. IRF occurred in 22% of patients who had a mean age of 69 years, 58% were men, 72% were white, and median admission eGFR was 49 mL/min/1.73 m2. IRF patients had more severe heart failure reflected by lower admission eGFR, higher blood urea nitrogen, lower systolic blood pressure, lower sodium, and higher use of inotropes. IRF patients had higher 1‐year mortality (25%) than non‐IRF patients (15%) (P < 0.01). However, this relationship differed by BNP trajectory (P‐interaction = 0.03). When stratified by BNP change, non‐IRF patients and IRF patients with decreasing BNP had lower 1‐year mortality than either non‐IRF and IRF patients without decreasing BNP. However, in multivariate analysis, IRF was not associated with mortality [adjusted hazard ratio (HR) 1.0, 95% confidence interval (CI) 0.7–1.5] while BNP was (adjusted HR 0.5, 95% CI 0.3–0.7). When IRF was evaluated as transiently occurring or persisting at discharge, again only BNP change was significantly associated with mortality. Conclusion: Improving renal function is associated with mortality in AHF but not independent of other variables and congestion status. Achieving adequate decongestion, as reflected by lower BNP, in AHF is more strongly associated with mortality than IRF. [ABSTRACT FROM AUTHOR]

Background: Multiple different pathophysiologic processes can contribute to worsening renal function (WRF) in acute heart failure.Methods and Results: We retrospectively analyzed 787 patients with acute heart failure for the relationship between changes in serum creatinine and biomarkers including brain natriuretic peptide, high sensitivity cardiac troponin I, galectin 3, serum neutrophil gelatinase-associated lipocalin, and urine neutrophil gelatinase-associated lipocalin. WRF was defined as an increase of greater than or equal to 0.3 mg/dL or 50% in creatinine within first 5 days of hospitalization. WRF was observed in 25% of patients. Changes in biomarkers and creatinine were poorly correlated (r ≤ 0.21) and no biomarker predicted WRF better than creatinine. In the multivariable Cox analysis, brain natriuretic peptide and high sensitivity cardiac troponin I, but not WRF, were significantly associated with the 1-year composite of death or heart failure hospitalization. WRF with an increasing urine neutrophil gelatinase-associated lipocalin predicted an increased risk of heart failure hospitalization.Conclusions: Biomarkers were not able to predict WRF better than creatinine. The 1-year outcomes were associated with biomarkers of cardiac stress and injury but not with WRF, whereas a kidney injury biomarker may prognosticate WRF for heart failure hospitalization. [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: We assessed the interplay between hyperkalaemia (HK) and renin-angiotensin-aldosterone system inhibitor (RAASi) use, dose and discontinuation, and their association with all-cause or cardiovascular death in patients with chronic heart failure (HF). We hypothesized that HK-associated increased death may be related to RAASi withdrawal.Methods and Results: The ESC-HFA-EORP Heart Failure Long-Term Registry was used. Among 9222 outpatients (HF with reduced ejection fraction: 60.6%, HF with mid-range ejection fraction: 22.9%, HF with preserved ejection fraction: 16.5%) from 31 countries, 16.6% had HK (≥5.0 mmol/L) at baseline. Angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) was used in 88.3%, a mineralocorticoid receptor antagonist (MRA) in 58.7%, or a combination in 53.2%; of these, at ≥50% of target dose in ACEi: 61.8%; ARB: 64.7%; and MRA: 90.3%. At a median follow-up of 12.2 months, there were 789 deaths (8.6%). Both hypokalaemia and HK were independently associated with higher mortality, and ACEi/ARB prescription at baseline with lower mortality. MRA prescription was not retained in the model. In multivariable analyses, HK at baseline was independently associated with MRA non-prescription at baseline and subsequent discontinuation. When considering subsequent discontinuation of RAASi (instead of baseline use), HK was no longer found associated with all-cause deaths. Importantly, all RAASi (ACEi, ARB, or MRA) discontinuations were strongly associated with mortality.Conclusions: In HF, hyper- and hypokalaemia were associated with mortality. However, when adjusting for RAASi discontinuation, HK was no longer associated with mortality, suggesting that HK may be a risk marker for RAASi discontinuation rather than a risk factor for worse outcomes. [ABSTRACT FROM AUTHOR]

Aims: Guidelines recommend down-titration of loop diuretics (LD) once euvolaemia is achieved. In outpatients with heart failure (HF), we investigated LD dose changes in daily cardiology practice, agreement with guideline recommendations, predictors of successful LD down-titration and association between dose changes and outcomes.Methods and Results: We included 8130 HF patients from the ESC-EORP Heart Failure Long-Term Registry. Among patients who had dose decreased, successful decrease was defined as the decrease not followed by death, HF hospitalization, New York Heart Association class deterioration, or subsequent increase in LD dose. Mean age was 66 ± 13 years, 71% men, 62% HF with reduced ejection fraction, 19% HF with mid-range ejection fraction, 19% HF with preserved ejection fraction. Median [interquartile range (IQR)] LD dose was 40 (25-80) mg. LD dose was increased in 16%, decreased in 8.3% and unchanged in 76%. Median (IQR) follow-up was 372 (363-419) days. Diuretic dose increase (vs. no change) was associated with HF death [hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.12-2.08; P = 0.008] and nominally with cardiovascular death (HR 1.25, 95% CI 0.96-1.63; P = 0.103). Decrease of diuretic dose (vs. no change) was associated with nominally lower HF (HR 0.59, 95% CI 0.33-1.07; P = 0.083) and cardiovascular mortality (HR 0.62, 95% CI 0.38-1.00; P = 0.052). Among patients who had LD dose decreased, systolic blood pressure [odds ratio (OR) 1.11 per 10 mmHg increase, 95% CI 1.01-1.22; P = 0.032], and absence of (i) sleep apnoea (OR 0.24, 95% CI 0.09-0.69; P = 0.008), (ii) peripheral congestion (OR 0.48, 95% CI 0.29-0.80; P = 0.005), and (iii) moderate/severe mitral regurgitation (OR 0.57, 95% CI 0.37-0.87; P = 0.008) were independently associated with successful decrease.Conclusion: Diuretic dose was unchanged in 76% and decreased in 8.3% of outpatients with chronic HF. LD dose increase was associated with worse outcomes, while the LD dose decrease group showed a trend for better outcomes compared with the no-change group. Higher systolic blood pressure, and absence of (i) sleep apnoea, (ii) peripheral congestion, and (iii) moderate/severe mitral regurgitation were independently associated with successful dose decrease. [ABSTRACT FROM AUTHOR]

Aims: To study the association between an atrial fibrillation (AF) genetic risk score with prevalent AF and all-cause mortality in patients with heart failure.Methods and Results: An AF genetic risk score was calculated in 3759 European ancestry individuals (1783 with sinus rhythm, 1976 with AF) from the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) by summing 97 single nucleotide polymorphism (SNP) alleles (ranging from 0-2) weighted by the natural logarithm of the relative SNP risk from the latest AF genome-wide association study. Further, we assessed AF risk variance explained by additive SNP variation, and performance of clinical or genetic risk factors, and the combination in classifying AF prevalence. AF was classified as AF or atrial flutter (AFL) at baseline electrocardiogram and/or a history of AF or AFL. The genetic risk score was associated with AF after multivariable adjustment. Odds ratio for AF prevalence per 1-unit increase genetic risk score was 2.12 (95% confidence interval 1.84-2.45, P = 2.15 × 10-24 ) in the total cohort, 2.08 (1.72-2.50, P = 1.30 × 10-14 ) in heart failure with reduced ejection fraction (HFrEF) and 2.02 (1.37-2.99, P = 4.37 × 10-4 ) in heart failure with preserved ejection fraction (HFpEF). AF-associated loci explained 22.9% of overall AF SNP heritability. Addition of the genetic risk score to clinical risk factors increased the C-index by 2.2% to 0.721.Conclusions: The AF genetic risk score was associated with increased AF prevalence in HFrEF and HFpEF. Genetic variation accounted for 22.9% of overall AF SNP heritability. Addition of genetic risk to clinical risk improved model performance in classifying AF prevalence. [ABSTRACT FROM AUTHOR]

Aims: Kidney impairment has been associated with worse outcomes in acute heart failure (AHF), although recent studies challenge this association. Neutrophil gelatinase-associated lipocalin (NGAL) is a novel biomarker of kidney tubular injury. Its prognostic role in AHF has not been evaluated in large cohorts. The present study aimed to determine if serum NGAL (sNGAL) or urine NGAL (uNGAL) is superior to creatinine for predicting short-term outcomes in AHF.Methods and Results: The study was conducted in an international, multicentre, prospective cohort consisting of 927 patients with AHF. Admission and peak values of sNGAL, uNGAL and uNGAL/urine creatinine (uCr) ratio were compared to admission and peak serum creatinine (sCr). The composite endpoints were death, initiation of renal replacement therapy, heart failure (HF) readmission and any emergent HF-related outpatient visit within 30 and 60 days, respectively. The mean age of the cohort was 69 years and 62% were male. The median length of stay was 6 days. The composite endpoint occurred in 106 patients and 154 patients within 30 and 60 days, respectively. Serum NGAL was more predictive than uNGAL and the uNGAL/uCr ratio but was not superior to sCr [area under the curve: admission sNGAL 0.61, 95% confidence interval (CI) 0.55-0.67, and 0.59, 95% CI 0.54-0.65; peak sNGAL: 0.60, 95% CI 0.54-0.66, and 0.57, 95% CI 0.52-0.63; admission sCr: 0.60, 95% CI 0.54-0.64, and 0.59, 95% CI 0.53-0.64; peak sCr: 0.61, 95% CI 0.55-0.67, and 0.59, 95% CI 0.54-0.64, at 30 and 60 days, respectively]. NGAL was not predictive of the composite endpoint in multivariate analysis.Conclusions: Serum NGAL outperformed uNGAL but neither was superior to admission or peak sCr for predicting adverse events. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) patients are at high-risk of cardiovascular (CV) events, including CV death. Nonetheless, a substantial proportion of these patients die from non-CV causes. Identifying patients at higher risk for each individual event may help selecting patients for clinical trials and tailoring cardiovascular therapies. The aims of the present study are to: (i) characterize patients according to CV vs. non-CV death; (ii) develop models for the prediction of the respective events; (iii) assess the models' performance to differentiate CV from non-CV death.Methods and Results: This study included 2309 patients with HF from the BIOSTAT-CHF (a systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study. Competing-risk models were used to assess the best combination of variables associated with each cause-specific death. Results were validated in an independent cohort of 1738 HF patients. The best model to predict CV death included low blood pressure, estimated glomerular filtration rate ≤ 60 mL/min, peripheral oedema, previous HF hospitalization, ischaemic HF, chronic obstructive pulmonary disease, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin (c-index = 0.73). The non-CV death model incorporated age > 75 years, anaemia and elevated NT-proBNP (c-index = 0.71). Both CV and non-CV death rose by quintiles of the risk scores; yet these models allowed the identification of patients in whom absolute CV death rates clearly outweigh non-CV death ones. These findings were externally replicated, but performed worse in a less severely diseased population.Conclusions: Risk models for predicting CV and non-CV death allowed the identification of patients at higher absolute risk of dying from CV causes (vs. non-CV ones). Troponin helped in predicting CV death only, whereas NT-proBNP helped in the prediction of both CV and non-CV death. These findings can be useful both for tailoring therapies and for patient selection in HF trials in order to attain CV event enrichment. [ABSTRACT FROM AUTHOR]

Aim To investigate the characteristics long-term prognostic implications (up to ∼2.2 years) of atrial fibrillation (AF) compared to sinus rhythm (SR), between acute and chronic heart failure (HF) with reduced (HFrEF < 40%), mid-range (HFmrEF 40–49%), and preserved (HFpEF ≥ 50%) ejection fraction (EF). Methods and results Data from the observational, prospective, HF long-term registry of the European Society of Cardiology were analysed. A total of 14 964 HF patients (age 66 ± 13 years, 67% male; 53% HFrEF, 21% HFmrEF, 26% HFpEF) were enrolled. The prevalence of AF was 27% in HFrEF, 29% in HFmrEF, and 39% in HFpEF. Atrial fibrillation was associated with older age, lower functional capacity, and heightened physical signs of HF. Crude rates of mortality and HF hospitalization were higher in patients with AF compared to SR, in each EF subtype. After multivariable adjustment, the hazard ratio of AF for HF hospitalizations was: 1.036 (95% CI 0.888–1.208, P  =   0.652) in HFrEF, 1.430 (95% CI 1.087–1.882, P  =   0.011) in HFmrEF, and 1.487 (95% CI 1.195–1.851, P  <   0.001) in HFpEF; and for combined all-cause death or HF hospitalizations: 0.957 (95% CI 0.843–1.087, P  =   0.502), 1.302 (95% CI 1.055–1.608, P  =   0.014), and 1.365 (95% CI 1.152–1.619, P  <   0.001), respectively. In patients with HFrEF, AF was not associated with worse outcomes in those presenting with either an acute or a chronic presentation of HF. Conclusions The prevalence of AF increases with increasing EF but its association with worse cardiovascular outcomes, remained significant in patients with HFpEF and HFmrEF, but not in those with HFrEF. [ABSTRACT FROM AUTHOR]

Background: Cardiac resynchronisation therapy (CRT) reduces morbidity and mortality in appropriately selected patients with heart failure and is strongly recommended for such patients by guidelines. A European Society of Cardiology (ESC) CRT survey conducted in 2008-2009 showed considerable variation in guideline adherence and large individual, national and regional differences in patient selection, implantation practice and follow-up. Accordingly, two ESC associations, the European Heart Rhythm Association and the Heart Failure Association, designed a second prospective survey to describe contemporary clinical practice regarding CRT.Methods and Results: A survey of the clinical practice of CRT-P and CRT-D implantation was conducted from October 2015 to December 2016 in 42 ESC member countries. Implanting centres provided information about their hospital and CRT service and were asked to complete a web-based case report form collecting information on patient characteristics, investigations, implantation procedures and complications during the index hospitalisation. The 11 088 patients enrolled represented 11% of the total number of expected implantations in participating countries during the survey period; 32% of patients were aged ≥75 years, 28% of procedures were upgrades from a permanent pacemaker or implantable cardioverter-defibrillator and 30% were CRT-P rather than CRT-D. Most patients (88%) had a QRS duration ≥130 ms, 73% had left bundle branch block and 26% were in atrial fibrillation at the time of implantation. Large geographical variations in clinical practice were observed.Conclusion: CRT Survey II provides a valuable source of information on contemporary clinical practice with respect to CRT implantation in a large sample of ESC member states. The survey permits assessment of guideline adherence and demonstrates variations in patient selection, management, implantation procedure and follow-up strategy. [ABSTRACT FROM AUTHOR]

Cancer and heart failure (HF) are common medical conditions with a steadily rising prevalence in industrialized countries, particularly in the elderly, and they both potentially carry a poor prognosis. A new diagnosis of malignancy in subjects with pre-existing HF is not infrequent, and challenges HF specialists as well as oncologists with complex questions relating to both HF and cancer management. An increased incidence of cancer in patients with established HF has also been suggested. This review paper summarizes the epidemiology and the prognostic implications of cancer occurrence in HF, the impact of pre-existing HF on cancer treatment decisions and the impact of cancer on HF therapeutic options, while providing some practical suggestions regarding patient care and highlighting gaps in knowledge. [ABSTRACT FROM AUTHOR]

Objectives: Coronary angiography is regularly performed in patients with worsening signs and/or symptoms of heart failure (HF). However, little is known on the determinants, findings and associated clinical outcomes of coronary angiography performed in patients with worsening HF.Methods: The BIOSTAT-CHF (a systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) programme enrolled 2516 patients with worsening symptoms and/or signs of HF, either hospitalised or in the outpatient setting. All patients were included in the present analysis.Results: Of the 2516 patients included, 315 (12.5%) underwent coronary angiography within the 30 days after the onset of worsening symptoms and/or signs of HF. Subjects who underwent angiography were more often observed as inpatients, had more often an overt acute coronary syndrome, had higher troponin I levels, were younger and had better renal function (all p≤0.01). Patients who underwent coronary angiography had a lower risk of the primary outcome of death and/or HF hospitalisation (adjusted HR=0.71, 95% CI 0.57 to 0.89, p=0.003) and death (adjusted HR=0.59, 95% CI 0.43 to 0.80, p=0.001). Among the patients who underwent coronary angiography, those with a coronary stenosis (39%) had a worse prognosis than those without stenosis (adjusted HR for the primary outcome=1.71, 95% CI 1.10 to 2.64, p=0.016).Conclusions: Coronary angiography was performed in <13% of patients with symptoms and/or signs of worsening HF. These patients were remarkably different from those who did not undergo coronary angiography and had a lower risk of subsequent events. The presence of coronary stenosis on coronary angiography was associated with a worse prognosis. [ABSTRACT FROM AUTHOR]

Aims: Previously, low high-density lipoprotein (HDL) cholesterol was found to be one of the strongest predictors of mortality and/or heart failure (HF) hospitalisation in patients with HF. We therefore performed in-depth investigation of the multifunctional HDL proteome to reveal underlying pathophysiological mechanisms explaining the association between HDL and clinical outcome.Methods and Results: We selected a cohort of 90 HF patients with 1:1 cardiovascular death/survivor ratio from BIOSTAT-CHF. A novel optimised protocol for selective enrichment of lipoproteins was used to prepare plasma. Enriched lipoprotein content of samples was analysed using high resolution nanoscale liquid chromatography-mass spectrometry-based proteomics, utilising a label free approach. Within the HDL proteome, 49 proteins significantly differed between deaths and survivors. An optimised model of 12 proteins predicted death with 76% accuracy (Nagelkerke R2 =0.37, P < 0.001). The strongest contributors to this model were filamin-A (related to crosslinking of actin filaments) [odds ratio (OR) 0.31, 95% confidence interval (CI) 0.15-0.61, P = 0.001] and pulmonary surfactant-associated protein B (related to alveolar capillary membrane function) (OR 2.50, 95% CI 1.57-3.98, P < 0.001). The model predicted mortality with an area under the curve of 0.82 (95% CI 0.77-0.87, P < 0.001). Internal cross validation resulted in 73.3 ± 7.2% accuracy.Conclusion: This study shows marked differences in composition of the HDL proteome between HF survivors and deaths. The strongest differences were seen in proteins reflecting crosslinking of actin filaments and alveolar capillary membrane function, posing potential pathophysiological mechanisms underlying the association between HDL and clinical outcome in HF. [ABSTRACT FROM AUTHOR]

Aims: Iron deficiency (ID) is a common co-morbidity in patients with heart failure (HF) and has been suggested to be associated with poor prognosis. Recently completed double-blind randomised controlled trials (RCTs) studying HF patients with ID have shown improvements in functional capacity, symptoms and quality of life when treated with i.v. ferric carboxymaltose (FCM). This individual patient data meta-analysis investigates the effect of FCM vs. placebo on recurrent hospitalisations and mortality in HF patients with ID.Methods and Results: Individual patient data were extracted from four RCTs comparing FCM with placebo in patients with systolic HF and ID. The main outcome measures were recurrent cardiovascular (CV) hospitalisations and CV mortality. Other outcomes included cause-specific hospitalisations and death. The main analyses of recurrent events were backed up by time-to-first-event analyses. In total, 839 patients, of whom 504 were randomised to FCM, were included. Compared with those taking placebo, patients on FCM had lower rates of recurrent CV hospitalisations and CV mortality [rate ratio 0.59, 95% confidence interval (CI) 0.40-0.88; P = 0.009]. Treatment with FCM also reduced recurrent HF hospitalisations and CV mortality (rate ratio 0.53, 95% CI 0.33-0.86; P = 0.011) and recurrent CV hospitalisations and all-cause mortality (rate ratio 0.60, 95% CI 0.41-0.88; P = 0.009). Time-to-first-event analyses showed similar findings, with somewhat attenuated treatment effects. The administration of i.v. FCM was not associated with an increased risk for adverse events.Conclusions: Treatment with i.v. FCM was associated with a reduction in recurrent CV hospitalisations in systolic HF patients with ID. [ABSTRACT FROM AUTHOR]

Aims: The objectives of the present study were to describe epidemiology and outcomes in ambulatory heart failure (HF) patients stratified by left ventricular ejection fraction (LVEF) and to identify predictors for mortality at 1 year in each group.Methods and Results: The European Society of Cardiology Heart Failure Long-Term Registry is a prospective, observational study collecting epidemiological information and 1-year follow-up data in 9134 HF patients. Patients were classified according to baseline LVEF into HF with reduced EF [EF <40% (HFrEF)], mid-range EF [EF 40-50% (HFmrEF)] and preserved EF [EF >50% (HFpEF)]. In comparison with HFpEF subjects, patients with HFrEF were younger (64 years vs. 69 years), more commonly male (78% vs. 52%), more likely to have an ischaemic aetiology (49% vs. 24%) and left bundle branch block (24% vs. 9%), but less likely to have hypertension (56% vs. 67%) or atrial fibrillation (18% vs. 32%). The HFmrEF group resembled the HFrEF group in some features, including age, gender and ischaemic aetiology, but had less left ventricular and atrial dilation. Mortality at 1 year differed significantly between HFrEF and HFpEF (8.8% vs. 6.3%); HFmrEF patients experienced intermediate rates (7.6%). Age, New York Heart Association (NYHA) class III/IV status and chronic kidney disease predicted mortality in all LVEF groups. Low systolic blood pressure and high heart rate were predictors for mortality in HFrEF and HFmrEF. A lower body mass index was independently associated with mortality in HFrEF and HFpEF patients. Atrial fibrillation predicted mortality in HFpEF patients.Conclusions: Heart failure patients stratified according to different categories of LVEF represent diverse phenotypes of demography, clinical presentation, aetiology and outcomes at 1 year. Differences in predictors for mortality might improve risk stratification and management goals. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the impact of physicians' adherence to guideline-recommended medications for heart failure with reduced ejection fraction (HFrEF), including ≥50% prescription of recommended doses, on clinical outcomes at 6-month follow-up.Methods and Results: In QUALIFY, an international, prospective, observational, longitudinal survey, 6669 outpatients with HFrEF were recruited 1-15 months after heart failure (HF) hospitalization from September 2013 to December 2014 in 36 countries and followed up at 6 months. A global adherence to guidelines score was developed for prescription of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs) and ivabradine and their dosages. Baseline global adherence score was good in 23% of patients, moderate in 55%, and poor in 22%. At 6-month follow-up, poor adherence was associated with significantly higher overall mortality [hazard ratio (HR) 2.21, 95% confidence interval (CI) 1.42-3.44, P=0.001], cardiovascular mortality (HR 2.27, 95% CI 1.36-3.77, P=0.003), HF mortality (HR 2.26, 95% CI 1.21-4.2, P=0.032), combined HF hospitalization or HF death (HR 1.26, 95% CI 1.08-1.71, P=0.024) and cardiovascular hospitalization or cardiovascular death (HR 1.35, 95% CI 1.08-1.69, P=0.013). There was a strong trend between poor adherence and HF hospitalization (HR 1.32, 95% CI 1.04-1.68, P=0.069).Conclusion: Good adherence to pharmacologic treatment guidelines for ACEIs, ARBs, BBs, MRAs and ivabradine, with prescription of at least 50% of recommended dosages, was associated with better clinical outcomes during 6-month follow-up. Continuing global educational initiatives are needed to emphasise the importance of guideline recommendations for optimising drug therapy and prescribing evidence-based doses in clinical practice. [ABSTRACT FROM AUTHOR]