Clinical features and outcomes of COVID-19 patients hospitalized for psychiatric disorders: a French multi-centered prospective observational study.

BACKGROUND: Patients with psychiatric disorders are exposed to high risk of COVID-19 and increased mortality. In this study, we set out to assess the clinical features and outcomes of patients with current psychiatric disorders exposed to COVID-19. METHODS: This multi-center prospective study was conducted in 22 psychiatric wards dedicated to COVID-19 inpatients between 28 February and 30 May 2020. The main outcomes were the number of patients transferred to somatic care units, the number of deaths, and the number of patients developing a confusional state. The risk factors of confusional state and transfer to somatic care units were assessed by a multivariate logistic model. The risk of death was analyzed by a univariate analysis. RESULTS: In total, 350 patients were included in the study. Overall, 24 (7%) were transferred to medicine units, 7 (2%) died, and 51 (15%) patients presented a confusional state. Severe respiratory symptoms predicted the transfer to a medicine unit [odds ratio (OR) 17.1; confidence interval (CI) 4.9-59.3]. Older age, an organic mental disorder, a confusional state, and severe respiratory symptoms predicted mortality in univariate analysis. Age >55 (OR 4.9; CI 2.1-11.4), an affective disorder (OR 4.1; CI 1.6-10.9), and severe respiratory symptoms (OR 4.6; CI 2.2-9.7) predicted a higher risk, whereas smoking (OR 0.3; CI 0.1-0.9) predicted a lower risk of a confusional state. CONCLUSION: COVID-19 patients with severe psychiatric disorders have multiple somatic comorbidities and have a risk of developing a confusional state. These data underline the need for extreme caution given the risks of COVID-19 in patients hospitalized for psychiatric disorders.

COVID-19 crisis and the incidence of hospital admissions for psychosis in France.

OBJECTIVES: We aimed to assess the impact of the COVID-19 crisis on the occurrence of new hospital admissions for cases of psychosis in France. METHOD: We conducted a retrospective observational study from the French national PMSI database. We included patients hospitalized between 2018 and 2020 with a principal diagnosis of schizophrenia or delusional disorder with no history of psychosis in the previous 10 years. In total, we included 77,172 inpatients at crisis centers and/or in full-time hospitalization at 465 French hospitals. We assessed the number of inpatients during the year of the Covid crisis (2020) and the two years prior (2018, 2019). RESULTS: The number of inpatients in full-time hospitalization decreased gradually from 2018 to 2020 by 10.6%. This downward trend was observed in all age groups. In contrast, in crisis centers the number of inpatients increased by 13.4% between 2019 and 2020, while a 7.6% decrease was seen between 2018 and 2019. The greatest increase was observed in the 31-60-year age category, and particularly amongst 46-60-year-olds, i.e. 38.0%. CONCLUSION: The COVID-19 crisis was associated with an increase in the number of inpatients with a new episode of psychosis in crisis centers but not in full-time hospitalization. The profile of patients in crisis centers was different from that seen in preceding years and included more middle-to-late age adults. Particular attention should be given to this category of patients in the crisis environment to prevent the occurrence of new cases of psychosis in France.

Enhanced clinical phenotyping by mechanistic bioprofiling in heart failure with preserved ejection fraction: insights from the MEDIA-DHF study (The Metabolic Road to Diastolic Heart Failure).

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome for which clear evidence of effective therapies is lacking. Understanding which factors determine this heterogeneity may be helped by better phenotyping. An unsupervised statistical approach applied to a large set of biomarkers may identify distinct HFpEF phenotypes.Methods: Relevant proteomic biomarkers were analyzed in 392 HFpEF patients included in Metabolic Road to Diastolic HF (MEDIA-DHF). We performed an unsupervised cluster analysis to define distinct phenotypes. Cluster characteristics were explored with logistic regression. The association between clusters and 1-year cardiovascular (CV) death and/or CV hospitalization was studied using Cox regression.Results: Based on 415 biomarkers, we identified 2 distinct clusters. Clinical variables associated with cluster 2 were diabetes, impaired renal function, loop diuretics and/or betablockers. In addition, 17 biomarkers were higher expressed in cluster 2 vs. 1. Patients in cluster 2 vs. those in 1 experienced higher rates of CV death/CV hospitalization (adj. HR 1.93, 95% CI 1.12-3.32, p = 0.017). Complex-network analyses linked these biomarkers to immune system activation, signal transduction cascades, cell interactions and metabolism.Conclusion: Unsupervised machine-learning algorithms applied to a wide range of biomarkers identified 2 HFpEF clusters with different CV phenotypes and outcomes. The identified pathways may provide a basis for future research.Clinical significanceMore insight is obtained in the mechanisms related to poor outcome in HFpEF patients since it was demonstrated that biomarkers associated with the high-risk cluster were related to the immune system, signal transduction cascades, cell interactions and metabolismBiomarkers (and pathways) identified in this study may help select high-risk HFpEF patients which could be helpful for the inclusion/exclusion of patients in future trials.Our findings may be the basis of investigating therapies specifically targeting these pathways and the potential use of corresponding markers potentially identifying patients with distinct mechanistic bioprofiles most likely to respond to the selected mechanistically targeted therapies.

Association between resting heart rate, chronotropic index, and long-term outcomes in patients with heart failure receiving ß-blocker therapy: data from the HF-ACTION trial.

AIMS: The aim of this study was to assess the association between resting heart rate (HR), chronotropic index (CI), and clinical outcomes in optimally treated chronic heart failure (HF) patients on ß-blocker therapy. METHODS AND RESULTS: We performed a sub-study in 1118 patients with HF and reduced ejection fraction (EF < 35%) included in the HF-ACTION trial. Patients in sinus rhythm who received a ß-blocker and who performed with maximal effort on the exercise test were included. Chronotropic index was calculated as an index of HR reserve achieved, by using the equation (220-age) for estimating maximum HR. A sensitivity analysis using an equation developed for HF patients on ß-blockers was also performed. Cox proportional hazards models were fit to assess the association between CI and clinical outcomes. Median (25th, 75th percentiles) follow-up was 32 (21, 44) months. In a multivariable model including resting HR and CI as continuous variables, neither was associated with the primary outcome of all-cause mortality or hospitalization. However, each 0.1 unit decrease in CI <0.6 was associated with 17% increased risk of all-cause mortality (hazard ratio 1.17, 95% confidence interval 1.01-1.36; P = 0.036), and 13% increased risk of cardiovascular mortality or HF hospitalization (hazard ratio 1.13, 1.02-1.26; P = 0.025). Overall, 666 of 1118 (60%) patients had a CI <0.6. Chronotropic index did not retain statistical significance when dichotomized at a value of ≤ 0.62. CONCLUSION: In HF patients receiving optimal medical therapy, a decrease in CI <0.6 was associated with adverse clinical outcomes. Obtaining an optimal HR response to exercise, even in patients receiving optimal ß-blocker therapy, may be a therapeutic target in the HF population.

Determinants and consequences of renal function variations with aldosterone blocker therapy in heart failure patients after myocardial infarction: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study.

BACKGROUND: We evaluated the effect of the selective mineralocorticoid receptor antagonist eplerenone on renal function and the interaction between changes in renal function and subsequent cardiovascular outcomes in patients with heart failure and left ventricular systolic dysfunction after an acute myocardial infarction in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). METHODS AND RESULTS: Serial changes in estimated glomerular filtration rate (eGFR) were available in 5792 patients during a 24-month follow-up. Patients assigned to eplerenone had a decline in eGFR with an adjusted mean difference of -1.4±0.3 mL · min(-1) · 1.73 m(-2) compared with placebo (P<0.0001), an effect that appeared within the first month (-1.3±0.4 mL · min(-1) · 1.73 m(-2)) and persisted throughout the study. Overall, 914 patients experienced a decline in eGFR >20% in the first month, 16.9% and 14.7% in the eplerenone and placebo groups, respectively (odds ratio, 1.15; 95% confidence interval, 1.02-1.30; P=0.017). In multivariate analyses, determinants of this early decline in eGFR were female sex, age ≥65 years, smoking, left ventricular ejection fraction <35%, and use of eplerenone and loop diuretic. An early decline in eGFR by >20% was associated with worse cardiovascular outcomes independently of baseline eGFR and of the use of eplerenone, which retained its prognostic benefits even under these circumstances. CONCLUSIONS: In patients with heart failure after acute myocardial infarction and receiving standard medical care, an early decline in eGFR is not uncommon and is associated with poor long-term outcome. Eplerenone induced a moderately more frequent early decline in eGFR, which did not affect its clinical benefit on cardiovascular outcomes.

Behind the scenes of the healthcare COVID-19 pandemic crisis: potential affecting factors of healthcare work sustainability in Romania during 2020-2022.

Aim: The COVID-19 pandemic represented a great disturbance for medical systems around the world, putting medical personnel on the front lines of the fight against the SARS-Cov2 virus. This fight was particularly impactful in countries with medical systems already facing various challenges, including Romania; where the pandemic unfolded in five waves that severely affected the psychological and physical well-being of medical professionals in terms of overload and continuous exposure to health threats. Against this background, our research aims to identify the mediating role of potential affecting factors of healthcare work sustainability during the change-related uncertainty conditions generated by the COVID 19 crisis. Dynamics and relations of nine carefully selected constructs were tracked along all five pandemic waves in Romania, which span from March 2020 to April 2022. The tested variables and constructs are perception of healthcare workers of their own state of health, their workplace safety, the work-family conflict, the satisfaction of basic needs, the work meaningfulness and work engagement, patient care, pandemic stress and burnout. Methods: This cross-sectional study is based on an online snowball sampling of 738 health workers from 27 hospitals. Panel research is limited to a maximum of 61 respondents for two successive waves. The analytical part is built on means comparison of analysed variables between all five pandemic waves and an in-depth model to explain the relationships between the variables. Results: The results indicate statistically significant correlations between the perception of health risks and all selected factors excluding patient care, which seems to be above the own health perception. The factors' dynamics was followed along all five pandemic waves. The developed model identified that one's health status satisfaction is a mediator of the family-work conflict and, together, of work engagement. In turn, work engagement plays a significant role in satisfying basic psychological needs and supporting work meaningfulness. Also, work meaningfulness influences the satisfaction of basic psychological needs. Discussion: Health workers with higher levels of positive perceived health are better at managing pandemic stress, burnout effects and work-family imbalances. Adaptive behaviors and attitudes towards COVID-19 pandemic threats could be identified in later pandemic waves due to the progress in terms of medical protocols and procedures.

Assessment of Properties and Microstructure of Concrete with Cotton Textile Waste and Crushed Bricks.

Cotton textile waste (CW) and crushed bricks (CB) are wastes generated by the textile and construction industries that cause adverse effects on the environment. This paper explores the effect of adding 1, 2, 5, and 10 wt.% of CW and CB, instead of natural sand under 1 mm (50 to 100 vol.%), on the properties of concrete. The study included the analysis of workability, density, water absorption, thermal conductivity, mechanical strengths, and electron microscopy. The results show that the presence of CW and CB increased the water required to obtain the same slump value as reference, R. Concretes with CW provided better performance in terms of density, water absorption (for 1 wt.%), and splitting strength (for 1 to 2 wt.%). The 28 days of compressive strength decreased with increasing CW (33.3 MPa for R and 26.9 MPa for 2 wt.% of CW). The partial substitution of sand decreased the workability and density and increased the mechanical strength of concrete. The presence of both CW and CB decreased workability, density, and mechanical strengths. Regarding the ability of concrete to transfer heat, the addition of CW and CB decreased the thermal conductivity value (e.g., 0.32 W/(m·K) for 1 wt.% of CW compared to 0.37 W/(m·K) for reference).

Hypo- and hyperglycemia predict outcome in patients with left ventricular dysfunction after acute myocardial infarction: data from EPHESUS.

BACKGROUND: Hyperglycemia predicts death in cardiovascular disease, but intensive glucose-lowering strategies increase mortality rates in diabetes. The present analysis investigated the prognostic value of postadmission blood glucose (BG) concentration on clinical outcomes in high-risk patients with heart failure after acute myocardial infarction. METHODS AND RESULTS: A total of 6,496 patients from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) were categorized into 4 groups by plasma glucose concentration: ≤4.5 mmol/L (hypoglycemia), 4.5-5.5 mmol/L (normoglycemia), 5.5-8.3 mmol/L (elevated glucose level), and >8.3 mmol/L (severe hyperglycemia). We evaluated the time to all-cause death (primary end point) and time to cardiovascular death or hospitalization (secondary end point). Hypo- and severe hyperglycemia were prevalent in 509 (8%) and 1,588 (24%) patients, respectively. There was a U-shaped relationship between BG level and incidence of all-cause death (11.8% in patients with normoglycemia vs 15.1% and 19.9% in those with hypo- and severe hyperglycemia; P < .001). The incidence of the secondary end point was increased only in hyperglycemic patients (36% vs 23% in normoglycemic patients; P < .001). In multivariate Cox regression analysis, hypoglycemia (hazard ratio [HR] 1.38, 95% confidence interval [CI] 1.06-1.81; P = .002) and severe hyperglycemia (HR 1.52, CI 1.27-1.83; P < .0001) proved to be strong predictors of all-cause death. There was no significant interaction between eplerenone treatment and blood glucose levels regarding clinical outcomes. CONCLUSIONS: In heart failure after acute myocardial infarction, both hypo- and hyperglycemia at the postacute phase identify patients with increased risk of death during long-term follow-up.

Can we prevent or treat renal dysfunction in chronic heart failure?

We aimed to summarize the predictors of renal dysfunction and present strategies to prevent and/or treat renal dysfunction in Chronic Heart Failure (CHF). Several factors may predict renal dysfunction in CHF, including older age, comorbidities (anemia, hypertension, diabetes), severity of underlying heart disease (systolic and diastolic dysfunction, central venous pressure) as well as certain therapies in specific circumstances (diuretics, nonsteroid acute inflammatory drugs, and renine-angiotensin-aldosterone (RAAS) inhibitors). Thus, prevention of renal dysfunction is possible in CHF by treating comorbidities and underlying heart disease as well as by monitoring therapies with potential toxic renal effect. At present, there is no specific treatment for renal dysfunction, but several new entities are under investigation. In conclusion, prevention of renal dysfunction is possible in CHF, but treatment is still under investigation. New studies are necessary to establish whether a specific algorithm may be used to prevent renal dysfunction in CHF patients.

A review of methods used in assessing non-serious adverse drug events in observational studies among type 2 diabetes mellitus patients.

Clinical drug trials are often conducted in selective patient populations, with relatively small numbers of patients, and a short duration of follow-up. Observational studies are therefore important for collecting additional information on adverse drug events (ADEs). Currently, there is no guidance regarding the methodology for measuring ADEs in such studies. Our aim was to evaluate whether the methodology used to assess non-serious ADEs in observational studies is adequate for detecting these ADEs, and for addressing limitations from clinical trials in patients with type 2 diabetes mellitus. We systematically searched MEDLINE and EMBASE for observational studies reporting non-serious ADEs (1999-2008). Methods to assess ADEs were classified as: 1) medical record review; 2) surveillance by health care professionals (HCP); 3) patient survey; 4) administrative data; 5) laboratory/clinical values; 6) not specified. We compared the range of ADEs identified, number and selection of patients included, and duration of follow-up. Out of 10,125 publications, 68 studies met our inclusion criteria. The most common methods were based on laboratory/clinical values (n = 25) and medical record review (n = 18). Solicited surveillance by HCP (n = 17) revealed the largest diversity of ADEs. Patient surveys (n = 15) focused mostly on hypoglycaemia and gastrointestinal ADEs, laboratory values based studies on hepatic and metabolic ADEs, and administrative database studies (n = 5) on cardiovascular ADEs. Four studies presented ADEs that were identified with the use of more than one method. The patient population was restricted to a lower risk population in 19% of the studies. Less than one third of the studies exceeded pre-approval regulatory requirements for sample size and duration of follow-up. We conclude that the current assessment of ADEs is hampered by the choice of methods. Many observational studies rely on methods that are inadequate for identifying all possible ADEs. Patient-reported outcomes and combinations of methods are underutilized. Furthermore, while observational studies often include unselective patient populations, many do not adequately address other limitations of pre-approval trials. This implies that these studies will not provide sufficient information about ADEs to clinicians and patients. Better protocols are needed on how to assess adverse drug events not only in clinical trials but also in observational studies.

Rate and predictors of interrupted patient follow-up after first-episode psychosis - a retrospective cohort study in France.

BACKGROUND: Patient adherence to follow-up after a first episode of psychosis (FEP) is currently a major challenge. Patient's early adherence reduces the risk of relapse and improves their prognosis in the short and long term. The primary goal of our study was to determine the incidence of treatment disengagement at 1-year follow-up in patients with first-episode schizophrenia, schizophreniform or schizoaffective disorder. The secondary goal was to assess the factors associated with treatment disengagement in this patient population. METHODS: We conducted a monocentric retrospective study of 136 patients in France. Relevant information was collected on sociodemographic, pre-morbidities and co-morbidities data, as well as the management and treatment characteristics at 1.3 and 12 months. Survival analysis was used to assess the association between clinical variables, management and treatment disengagement. RESULTS: Eighty-four patients (62%) have interrupted their medical follow-up at 1 year, 16% at 1 month and 34% at 3 months. A higher number of out-patient appointments after a FEP was associated with better adherence (HR:0.85 p < .0001 95% IC = [0.0-0.9]). Initial management seems to play an important role. Involuntary admissions (HR:7.14 p = .015 95% IC = [1.48-34.52]) and total number of admissions (HR:6.86 p < .0001 95% IC = [2.47-19.05]) predict disengagement at 1 month while an increased number of out-patient appointments at 3 months predicts adherence (HR:0.60 p < .0001 95% IC = [0.00-0.74]). Being a single parent is associated with disengagement at 3 months (HR:15.51 p = .022 95% IC = [1.49-161.65]). CONCLUSIONS: Incidence of disengagement is high. It might be necessary to change our management in order to develop out-patient or day-admission care and intensify care for patients at risk.

Sex differences in circulating proteins in heart failure with preserved ejection fraction.

BACKGROUND: Many patients with heart failure with preserved ejection fraction (HFpEF) are women. Exploring mechanisms underlying the sex differences may improve our understanding of the pathophysiology of HFpEF. Studies focusing on sex differences in circulating proteins in HFpEF patients are scarce. METHODS: A total of 415 proteins were analyzed in 392 HFpEF patients included in The Metabolic Road to Diastolic Heart Failure: Diastolic Heart Failure study (MEDIA-DHF). Sex differences in these proteins were assessed using adjusted logistic regression analyses. The associations between candidate proteins and cardiovascular (CV) death or CV hospitalization (with sex interaction) were assessed using Cox regression models. RESULTS: We found 9 proteins to be differentially expressed between female and male patients. Women expressed more LPL and PLIN1, which are markers of lipid metabolism; more LHB, IGFBP3, and IL1RL2 as markers of transcriptional regulation; and more Ep-CAM as marker of hemostasis. Women expressed less MMP-3, which is a marker associated with extracellular matrix organization; less NRP1, which is associated with developmental processes; and less ACE2, which is related to metabolism. Sex was not associated with the study outcomes (adj. HR 1.48, 95% CI 0.83-2.63), p = 0.18. CONCLUSION: In chronic HFpEF, assessing sex differences in a wide range of circulating proteins led to the identification of 9 proteins that were differentially expressed between female and male patients. These findings may help further investigations into potential pathophysiological processes contributing to HFpEF.

Albuminuria in heart failure: what do we really know?

PURPOSE OF THE REVIEW: To describe the role of albuminuria as a risk marker for heart failure and a predictor for treatment effect on heart failure prognosis. RECENT FINDINGS: The level of albumin in the urine is a predictor of heart failure in the general population and in patients with cardiovascular risk, such as those with diabetes. Mild elevations of albuminuria, in the microalbuminuria range, appear to be associated with impaired systemic endothelial function. This increases the chance of developing hypertension, diabetes and cardiovascular disease, ultimately leading to heart failure. Higher levels of albuminuria, in the proteinuric range, reflect marked renal pathology, which increases cardiovascular risk due to renal function decline. In patients with established heart failure, microalbuminuria is highly prevalent (30%). Although more frequent in diastolic than systolic dysfunction, it appears to indicate a worse prognosis in the latter class. Diabetes is a multiplier of risk, probably due to bidirectional relationship between diabetes and heart failure. Treatment with drugs that intervene in the renin-angiotensin-aldosterone system (RAAS) lowers albuminuria and is associated with prevention of the onset and worsening of heart failure and other cardiovascular disorders. SUMMARY: Albuminuria is associated with increased heart failure risk. Lowering of albuminuria using RAAS inhibitors appears to lower the risk for heart failure.

[Identification of abuse/dependence cases by the French addictovigilance network (FAN): A pilot study of the addictovigilance center and the psychotherapeutic center of Nancy (France)]. / Identification de cas d'abus/dépendance par le réseau français d'addictovigilance : une étude pilote du CEIP-A et du Centre psychothérapique de Nancy.

OBJECTIVES: France is the only European country with a dedicated addictovigilance network (French addictovigilance network [FAN]). However, the reporting of cases of abuse/dependence is insufficient. In an attempt to overcome this under-reporting, data from the medical information systems program (PMSI) is regularly used to identify cases. Since addictions are frequently associated with psychiatric comorbidities, a pilot study was conducted for the first time in a psychiatric hospital. It aims, through a PMSI request, to identify the sociodemographic characteristics and psychiatric diagnoses of patients consuming psychoactive substances (PAS) and the PAS types consumed. METHODS: This is a retrospective observational study conducted over a nine-month period at the psychotherapeutic center of Nancy (CPN). The codes used for the PMSI request are those of the international classification of diseases, tenth revision (ICD-10), codes F10 to F19 that characterize mental and behavioral disorders associated with the use of PAS. Cases presenting the four criteria necessary for an addictovigilance notification: (1) identified notifier, (2) identified patient, (3) known consumed product (s) and (4) presence of an effect related to the abuse/dependence of PAS; were retained and analyzed. RESULTS: On an initial number of 252 cases, 82 cases of abuse/dependence were retained. The selected sample is predominantly male (67%). Cannabis (29%) and heroin (15%) are the most common illicit PAS. Regarding drugs, the consumption of benzodiazepines, a predominantly female phenomenon, is observed in 34% of subjects. Sixty-four per cent of the subjects were diagnosed "disorders related to the use of PAS", 14% as neurotic disorders, 9% as schizophrenia and 5% as of the mood disorders. CONCLUSION: This study identified a significant number of potentially reportable cases to the French Addictovigilance Network and demonstrated the interest of investigating cases of abuse/dependence in a psychiatric hospital.

Empathy and Burnout - A Cross-Sectional Study Among Mental Healthcare Providers in France.

Previous studies have established a correlation between empathy and burnout among healthcare providers. The aim of this study is to explore whether empathy - the ability to understand what another person is experiencing, was related to mental healthcare staffs' burnout. We performed a descriptive, cross-sectional, observational study among medical and nursing mental healthcare staff working in the district of Moselle, France. Participants completed a survey including The French versions of the Jefferson Scale of Empathy (JSPE) and The Maslach Burnout Inventory-Human Services Survey (MBI-HSS). The sample included 241 (n=241) participants (N=420, response rate=51.7%). 187 (77.6%) respondents had low burnout, 43 (17.8%) had intermediate burnout and 11 (4.6%) had high burnout. 41 (17%) had low empathy, 156 (64.7) had moderate empathy and 44 (18.3%) scored high. Empathy scores were positively correlated with scores of personal accomplishment of the MBI-HSS (r=0.2; p<0.001), but negatively correlated with scores of depersonalization (r=-0.2; p<0.003). Highest means of depersonalization (DP) (M=8.7; SD=6.8; p<0.009) and lowest means of compassionate care (M=40.05; SD=7.9; p=0.0001) were found among forensic psychiatric security units staff. Participation in the Omega educational program was associated with lower scores of EE on the MBI-HSS survey (mean score 14.7 versus a mean score of 19.7 for nonparticipants). Empathic mental healthcare providers have lower levels of burnout. Forensic psychiatric staff showed low means of compassionate care and high depersonalization. Interventions designed to foster attributes and skills such as empathy, resilience, and perception of security may be an essential step in reducing and preventing burnout.

Does the European clinical trials directive really improve clinical trial approval time?

AIMS: To facilitate and improve clinical research within Europe, the European Union (EU) adopted in 2001 the Clinical Trials Directive (EUCTD). The aim of this study was to compare duration between submission of a clinical drug trial application and approval by regulatory authorities in EU countries regulated by EUCTD vs. EU countries regulated by local legislation and, second, to compare the duration of regulatory approval in Europe vs. the USA and Australia. METHODS: Application for clinical drug trial initiation was submitted to the regulatory authorities of 14 European countries, to the USA and to Australia. In Europe, 10 countries were regulated by EUCTD and four by local legislation. RESULTS: In Europe, the median duration of regulatory procedures was longer in EUCTD countries compared with countries following local legislation (75 vs. 59 days; P < 0.001). Five EUCTD countries had a time to approval of >60 days (maximum within EUCTD rules). The long duration of regulatory procedures was the consequence of (i) sequential instead of simultaneous submission of trial application to regulatory authorities, and (ii) involvement of local ethics committees in procedures that should be followed only by central ethics committees. The duration of regulatory procedures was similar in Australia (67 vs. 68 days, P = 0.388), but significantly shorter in the USA (67 vs. 15 days, P < 0.001). CONCLUSIONS: In this early stage of implementation, EUCTD appears not to shorten the duration of regulatory procedures for clinical trial initiation. Furthermore, Europe lags behind the USA in speed of regulatory procedures.

Heart rate, pulse pressure and mortality in patients with myocardial infarction complicated by heart failure.

OBJECTIVE: To assess the relationship between heart rate (HR), pulse pressure (PP), and their association with mortality in a population of high-risk patients following acute myocardial infarction (MI). METHODS: We performed an analysis in 22,398 patients included in "The High-Risk Myocardial Infarction Database Initiative", a database of clinical trials evaluating pharmacologic interventions in patients with MI complicated by signs of heart failure (HF) or left ventricular dysfunction. We found an interaction between HR and PP. Based on median HR and median PP, patients were divided in four categories: (1) HR < 75 bpm and PP ≥ 50 mm Hg (reference), (2) HR < 75 bpm and PP < 50 mm Hg, (3) HR ≥ 75 bpm and PP ≥ 50 mm Hg, and (4) HR ≥ 75 bpm and PP < 50 mm Hg. The association between these categories and outcomes was studied using a Cox proportional hazard model. RESULTS: After a median follow-up of 24 (18-33) months, 3561 (16%) patients died of all-causes and 3048 (14%) patients of cardiovascular (CV) causes. In multivariate analysis, patients from the fourth category had the highest risk of all-cause mortality (hazard ratio of 1.69; 95% CI: 1.53-1.86) and CV mortality (hazard ratio of 1.78; 95% CI: 1.60-1.97). CONCLUSIONS: There is an interaction between HR and PP in patients with HF following MI, with the highest risk being conferred by a clinical status with both an elevated HR and a lower PP. These findings identify a high-risk population likely to require an aggressive diagnostic and management strategy.

Tolerability and dose-related effects of nebivolol in elderly patients with heart failure: data from the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS) trial.

BACKGROUND: The SENIORS trial showed that nebivolol reduced the risk of death or cardiovascular (CV) hospitalization in elderly patients with heart failure (HF). We aimed to assess tolerability and dose-related effects of the beta-blocker nebivolol in elderly patients from the SENIORS trial. METHODS: Patients assigned to nebivolol (n = 1031) were classified into 4 groups, according to the dose achieved at the end of titration phase (maintenance dose): 0 mg (n = 74), low dose (1.25 or 2.5 mg, n = 142), medium dose (5 mg, n = 127), and target dose (10 mg, n = 688) and compared with those allocated to placebo (n = 1030). Age, sex and ejection fraction were similar between the groups, but prior myocardial infarction, coronary revascularization, and serum creatinine levels were lower in patients who achieved higher maintenance doses of nebivolol. RESULTS: After adjustment, all-cause mortality or CV hospitalization was significantly reduced in the 10 mg dose group compared with placebo (hazard ratio [HR] 0.75, 95% CI 0.63-0.90) which was similar to the medium dose group (HR 0.73, 95% CI 0.52-1.02). The low dose group had an apparently lower benefit (HR 0.88, 95% CI 0.64-1.20), whereas patients unable to tolerate any dose of nebivolol had an increased risk of death or CV hospitalization (HR 1.95, 95% CI 1.38-2.75). CONCLUSIONS: The benefits of nebivolol in elderly patients with HF appear to be related to the maintenance dose achieved. Patients unable to tolerate any dose have the worst prognosis.

Prescription of beta-blockers in patients with advanced heart failure and preserved left ventricular ejection fraction. Clinical implications and survival.

BACKGROUND: The effects of beta-blockers in patients with heart failure (HF) and preserved left ventricular ejection fraction (LVEF) are not well established. AIMS: To assess the association between beta-blocker prescription at discharge and mortality in a cohort of patients with advanced HF and preserved LVEF. METHODS AND RESULTS: We prospectively studied a cohort of 443 patients with advanced HF and preserved LVEF (LVEF> or =40%). Mean age was 78 years, 56% female, 33% NYHA class IV. Overall, 227 patients (51%) had a beta-blocker prescribed at discharge. Mean duration of follow-up was 25 (+/-18) months. Death (all cause) occurred in 40 patients (17.6%) who were receiving a beta-blocker at discharge and 73 patients (33.8%) who were not on a beta-blocker. In multivariate Cox analysis, including adjustment for propensity score, prescription of a beta-blocker remained associated with a 43% relative mortality risk reduction (HR 0.57, 95% CI 0.37 to 0.88, p=0.01). CONCLUSIONS: In this cohort of patients with advanced HF and preserved LVEF, prescription of a beta-blocker was associated with a significant mortality reduction. This beneficial effect of beta-blocker use needs to be further confirmed in prospective, randomised clinical trials.

beta-Adrenoceptor antagonists in elderly patients with heart failure: a critical review of their efficacy and tolerability.

Heart failure (HF) is a major public health problem among the elderly. The syndrome of HF may arise in the presence of either a depressed or apparently normal left-ventricular ejection fraction (LVEF). The latter entity is more common in the elderly. In elderly patients with HF, prescription of a beta-adrenoceptor antagonist may raise concerns regarding efficacy and tolerability. Because of these concerns, but also as a result of a paucity of published data, beta-adrenoceptor antagonists are under-prescribed to elderly patients with HF in general practice. We review the evidence regarding the efficacy and tolerability of beta-adrenoceptor antagonist therapy in elderly patients with HF. We found three major sources of evidence: one prospective, randomised controlled trial (RCT), SENIORS (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure); a subgroup meta-analysis of elderly patients included in systolic HF trials; and a large number of observational studies. SENIORS showed that the third-generation beta-adrenoceptor antagonist nebivolol reduces the risk of all-cause mortality or cardiovascular admission in elderly patients (aged > or =70 years) with HF and a broad range of LVEF. The subgroup meta-analysis of RCTs showed that beta-adrenoceptor antagonists reduce mortality in elderly patients (aged 60-80 years) with systolic HF, and that the benefit is similar to that observed in non-elderly patients (aged <60 years). The observational studies showed a beneficial effect of beta-adrenoceptor antagonists in elderly populations in daily practice, including those with depressed and preserved LVEF. However, the effect of beta-adrenoceptor antagonists on all-cause mortality may be lower in very elderly patients (aged >75 years). Approximately two-thirds of elderly patients with HF tolerate a beta-adrenoceptor antagonist, but only 40-70% of the target doses recommended in RCTs are achieved. Some clinical variables may predict low beta-adrenoceptor antagonist tolerability, such as low systolic blood pressure, higher New York Heart Association HF severity class, advanced age and ischaemic cause of HF. Furthermore, prescription of a high diuretic dose and calcium channel antagonists may also decrease beta-adrenoceptor antagonist tolerability. However, it is difficult to identify on clinical grounds patients intolerant to any beta-adrenoceptor antagonist dose. Low-dose therapy (<50% target dose) may be effective in an elderly population with HF, but prescription of at least a medium dose (> or =50% target dose) may achieve a higher benefit. In conclusion, although elderly patients with HF take lower doses of beta-adrenoceptor antagonists, these agents are still effective and overall well tolerated in this population. Elderly patients with HF should therefore not be denied beta-adrenoceptor antagonist therapy. The dilemma relies on dose-benefit balance, as higher doses would be more effective but may raise tolerability concerns. The beneficial effects of use of beta-adrenoceptor antagonists in elderly patients with HF and preserved LVEF need to be further confirmed in large RCTs.