Search

Background: The 6-minute walk test (6MWT) is a simple and inexpensive way of measuring exercise capacity in patients with heart failure (HF) that predicts morbidity and mortality. However, there are few reports from large multicentre cohorts assessing the predictive value of baseline and changing walk distance.Methods and Results: In BIOSTAT-CHF, a 6MWT was performed at baseline (n = 1714) and 9 months (n = 1520). Cox proportional hazards models were used to assess the associations between 6MWT distance and the composite of HF hospitalization and/or death. Median follow-up was 21 months. The median (pct25-75 ) of the 6MWT distance at baseline was 300 m (200-388 m). Independent predictors of a shorter 6MWT distance included older age, female sex, higher heart rate, New York Heart Association class III/IV, orthopnoea, ischaemic heart disease, a previous stroke, current malignancy, and higher N-terminal pro-B-type natriuretic peptide (all P < 0.05). Patients in the lowest baseline 6MWT tertile (≤ 240 m) were less likely to receive guideline-recommended doses of disease-modifying therapies (P < 0.05). Compared to patients in the highest baseline 6MWT tertile (> 360 m), those in the lowest and middle tertiles had a worse prognosis [adjusted hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.38-2.18]. Patients with a decrease in the distance walked had a worse prognosis (adjusted HR for each 50 m decrease 1.09, 95% CI 1.06-1.12). 6MWT distance was not modified by treatment up-titration nor the 6MWT improved the BIOSTAT-CHF prognostic models.Conclusions: The 6-minute walk test distance at baseline and a decline in walking distance were both associated with worse prognosis but did not improve the prognostic models. 6MWT distance was not modified by treatment up-titration and its use for assessing the benefits of pharmacologic treatment up-titration may be limited. [ABSTRACT FROM AUTHOR]

Introduction: Patients with symptomatic heart failure (HF) require additive therapies and have a poor prognosis. However, patient characteristics and clinical outcome between HF patients treated in the outpatient setting vs. those who are hospitalized remain scarce.Methods and Results: The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) included 2516 patients with symptoms and/or signs of HF: 1694 as inpatients and 822 as outpatients. Compared to ambulatory HF patients, inpatients had higher heart rate, urea, N-terminal pro-brain natriuretic peptide, lower blood pressure, lower estimated glomerular filtration rate, sodium, potassium, high-density lipoprotein cholesterol, had more often peripheral oedema, diabetes, anaemia, and were less often treated with beta-blockers and angiotensin-converting enzyme inhibitors (ACEi). Outpatients had a more frequent history of HF hospitalization and received more frequently beta-blockers and/or ACEi/angiotensin receptor blockers up-titrated to target doses (P < 0.001). Inpatients had higher rates of the primary outcome of death or HF hospitalization: incidence rate per 100 person-years of 33.4 [95% confidence interval (CI) 31.1-35.9] for inpatients vs. 18.5 (95% CI 16.4-21.0) for outpatients; adjusted hazard ratio 1.24 (95% CI 1.07-1.43). Subdividing patients into low, intermediate and high-risk categories, the primary outcome event rates were 14.3 (95% CI 12.3-16.7), 36.6 (95% CI 32.2-41.5), and 71.3 (95% CI 64.4-79.0) for inpatients vs. 8.4 (95% CI 6.6-10.6), 29.8 (95% CI 24.5-36.2), and 43.3 (95% CI 34.7-54.0) for outpatients, respectively. These findings were externally replicated.Conclusions: Marked differences were observed between inpatients and outpatients with HF. Overall, inpatients were sicker and had higher event rates. However, a substantial proportion of outpatients had similar or higher event rates compared to inpatients. These findings suggest that HF outpatients also have poor prognosis and may be the focus of future trials. [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]

There is an unmet need for effective treatment strategies to reduce morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Until recently, attention in patients with HFpEF was almost exclusively focused on the left side. However, it is now increasingly recognized that right heart dysfunction is common and contributes importantly to poor prognosis in HFpEF. More insights into the development of right heart dysfunction in HFpEF may aid to our knowledge about this complex disease and may eventually lead to better treatments to improve outcomes in these patients. In this position paper from the Heart Failure Association of the European Society of Cardiology, the Committee on Heart Failure with Preserved Ejection Fraction reviews the prevalence, diagnosis, and pathophysiology of right heart dysfunction and failure in patients with HFpEF. Finally, potential treatment strategies, important knowledge gaps and future directions regarding the right side in HFpEF are discussed. [ABSTRACT FROM AUTHOR]

Aims: Mineralocorticoid receptor antagonists (MRAs) are recommended (unless contraindicated) to all patients with heart failure with reduced ejection fraction (HFrEF). However, MRAs are still largely underused in routine clinical practice. This study aims to describe the determinants and pattern of use of MRAs in HFrEF.Methods and Results: BIOSTAT-CHF is a European multicentre, prospective study which enrolled patients suboptimally treated with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs) and/or beta-blockers, with the aim of optimizing guideline-based use of these agents. From the original 2516 subjects, this retrospective post hoc analysis included the 1325 patients with an indication for MRA therapy (i.e. left ventricular ejection fraction ≤35%, estimated glomerular filtration rate ≥30 mL/min/1.73 m2 , K+ ≤5.0 mmol/L). The mean age was 66.1 ± 12.2 years. At baseline an MRA was prescribed to 741 (56%) patients. Patients who were prescribed MRAs at baseline were younger, more often male, had higher body mass index, lower sodium, higher proportion of hypertension history and ACEi/ARB prescription (all P < 0.05). Of the 1049 patients who completed the baseline plus the 9 month visit, 585 (56%) had an MRA prescribed at baseline and 662 (63%) had an MRA prescribed at 9 months. Among the 585 patients with MRA at baseline, 91 (16%) had discontinued therapy and among the 461 (44%) patients without MRA at baseline 168 (36%) had initiated therapy subsequently. MRA discontinuation was more likely in subjects with higher left ventricular ejection fraction and NYHA class III/IV (P < 0.05 for both). MRA prescription both at baseline and 9 months was not associated with the outcome of death or heart failure hospitalization (adjusted hazard ratio 1.02, 95% confidence interval 0.66-1.58; P = 0.93).Conclusions: In this prospective observational study across Europe, MRAs were largely under-prescribed and frequently discontinued. Owing to these dynamic changes, outcome inferences are inconclusive. [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]

Aims: Although hypokalaemia is common among patients with heart failure (HF), the prognostic significance of baseline hypokalaemia and hypokalaemia during follow-up in HF patients receiving a mineralocorticoid receptor antagonist (MRA) remains uncertain.Methods and Results: Results of the EMPHASIS-HF trial in patients (n = 2737) with HF and reduced EF with mild symptoms, randomized to eplerenone or placebo, were analysed with regard to the presence or occurrence of hypokalaemia (serum K+ <4.0 mmol/L) and the risk of cardiovascular death or hospitalization for HF (primary endpoint). Median follow-up was 21 months. Baseline hypokalaemia and hypokalaemia during follow-up were common occurrences (19.6% and 40.6%, respectively). Hypokalaemia during follow-up was associated with worse outcomes in multivariable analyses [hazard ratio (HR) 1.26, 95% confidence interval (CI) 1.05-1.52, P = 0.01] without evidence of interaction with eplerenone. In contrast, baseline hypokalaemia was associated with outcomes in the placebo group (HR 1.37, 95% CI 1.05-1.79, P = 0.02) but not in the eplerenone group (HR 0.87, 95% CI 0.62-1.23, P = 0.44; P for interaction = 0.04). Concurrently, eplerenone was found to be more protective in patients with baseline hypokalaemia vs. patients without baseline hypokalaemia compared with placebo (HR 0.44, 95% 0.30-0.64, P < 0.0001 vs. 0.69, 95% CI 0.57-0.83, P = 0.0001; P for interaction = 0.04). In patients without baseline hypokalaemia, eplerenone use decreased the rate of hypokalaemia during follow-up (HR 0.69, 95% CI 0.59-0.80, P < 0.001). A potassium level >4.0 mmol/L at 1 month after randomization mediated 26.0% (0.6-51.4%) of the eplerenone treatment effect (P = 0.04).Conclusion: In HF patients receiving optimal therapy but not treated with eplerenone, baseline hypokalaemia was associated with worse outcomes. Conversely, hypokalaemia amplified the treatment effect of eplerenone. [ABSTRACT FROM AUTHOR]

Aims: Despite major improvements in pharmacological and device treatments, heart failure remains a syndrome with high morbidity and mortality, poor quality of life, and high health-care costs. Given the extensive heterogeneity among patients with heart failure, substantial differences in the response to therapy can be expected. We hypothesize that individualized therapy is an essential next step to improve outcomes in patients with heart failure.Methods: The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) included 2516 patients with worsening signs and/or symptoms of heart failure from 11 European countries, who were considered to be on suboptimal medical treatment. Another 1738 patients from Scotland were included in a validation cohort. Overall, both patient cohorts were well matched. The majority of patients were hospitalized for acute heart failure, and the remainder presented with worsening signs and/or symptoms of heart failure at outpatient clinics. Approximately half of the patients were in New York Heart Association class III, and 7% vs 34% of patients of the index vs validation cohort had heart failure with preserved ejection fraction. According to study design, all patients used diuretics, but owing to the inclusion criteria of both cohorts, patients were not on optimal, evidence-based medical therapy. In the follow-up phase, uptitration to guideline-recommended doses was encouraged.Conclusion: By using a novel systems biology approach, incorporating demographics, biomarkers, genome-wide analysis, and proteomics, a model that predicts response to therapy will be developed, which should be instrumental in developing alternative therapies for patients with suboptimal response to currently recommended therapies and thus further improve care for patients with heart failure. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) patients increasingly receive device therapy, either an implantable cardioverter defibrillator (ICD) or a biventricular pacemaker, also called cardiac resynchronization therapy (CRT), or a CRT device with an ICD (CRT-D). However, epidemiological data on the use of device therapy in Europe are limited. [ABSTRACT FROM PUBLISHER]

Abstract: In The Netherlands, the incidence and prevalence of heart failure are rising as is the case in most other European countries. Overall, there are 200,000 patients with heart failure in The Netherlands and around 25,000 hospitalisations annually with a discharge diagnosis of heart failure. Most of these patients are managed in primary care, often together with a cardiologist. There is an active guideline program in different professional organisations (e.g. general practitioners, cardiologists) and in 2002 a collaborative multidisciplinary guideline for management of chronic heart failure was developed. However, there is clearly room for improvement in the adherence to these guidelines both with regard to the diagnosis and the treatment of HF patients. For example, ACE-I and β-blockers are still under-prescribed. In particular, the more severely ill patients seem to be under treated. At present, general practitioners and cardiologists differ in their views on heart failure, resulting in differences in diagnosis and management. In addition to the multidisciplinary guidelines, several other initiatives have been developed to improve outcomes in these patients, such as rapid access clinics and outpatient heart failure clinics. [Copyright &y& Elsevier]

Introduction: From a prospective multicentre multicountry clinical trial, we developed and validated risk models to predict prospective all-cause mortality and hospitalizations because of heart failure (HF) in patients with HF.Methods and Results: BIOSTAT-CHF is a research programme designed to develop and externally validate risk models to predict all-cause mortality and HF hospitalizations. The index cohort consisted of 2516 patients with HF from 69 centres in 11 European countries. The external validation cohort consisted of 1738 comparable patients from six centres in Scotland, UK. Patients from the index cohort had a mean age of 69 years, 27% were female, 83% were in New York Heart Association (NYHA) class II-III and the mean left ventricular ejection fraction (LVEF) was 31%. The full prediction models for mortality, hospitalization owing to HF, and the combined outcome, yielded c-statistic values of 0.73, 0.69, and 0.71, respectively. Predictors of mortality and hospitalization owing to HF were remarkably different. The five strongest predictors of mortality were more advanced age, higher blood urea nitrogen and N-terminal pro-B-type natriuretic peptide, lower haemoglobin, and failure to prescribe a beta-blocker. The five strongest predictors of hospitalization owing to HF were more advanced age, previous hospitalization owing to HF, presence of oedema, lower systolic blood pressure and lower estimated glomerular filtration rate. Patients from the validation cohort were aged 74 years, 34% were female, 85% were in NYHA class II-III, and mean LVEF was 41%; c-statistic values for the full and compact model were comparable to the index cohort.Conclusion: A small number of variables, which are usually readily available in the routine clinical setting, provide useful prognostic information for patients with HF. Predictors of mortality were remarkably different from predictors of hospitalization owing to HF. [ABSTRACT FROM AUTHOR]

Aims: Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. We aim to better understand the underlying pathophysiological processes associated with ageing in HFrEF potentially leading to targeted therapies in this vulnerable population., Methods and Results: From a panel of 363 cardiovascular biomarkers available in 1611 patients with HFrEF in the BIOSTAT-CHF index cohort and cross-validated in 823 patients in the BIOSTAT-CHF validation cohort, we tested which biomarkers were dysregulated in patients aged >75 vs. <65 years. Second, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in elderly vs. younger patients. After adjustment, multiple test correction [false discovery rate (FDR) 1%], and cross-validation, 27/363 biomarkers were associated with older age, 22 positively and 5 negatively. The biomarkers that were positively associated with older age were associated with tumour cell regulation, extra-cellular matrix organization, and inflammatory processes, whereas biomarkers negatively associated with older age were associated with pathways that may point to cell proliferation and tumourigenesis. Among the 27 biomarkers, WFDC2 (WAP four-disulphide core domain protein 2)-that broadly functions as a protease inhibitor-was associated with older age and had the strongest association with all outcomes. No protein-by-sex interaction was observed., Conclusions: In elderly HFrEF patients, pathways associated with extra-cellular matrix organization, inflammatory processes, and tumour cell regulation were activated, while pathways associated with tumour proliferation functions were down-regulated. These findings may help in a better understanding of the ageing processes in HFrEF and identify potential therapeutic targets., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background We recently showed that, in patients with heart failure, lower high-density lipoprotein (HDL) cholesterol concentration was a strong predictor of death or hospitalization for heart failure. In a follow-up study, we suggested that this association could be partly explained by HDL proteome composition. However, whether the emerging concept of HDL function contributes to the prognosis of patients with heart failure has not been addressed. Methods and Results We measured 3 key protective HDL function metrics, namely, cholesterol efflux, antioxidative capacity, and anti-inflammatory capacity, at baseline and after 9 months in 446 randomly selected patients with heart failure from BIOSTAT-CHF (A Systems Biology Study to Tailored Treatment in Chronic Heart Failure). Additionally, the relationship between HDL functionality and HDL proteome composition was determined in 86 patients with heart failure. From baseline to 9 months, HDL cholesterol concentrations were unchanged, but HDL cholesterol efflux and anti-inflammatory capacity declined (both P <0.001). In contrast, antioxidative capacity increased ( P <0.001). Higher HDL cholesterol efflux was associated with lower mortality after adjusting for BIOSTAT-CHF risk models and log HDL cholesterol (hazard ratio, 0.81; 95% CI, 0.71-0.92; P =0.001). Other functionality measures were not associated with outcome. Several HDL proteins correlated with HDL functionality, mainly with cholesterol efflux. Apolipoprotein A1 emerged as the main protein associated with all 3 HDL functionality measures. Conclusions Better HDL cholesterol efflux at baseline was associated with lower mortality during follow-up, independent of HDL cholesterol. HDL cholesterol efflux and anti-inflammatory capacity declined during follow-up in patients with heart failure. Measures of HDL function may provide clinical information in addition to HDL cholesterol concentration in patients with heart failure.

Aims: We sought to describe the clinical presentation, management, and 6-month outcomes in women with peripartum cardiomyopathy (PPCM) globally., Methods and Results: In 2011, >100 national and affiliated member cardiac societies of the European Society of Cardiology (ESC) were contacted to contribute to a global registry on PPCM, under the auspices of the ESC EURObservational Research Programme. These societies were tasked with identifying centres who could participate in this registry. In low-income countries, e.g. Mozambique or Burkina Faso, where there are no national societies due to a shortage of cardiologists, we identified potential participants through abstracts and publications and encouraged participation into the study. Seven hundred and thirty-nine women were enrolled in 49 countries in Europe (33%), Africa (29%), Asia-Pacific (15%), and the Middle East (22%). Mean age was 31 ± 6 years, mean left ventricular ejection fraction (LVEF) was 31 ± 10%, and 10% had a previous pregnancy complicated by PPCM. Symptom-onset occurred most often within 1 month of delivery (44%). At diagnosis, 67% of patients had severe (NYHA III/IV) symptoms and 67% had a LVEF ≤35%. Fifteen percent received bromocriptine with significant regional variation (Europe 15%, Africa 26%, Asia-Pacific 8%, the Middle East 4%, P < 0.001). Follow-up was available for 598 (81%) women. Six-month mortality was 6% overall, lowest in Europe (4%), and highest in the Middle East (10%). Most deaths were due to heart failure (42%) or sudden (30%). Re-admission for any reason occurred in 10% (with just over half of these for heart failure) and thromboembolic events in 7%. Myocardial recovery (LVEF > 50%) occurred only in 46%, most commonly in Asia-Pacific (62%), and least commonly in the Middle East (25%). Neonatal death occurred in 5% with marked regional variation (Europe 2%, the Middle East 9%)., Conclusion: Peripartum cardiomyopathy is a global disease, but clinical presentation and outcomes vary by region. Just under half of women experience myocardial recovery. Peripartum cardiomyopathy is a disease with substantial maternal and neonatal morbidity and mortality., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and β-blockers are guideline-recommended first-line therapies in heart failure (HF) with reduced ejection fraction (HFrEF). Previous studies showed that individual drug classes were under-dosed in many parts of Europe and Asia. In this study, we investigated the association of combined up-titration of ACEi/ARBs and β-blockers with all-cause mortality and its combination with hospitalization for HF., Methods and Results: A total of 6787 HFrEF patients (mean age 62.6 ± 13.2 years, 77.7% men, mean left ventricular ejection fraction 27.7 ± 7.2%) were enrolled in the prospective multinational European (BIOSTAT-CHF; n = 2100) and Asian (ASIAN-HF; n = 4687) studies. Outcomes were analysed according to achieved percentage of guideline-recommended target doses (GRTD) of combination ACEi/ARB and β-blocker therapy, adjusted for indication bias. Only 14% (n = 981) patients achieved ≥50% GRTD for both ACEi/ARB and β-blocker. The best outcomes were observed in patients who achieved 100% GRTD of both ACEi/ARB and β-blocker [hazard ratio (HR) 0.32, 95% confidence interval (CI) 0.26-0.39 vs. none]. Lower dose of combined therapy was associated with better outcomes than 100% GRTD of either monotherapy. Up-titrating β-blockers was associated with a consistent and greater reduction in hazards of all-cause mortality (HR for 100% GRTD: 0.40, 95% CI 0.25-0.63) than corresponding ACEi/ARB up-titration (HR 0.75, 95% CI 0.53-1.07)., Conclusion: This study shows that best outcomes were observed in patients attaining GRTD for both ACEi/ARB and β-blockers, unfortunately this was rarely achieved. Achieving >50% GRTD of both drug classes was associated with better outcome than target dose of monotherapy. Up-titrating β-blockers to target dose was associated with greater mortality reduction than up-titrating ACEi/ARB., (© 2020 European Society of Cardiology.)

Background: Geographical differences may impact the treatment of heart failure (HF) and the results of clinical trials. We have investigated the differences between geographical areas across Europe in the BIOSTAT-CHF program., Methods: Patients with worsening HF enrolled in BIOSTAT-CHF were subdivided, according to the European geographical areas, into those from Northern countries (The Netherlands, Norway, Sweden, UK), Central countries (Germany, Poland, Serbia, Slovenia), and Mediterranean countries (France, Greece, Italy). Patients were compared for baseline characteristics, treatment, and outcomes. The primary endpoint was a composite of all-cause mortality or HF hospitalization., Results: Among 2516 patients enrolled in BIOSTAT-CHF, 814 (32.3%) were from Northern European centers, 816 (32.4%) from Central European centers, and 886 (35.2%) from Mediterranean centers. Patients from Northern European centers were older, had more severe signs and symptoms of HF, and with lower incidence of non-cardiac comorbidities such as chronic kidney dysfunction, diabetes and, hypertension, compared to those from the Central and Mediterranean centers. Patients receiving ≥ 50% of the target dose of both ACE-I/ARB after the up-titration phase were higher in the Northern European centers compared with the other regions (60% versus 58.7% in the Central European centers and 46.5% in the Mediterranean ones; p < 0.001). The primary endpoint occurred at a higher rate in the Northern centers (44.3% versus 37.4% in central centers and 39.6% in Mediterranean centers; p = 0.014), this difference became non-significant after the adjustment for important confounders. Importantly, treatment up-titration reduced the event rates regardless of the geographical region (p for interaction > 0.05)., Conclusion: The BIOSTAT-CHF study showed significant differences in the clinical features, treatment and prognosis in European patients with HF. Patients from the Mediterranean centers less often had the HF treatments up-titrated; however, the treatment up-titration benefited patients irrespective of their geographical region and should be part of the "default" clinical practice.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has important implications for the safety of participants in clinical trials and the research staff caring for them and, consequently, for the trials themselves. Patients with heart failure may be at greater risk of infection with COVID-19 and the consequences might also be more serious, but they are also at risk of adverse outcomes if their clinical care is compromised. As physicians and clinical trialists, it is our responsibility to ensure safe and effective care is delivered to trial participants without affecting the integrity of the trial. The social contract with our patients demands no less. Many regulatory authorities from different world regions have issued guidance statements regarding the conduct of clinical trials during this COVID-19 crisis. However, international trials may benefit from expert guidance from a global panel of experts to supplement local advice and regulations, thereby enhancing the safety of participants and the integrity of the trial. Accordingly, the Heart Failure Association of the European Society of Cardiology on 21 and 22 March 2020 conducted web-based meetings with expert clinical trialists in Europe, North America, South America, Australia, and Asia. The main objectives of this Expert Position Paper are to highlight the challenges that this pandemic poses for the conduct of clinical trials in heart failure and to offer advice on how they might be overcome, with some practical examples. While this panel of experts are focused on heart failure clinical trials, these discussions and recommendations may apply to clinical trials in other therapeutic areas., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: The current pandemic coronavirus SARS-CoV-2 infects a wide age group but predominantly elderly individuals, especially men and those with cardiovascular disease. Recent reports suggest an association with use of renin-angiotensin-aldosterone system (RAAS) inhibitors. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for coronaviruses. Higher ACE2 concentrations might lead to increased vulnerability to SARS-CoV-2 in patients on RAAS inhibitors., Methods and Results: We measured ACE2 concentrations in 1485 men and 537 women with heart failure (index cohort). Results were validated in 1123 men and 575 women (validation cohort).The median age was 69 years for men and 75 years for women. The strongest predictor of elevated concentrations of ACE2 in both cohorts was male sex (estimate = 0.26, P < 0.001; and 0.19, P < 0.001, respectively). In the index cohort, use of ACE inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs) was not an independent predictor of plasma ACE2. In the validation cohort, ACE inhibitor (estimate = -0.17, P = 0.002) and ARB use (estimate = -0.15, P = 0.03) were independent predictors of lower plasma ACE2, while use of an MRA (estimate = 0.11, P = 0.04) was an independent predictor of higher plasma ACE2 concentrations., Conclusion: In two independent cohorts of patients with heart failure, plasma concentrations of ACE2 were higher in men than in women, but use of neither an ACE inhibitor nor an ARB was associated with higher plasma ACE2 concentrations. These data might explain the higher incidence and fatality rate of COVID-19 in men, but do not support previous reports suggesting that ACE inhibitors or ARBs increase the vulnerability for COVID-19 through increased plasma ACE2 concentrations., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: Association of elevated circulating levels of trimethylamine N-oxide (TMAO) with adverse outcomes in patients with heart failure (HF) has been described. However, response of TMAO levels to treatment and medications has not been investigated. Therefore, we investigated whether TMAO levels are responsive to guideline-recommended treatment and medications, and further reflect changes in outcomes., Methods and Results: TMAO levels were investigated in the systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF), which addressed response to guideline-recommended pharmacological treatment. TMAO levels in 2234 patients with new-onset or progressively worsening HF showed strong associations with adverse events (mortality and/or rehospitalisation) at 1, 2 and 3 years [hazard ratio (HR) 1.37-1.51, P ≤ 0.019). Analysis of 972 patients with plasma available at both enrolment and follow-up visit showed reductions of B-type natriuretic peptide (BNP) levels with guideline-based treatment (P < 0.001), but not for TMAO levels. Moreover, patients with higher TMAO levels than median before and after treatment showed increased association with adverse outcomes [HR 2.21, 95% confidence interval (CI) 1.43-3.43, P < 0.001] compared to patients with lower than median levels either before or after treatment (HR 1.13, 95% CI 0.63-2.04, P = 0.684 and HR 1.14, 95% CI 0.64-2.03, P = 0.662, respectively)., Conclusion: TMAO levels were associated with adverse outcomes (mortality and/or rehospitalisation) in BIOSTAT-CHF, and did not respond to guideline-based pharmacological treatment in contrast to BNP levels which did as expected. Lower TMAO levels were associated with favourable outcome regardless of treatment., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Background: Increased resting heart rate is a risk factor for cardiovascular mortality and morbidity. Mineralocorticoid receptor antagonists (MRAs) have been shown to improve cardiac sympathetic nerve activity, reduce heart rate and attenuate left ventricular remodelling. Whether or not the beneficial effects of MRA are affected by heart rate in heart failure patients with reduced ejection fraction (HFREF) is unclear., Methods: We undertook a secondary analysis of data from the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure study to assess if clinical outcomes, as well as the efficacy of eplerenone, varied according to heart rate at baseline., Results: High resting heart rate of 80 bpm and above predisposed patients to greater risk of all outcomes in the trial, regardless of treatment allocation. The beneficial effects of eplerenone were observed across all categories of heart rate. Eplerenone reduced the risk of primary endpoint, the composite of cardiovascular death and hospitalisation for heart failure, by 30% (aHR 0.70; 95% CI 0.54-0.91) in subjects with heart rate ≥ 80 bpm, and by 48% (aHR 0.52; 95% CI 0.33-0.81) in subjects with heart rate ≤ 60 bpm. Eplerenone also reduced the risks of hospitalisation for heart failure, cardiovascular deaths and all-cause deaths independently of baseline heart rate., Conclusions: Baseline heart rate appears to be an important predictor of major clinical outcome events in patients with HFREF, as has been previously reported. The benefits of eplerenone were preserved across all categories of baseline heart rate, without observed heterogeneity in the responses.

The coexistence of type 2 diabetes mellitus (T2DM) and heart failure (HF), either with reduced (HFrEF) or preserved ejection fraction (HFpEF), is frequent (30-40% of patients) and associated with a higher risk of HF hospitalization, all-cause and cardiovascular (CV) mortality. The most important causes of HF in T2DM are coronary artery disease, arterial hypertension and a direct detrimental effect of T2DM on the myocardium. T2DM is often unrecognized in HF patients, and vice versa, which emphasizes the importance of an active search for both disorders in the clinical practice. There are no specific limitations to HF treatment in T2DM. Subanalyses of trials addressing HF treatment in the general population have shown that all HF therapies are similarly effective regardless of T2DM. Concerning T2DM treatment in HF patients, most guidelines currently recommend metformin as the first-line choice. Sulphonylureas and insulin have been the traditional second- and third-line therapies although their safety in HF is equivocal. Neither glucagon-like preptide-1 (GLP-1) receptor agonists, nor dipeptidyl peptidase-4 (DPP4) inhibitors reduce the risk for HF hospitalization. Indeed, a DPP4 inhibitor, saxagliptin, has been associated with a higher risk of HF hospitalization. Thiazolidinediones (pioglitazone and rosiglitazone) are contraindicated in patients with (or at risk of) HF. In recent trials, sodium-glucose co-transporter-2 (SGLT2) inhibitors, empagliflozin and canagliflozin, have both shown a significant reduction in HF hospitalization in patients with established CV disease or at risk of CV disease. Several ongoing trials should provide an insight into the effectiveness of SGLT2 inhibitors in patients with HFrEF and HFpEF in the absence of T2DM., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Objective: To determine the prevalence, clinical correlates and the effects on outcome of vitamin B12 and folic acid levels in patients with chronic heart failure (HF)., Methods: We studied an international pooled cohort comprising 610 patients with chronic HF. The main outcome measure was all-cause mortality., Results: Mean age of the patients was 68±12 years and median serum N-terminal prohormone brain natriuretic peptide level was 1801 pg/mL (IQR 705-4335). Thirteen per cent of the patients had an LVEF >45%. Vitamin B12 deficiency (serum level <200 pg/mL), folate deficiency (serum level <4.0 ng/mL) and iron deficiency (serum ferritin level <100 µg/L, or 100-299 µg/L with a transferrin saturation <20%) were present in 5%, 4% and 58% of the patients, respectively. No significant correlation between mean corpuscular volume and vitamin B12, folic acid or ferritin levels was observed. Lower folate levels were associated with an impaired health-related quality of life (p=0.029). During a median follow-up of 2.10 years (1.31-3.60 years), 254 subjects died. In multivariable proportional hazard models, vitamin B12 and folic acid levels were not associated with prognosis., Conclusions: Vitamin B12 and folate deficiency are relatively rare in patients with chronic HF. Since no significant association was observed between mean corpuscular volume and neither vitamin B12 nor folic acid levels, this cellular index should be used with caution in the differential diagnosis of anaemia in patients with chronic HF. In contrast to iron deficiency, vitamin B12 and folic acid levels were not related to prognosis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Aims: There is limited information about the effects of beta-blockers in heart failure (HF) stratified by blood pressure, especially in the elderly and those with preserved EF. We evaluate the effects of nebivolol on outcomes in elderly patients with HF stratified by baseline systolic blood pressure (SBP) and EF., Methods and Results: The SENIORS trial evaluated the effects of nebivolol and enrolled 2128 patients ≥ 70 years of age with HF. Patients were divided into three baseline pre-treatment SBP categories (<110, 110-130, and >130 mmHg). In addition, we evaluated the influence of SBP (≤ 130 and > 130 mmHg) on patients with LVEF <40% vs. ≥ 40%. Low baseline SBP was associated with worse clinical outcomes irrespective of treatment group, both in patients with reduced EF and in those with preserved EF. Nebivolol had similar benefits irrespective of baseline SBP: the hazard ratio (HR) for primary outcome of all-cause mortality or cardiovascular hospitalization in the three SBP categories for nebivolol vs. placebo was 0.85 [95% confidence interval (CI) 0.50-1.45], 0.79 (95% CI 0.61-1.01), and 0.88 (95% CI 0.72-1.07), respectively (P for interaction = 0.61). Similar results were obtained for the secondary endpoint of all-cause mortality. There was no significant interaction for the effects of nebivolol by baseline SBP stratified by LVEF., Conclusions: Elderly HF patients with lower SBP have a worse outcome than those with higher SBP, but nebivolol appears to be safe and well tolerated, with similar benefits on the composite outcome of death or cardiovascular hospital admission irrespective of baseline SBP and LVEF., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

Patients affected by chronic heart failure (CHF) present significant impairment of health-related quality of life (HRQoL). Iron deficiency (ID) is a common comorbidity in CHF with negative impact in prognosis and functional capacity. The role of iron in energy metabolism could be the link between ID and HRQoL. There is little information about the role of ID on HRQoL in patients with CHF. We evaluate the impact of ID on HRQoL and the interaction with the anaemia status, iron status, clinical baseline information and HRQoL, measured with the Minnesota Living with Heart Failure questionnaire (MLHFQ) was obtained at baseline in an international cohort of 1278 patients with CHF. Baseline characteristics were median age 68 ± 12, 882 (69%) were males, ejection fraction was 38% ± 15 and NYHA class was I/II/III/IV (156/247/487/66). ID (defined as ferritin level< 100 µg/L or serum ferritin 100-299 µg/L in combination with a TSAT<20%) was present in 741 patients (58%). 449 (35%) patients were anaemic. Unadjusted global scores of MLHFQ (where higher scores reflect worse HRQoL) were worse in ID and anaemic patients (ID+: 42 ± 25 vs. ID-: 37 ± 25; p-value=0.001 and A+: 46 ± 25 vs. A-: 37 ± 25; p-value<0.001). The combined influence of ID and anaemia was explored with different multivariable regression models, showing that ID but not anaemia was associated with impaired HRQoL. ID has a negative impact on HRQoL in CHF patients, and this is independent of the presence of anaemia., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Aims: The aim of this document was to obtain a real-life contemporary analysis of the demographics and heart failure (HF) statistics, as well as the organization and major activities of the Heart Failure National Societies (HFNS) in European Society of Cardiology (ESC) member countries., Methods and Results: Data from 33 countries were collected from HFNS presidents/representatives during the first Heart Failure Association HFNS Summit (Belgrade, Serbia, 29 October 2011). Data on incidence and/or prevalence of HF were available for 22 countries, and the prevalence of HF ranged between 1% and 3%. In five European and one non-European ESC country, heart transplantation was reported as not available. Natriuretic peptides and echocardiography are routinely applied in the management of acute HF in the median of 80% and 90% of centres, respectively. Eastern European and Mediterranean countries have lower availability of natriuretic peptide testing for acute HF patients, compared with other European countries. Almost all countries have organizations dealing specifically with HF. HFNS societies for HF patients exist in only 12, while in 16 countries HF patient education programmes are active. Most HFNS reported that no national HF registry exists in their country. Fifteen HFNS produced national HF guidelines, while 19 have translated the ESC HF guidelines. Most HFNS (n = 23) participated in the organization of the European HF Awareness Day., Conclusion: This document demonstrated significant heterogeneity in the organization of HF management, and activities of the national HF working groups/associations. High availability of natriuretic peptide and echocardiographic measurements was revealed, with differences between developed countries and countries in transition.

Aims: The European CRT Survey is a joint initiative of the Heart Failure Association (HFA) and the European Heart Rhythm Association (EHRA) of the European Society of Cardiology evaluating the contemporary implantation practice of cardiac resynchronization therapy (CRT) in Europe., Methods and Results: Patients who had a successful CRT implantation were enrolled from 141 centres in 13 countries between November 2008 and June 2009. Baseline demographics, clinical and implantation data were collected, with a follow-up of ∼1 year (9-15 months). The current report describes clinical outcomes including symptom severity, cardiovascular (CV) hospitalization, and survival. A total of 2438 patients were enrolled, and follow-up data were acquired from 2111 patients (87%). The population included important groups of patients poorly represented in randomized controlled trials, including very elderly patients and those with prior device implantation, atrial fibrillation, and/or QRS duration <120 ms. Investigators reported substantial improvement in New York Heart Association (NYHA) functional class at follow-up. Patient self-assessment indicated that 81% of the patients felt improved, 16% reported no change, and 4% reported deterioration. During follow-up, 207 (10%) patients died, 346 (16%) had a CV hospitalization, and 501 (24%) died or had CV hospitalization. Worse NYHA functional class, atrial fibrillation, ischaemic aetiology, and device type (CRT-P, i.e. CRT alone) were associated with poorer survival. Women had a better outcome, as did patients who had a CRT-D (with an implantable cardioverter defibrillator function) device., Conclusions: Outcomes including death and hospitalization in this European CRT survey were consistent with results from clinical trials of CRT. At 1 year follow-up, most patients who received a CRT device considered their symptoms improved compared with their pre-implant assessment. Although prospective, this is an observational study of successful CRT implantations, and outcomes in subgroup analyses must be interpreted with appropriate conservatism.

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function.

Peripartum cardiomyopathy (PPCM) is a cause of pregnancy-associated heart failure. It typically develops during the last month of, and up to 6 months after, pregnancy in women without known cardiovascular disease. The present position statement offers a state-of-the-art summary of what is known about risk factors for potential pathophysiological mechanisms, clinical presentation of, and diagnosis and management of PPCM. A high index of suspicion is required for the diagnosis, as shortness of breath and ankle swelling are common in the peripartum period. Peripartum cardiomyopathy is a distinct form of cardiomyopathy, associated with a high morbidity and mortality, but also with the possibility of full recovery. Oxidative stress and the generation of a cardiotoxic subfragment of prolactin may play key roles in the pathophysiology of PPCM. In this regard, pharmacological blockade of prolactin offers the possibility of a disease-specific therapy.

Patients with acute heart failure (AHF) require urgent in-hospital treatment for relief of symptoms. The main reason for hospitalization is congestion, rather than low cardiac output. Although congestion is associated with a poor prognosis, many patients are discharged with persistent signs and symptoms of congestion and/or a high left ventricular filling pressure. Available data suggest that a pre-discharge clinical assessment of congestion is often not performed, and even when it is performed, it is not done systematically because no method to assess congestion prior to discharge has been validated. Grading congestion would be helpful for initiating and following response to therapy. We have reviewed a variety of strategies to assess congestion which should be considered in the care of patients admitted with HF. We propose a combination of available measurements of congestion. Key elements in the measurement of congestion include bedside assessment, laboratory analysis, and dynamic manoeuvres. These strategies expand by suggesting a routine assessment of congestion and a pre-discharge scoring system. A point system is used to quantify the degree of congestion. This score offers a new instrument to direct both current and investigational therapies designed to optimize volume status during and after hospitalization. In conclusion, this document reviews the available methods of evaluating congestion, provides suggestions on how to properly perform these measurements, and proposes a method to quantify the amount of congestion present.

Background: Several randomised studies of heart failure (HF) management programmes in the United States, Australia and Europe have shown a considerable reduction in hospitalisation rates for HF. In this article, a comprehensive review of these studies will be provided and their applicability to countries, with a primary care-based healthcare system, will be discussed. In addition, the design of the Deventer-Alkmaar HF Project (DEAL-HF), a randomised study of the effect of a nurse and physician-directed intervention over 1 year in The Netherlands, will also be presented., Aim: To discuss the applicability of the results of available studies on heart failure management programmes to countries with well-structured primary care facilities and to determine whether additional trials should be conducted in these countries., Methods: We performed a literature search in PubMed. In a review of the available studies, essential methodological aspects, in particular, the population involved, the sample size, follow-up period, setting, type of intervention, and the outcome parameters, are discussed critically. Also, the applicability of these studies to countries with a primary care-based healthcare system and easy access to medical care is evaluated., Conclusion: Applicability of the results of the available studies on the efficacy of heart failure management programmes to countries with a primary care-based health care system is doubtful. An efficacy trial in a country with a well-established primary care-based healthcare system, such as The Netherlands, is due to report soon (DEAL-HF).