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Aims: Decongestion strategies for acute decompensated heart failure (ADHF) characterized by volume overload differ widely. The aim of this independent international academic web‐based survey was to capture the therapeutic strategies that physicians use to treat ADHF and to assess differences in therapeutic approaches between cardiologists versus non‐cardiologists. Methods and results: Physicians were invited to complete a web‐based questionnaire, capturing anonymized data on physicians' characteristics and treatment preferences based on a hypothetical clinical scenario of a patient hospitalized with ADHF. A total of 641 physicians from 60 countries participated. A wide variation in the management of the patient was observed. There was conservative use of diuretics, i.e. only 7% started intravenous furosemide at a dose ≥2 times the baseline oral dose, and infrequent use of ultrasound in assessing congestion (20.4%). Spot urinary sodium was infrequently or never measured by ≥85% of physicians. A third considered a patient with ongoing oedema as being stabilized. There were significant differences between cardiologists and non‐cardiologists in the management of ADHF, the targets for daily body weight loss and urine output, diuretic escalation strategies (66.3% vs. 40.7% would escalate diuresis by adding a thiazide) and assessment of response to treatment (27.0% vs. 52.9% considered patients with minimal congestion as stabilized). Conclusions: There is substantial variability amongst physicians and between cardiologists and non‐cardiologists in the management of patients with ADHF, with regard to clinical parameters used to tailor treatment, treatment goals, diuretic dosing and escalation strategies. [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]

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

Aims: 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. [ABSTRACT FROM AUTHOR]

Cardiomyopathies are a heterogeneous group of heart muscle diseases and an important cause of heart failure (HF). Current knowledge on incidence, pathophysiology and natural history of HF in cardiomyopathies is limited, and distinct features of their therapeutic responses have not been systematically addressed. Therefore, this position paper focuses on epidemiology, pathophysiology, natural history and latest developments in treatment of HF in patients with dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathies. In DCM, HF with reduced ejection fraction (HFrEF) has high incidence and prevalence and represents the most frequent cause of death, despite improvements in treatment. In addition, advanced HF in DCM is one of the leading indications for heart transplantation. In HCM, HF with preserved ejection (HFpEF) affects most patients with obstructive, and ∼10% of patients with non-obstructive HCM. A timely treatment is important, since development of advanced HF, although rare in HCM, portends a poor prognosis. In RCM, HFpEF is common, while HFrEF occurs later and more frequently in amyloidosis or iron overload/haemochromatosis. Irrespective of RCM aetiology, HF is a harbinger of a poor outcome. Recent advances in our understanding of the mechanisms underlying the development of HF in cardiomyopathies have significant implications for therapeutic decision-making. In addition, new aetiology-specific treatment options (e.g. enzyme replacement therapy, transthyretin stabilizers, immunoadsorption, immunotherapy, etc.) have shown a potential to improve outcomes. Still, causative therapies of many cardiomyopathies are lacking, highlighting the need for the development of effective strategies to prevent and treat HF in cardiomyopathies. [ABSTRACT FROM AUTHOR]

Background: Hyperkalaemia is a common co-morbidity in patients with heart failure with reduced ejection fraction (HFrEF). Whether it affects the use of renin-angiotensin-aldosterone system inhibitors and thereby negatively impacts outcome is unknown. Therefore, we investigated the association between potassium and uptitration of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and its association with outcome.Methods and Results: Out of 2516 patients from the BIOSTAT-CHF study, potassium levels were available in 1666 patients with HFrEF. These patients were sub-optimally treated with ACEi/ARB or beta-blockers and were anticipated and encouraged to be uptitrated. Potassium levels were available at inclusion and at 9 months. Outcome was a composite of all-cause mortality and heart failure hospitalization at 2 years. Patients' mean age was 67 ± 12 years and 77% were male. At baseline, median serum potassium was 4.3 (interquartile range 3.9-4.6) mEq/L. After 9 months, 401 (24.1%) patients were successfully uptitrated with ACEi/ARB. During this period, mean serum potassium increased by 0.16 ± 0.66 mEq/L (P < 0.001). Baseline potassium was an independent predictor of lower ACEi/ARB dosage achieved [odds ratio 0.70; 95% confidence interval (CI) 0.51-0.98]. An increase in potassium was not associated with adverse outcomes (hazard ratio 1.15; 95% CI 0.86-1.53). No interaction on outcome was found between baseline potassium, potassium increase during uptitration, or potassium at 9 months and increased dosage of ACEi/ARB (Pinteraction  > 0.5 for all).Conclusion: Higher potassium levels are an independent predictor of enduring lower dosages of ACEi/ARB. Higher potassium levels do not attenuate the beneficial effects of ACEi/ARB uptitration. [ABSTRACT FROM AUTHOR]

Aims To examine associations of below-target and target dose of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, with outcomes in patients with heart failure and reduced ejection fraction (HFrEF) in the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial. Methods and results Two thousand five hundred and sixty-nine patients with HFrEF (ejection fraction =35%) were randomized to below-target (5-10 mg/day) dose placebo (n = 1284) or enalapril (n = 1285). One month post-randomization, blind up-titration to target (20 mg/day) dose was attempted for both study drugs in 2458 patients. Among the 1444 patients who achieved dose up-titration (placebo, n=748; enalapril, n=696; mean dose for both groups, 20.0 mg/day), target dose enalapril (vs. target dose placebo) was associated with a 9% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality [adjusted hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.60-0.81; P < 0.001] during 4 years of follow-up. Among the 1014 patients who could not achieve target dose (placebo, n=486; enalapril, n=528; mean dose for both groups, 8.8 mg/day), below-target dose enalapril (vs. below-target dose placebo) was associated with a 12% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 0.68; 95% CI 0.57-0.81; P < 0.001). Among the 1224 patients receiving enalapril, target (vs. below-target) dose had no association with the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 1.04; 95% CI 0.87-1.23; P = 0.695). Conclusion In patients with HFrEF, the clinical benefits of ACE inhibitors appear to be similar at both below-target and target doses. [ABSTRACT FROM AUTHOR]

Aims The aim of this study was to assess long-term safety of intravenous cardiovascular agents--vasodilators, inotropes and/or vasopressors--in acute heart failure (AHF). Methods and results The European Society of Cardiology Heart Failure Long-Term (ESC-HF-LT) registry was a prospective, observational registry conducted in 21 countries. Patients with unscheduled hospitalizations for AHF (n=6926) were included: 1304 (18.8%) patients received a combination of intravenous (i.v.) vasodilators and diuretics, 833 (12%) patients received i.v. inotropes and/or vasopressors. Primary endpoint was long-term all-cause mortality. Main secondary endpoints were in-hospital and post-discharge mortality. Adjusted hazard ratio (HR) showed no association between the use of i.v. vasodilator and diuretic and long-term mortality [HR 0.784, 95% confidence interval (CI) 0.596-1.032] nor in-hospital mortality (HR 1.049, 95% CI 0.592-1.857) in the matched cohort (n=976 paired patients). By contrast, adjusted HR demonstrated a detrimental association between the use of i.v. inotrope and/or vasopressor and long-term all-cause mortality (HR 1.434, 95% CI 1.128-1.823), as well as in-hospital mortality (HR 1.873, 95% CI 1.151-3.048) in the matched cohort (n=606 paired patients). No association was found between the use of i.v. inotropes and/or vasopressors and long-term mortality in patients discharged alive (HR 1.078, 95% CI 0.769-1.512). A detrimental association with inotropes and/or vasopressors was seen in all geographic regions and, among catecholamines, dopamine was associated with the highest risk of death (HR 1.628, 95% CI 1.031-2.572 vs. no inotropes). Conclusions Vasodilators did not demonstrate any association with long-term clinical outcomes, while inotropes and/or vasopressors were associated with increased risk of all-cause death, mostly related to excess of in-hospital mortality in AHF. [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]

Heart failure (HF) and type 2 diabetes mellitus (T2DM) are both growing public health concerns contributing to major medical and economic burdens to society. T2DM increases the risk of HF, frequently occurs concomitantly with HF, and worsens the prognosis of HF. Several anti-hyperglycaemic medications have been associated with a concern for worse HF outcomes. More recently, the results of the EMPA-REG OUTCOME trial showed that the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin was associated with a pronounced and precocious 38% reduction in cardiovascular mortality in subjects with T2DM and established cardiovascular disease [Correction added on 8 September 2017, after first online publication:"32%" in the previous sentence was corrected to"38%"]. These benefits were more related to a reduction in incident HF events rather than to ischaemic vascular endpoints. Several mechanisms have been put forward to explain these benefits, which also raise the possibility of using these drugs as therapies not only in the prevention of HF, but also for the treatment of patients with established HF regardless of the presence or absence of diabetes. Several large trials are currently exploring this postulate. [ABSTRACT FROM AUTHOR]

Aims: Left ventricular (LV) reverse remodelling is an important marker of improved outcomes in patients with advanced heart failure (HF). We examined the impact of the intramyocardial administration of bone-marrow-derived, lineage-directed, autologous cardiopoietic mesenchymal stem cells (C3BS-CQR-1) on LV remodelling in patients with advanced HF enrolled in the CHART-1 study.Methods and Results: Patients (n=351) with symptomatic advanced HF secondary to ischaemic heart disease, and reduced LV ejection fraction (LVEF <35%) were randomized to receive C3BS-CQR-1 or a sham procedure. In a post hoc analysis we examined the effect of C3BS-CQR-1 on LV reverse remodelling within 1 year of the procedure and the influence of C3BS-CQR-1 dosing in the 271 patients treated as randomized. Delivery of C3BS-CQR-1 was associated with a progressive decrease in both LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV) within 52 weeks after treatment. At 1 year, the LVEDV and LVESV of treated patients decreased by 17.0 mL and 12.8 mL greater than controls (P=0.006 and P=0.017, respectively). The effect on LVEDV was maintained after multivariable adjustment for baseline age, systolic blood pressure, LVEDV, LVEF and history of myocardial infarction. The largest reverse remodelling was evident in the patients receiving a moderate number of injections (<20).Conclusion: In CHART-1, intramyocardial administration of cardiopoietic stem cells led to reverse remodelling as evidenced by significant progressive decreases in LVEDV and LVESV through the 52 weeks of follow-up. Further studies are needed to explore the dose response with regard to cell number and injected volume, and reverse remodelling. [ABSTRACT FROM AUTHOR]

Aims: 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]

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/1.73m², 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]

Organ injury and impairment are commonly observed in patients with acute heart failure (AHF), and congestion is an essential pathophysiological mechanism of impaired organ function. Congestion is the predominant clinical profile in most patients with AHF; a smaller proportion presents with peripheral hypoperfusion or cardiogenic shock. Hypoperfusion further deteriorates organ function. The injury and dysfunction of target organs (i.e. heart, lungs, kidneys, liver, intestine, brain) in the setting of AHF are associated with increased risk for mortality. Improvement in organ function after decongestive therapies has been associated with a lower risk for post-discharge mortality. Thus, the prevention and correction of organ dysfunction represent a therapeutic target of interest in AHF and should be evaluated in clinical trials. Treatment strategies that specifically prevent, reduce or reverse organ dysfunction remain to be identified and evaluated to determine if such interventions impact mortality, morbidity and patient-centred outcomes. This paper reflects current understanding among experts of the presentation and management of organ impairment in AHF and suggests priorities for future research to advance the field. [ABSTRACT FROM AUTHOR]

Despite the availability of a number of different classes of therapeutic agents with proven efficacy in heart failure, the clinical course of heart failure patients is characterized by a reduction in life expectancy, a progressive decline in health-related quality of life and functional status, as well as a high risk of hospitalization. New approaches are needed to address the unmet medical needs of this patient population. The European Medicines Agency (EMA) is undertaking a revision of its Guideline on Clinical Investigation of Medicinal Products for the Treatment of Chronic Heart Failure. The draft version of the Guideline was released for public consultation in January 2016. The Cardiovascular Round Table of the European Society of Cardiology (ESC), in partnership with the Heart Failure Association of the ESC, convened a dedicated two-day workshop to discuss three main topic areas of major interest in the field and addressed in this draft EMA guideline: (i) assessment of efficacy (i.e. endpoint selection and statistical analysis); (ii) clinical trial design (i.e. issues pertaining to patient population, optimal medical therapy, run-in period); and (iii) research approaches for testing novel therapeutic principles (i.e. cell therapy). This paper summarizes the key outputs from the workshop, reviews areas of expert consensus, and identifies gaps that require further research or discussion. Collaboration between regulators, industry, clinical trialists, cardiologists, health technology assessment bodies, payers, and patient organizations is critical to address the ongoing challenge of heart failure and to ensure the development and market access of new therapeutics in a scientifically robust, practical and safe way. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to assess the net clinical and prognostic effects of intravenous (i.v.) iron therapy in patients with systolic heart failure (HF) and iron deficiency (ID).Methods and Results: We performed an aggregate data meta-analysis (random effects model) of randomized controlled trials that evaluated the effects of i.v. iron therapy in iron-deficient patients with systolic HF. We searched electronic databases up to September 2014. We identified five trials which fulfilled the inclusion criteria (509 patients received i.v. iron therapy in comparison with 342 controls). Intravenous iron therapy has been shown to reduce the risk of the combined endpoint of all-cause death or cardiovascular hospitalization [odds ratio (OR) 0.44, 95% confidence interval (CI) 0.30-0.64, P < 0.0001], and the combined endpoint of cardiovascular death or hospitalization for worsening HF (OR 0.39, 95% CI 0.24-0.63, P = 0.0001). Intravenous iron therapy resulted in a reduction in NYHA class (data are reported as a mean net effect with 95% CIs for all continuous variables) (-0.54 class, 95% CI -0.87 to -0.21, P = 0.001); an increase in 6-min walking test distance (+31 m, 95% CI 18-43, P < 0.0001); and an improvement in quality of life [Kansas City Cardiomyopathy Questionnaire (KCCQ) score +5.5 points, 95% CI 2.8-8.3, P < 0.0001; European Quality of Life-5 Dimensions (EQ-5D) score +4.1 points, 95% CI 0.8-7.3, P = 0.01; Minnesota Living With Heart Failure Questionnaire (MLHFQ) score -19 points, 95% CI:-23 to -16, P < 0.0001; and Patient Global Assessment (PGA) +0.70 points, 95% CI 0.31-1.09, P = 0004].Conclusion: The evidence indicates that i.v. iron therapy in iron-deficient patients with systolic HF improves outcomes, exercise capacity, and quality of life, and alleviates HF symptoms. [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: To assess physicians' adherence to guideline-recommended medications for the treatment of chronic heart failure (CHF) with reduced ejection fraction.Methods and Results: QUALIFY is an international prospective observational longitudinal survey of 7092 CHF outpatients recruited 1-15 months after hospitalization for heart failure from September 2013 to December 2014 in 547 centres in 36 countries. We constructed a five-class guideline adherence score for angiotensin converting enzyme inhibitors (ACEIs), beta-blockers, angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, and ivabradine. The adherence score was good in 67%, moderate in 25%, and poor in 8% of patients. Adherence was lower in women than men but there were differences in age (65.7 ± 12.5 years women vs. 62.2 ± 12.4 years men, P < 0.001) and the proportion of women at ≥50% target dose of beta-blockers was lower in those >67 years (median) (11% vs. 16.2%, P = 0.005). Geographic variations were observed with lower adherence scores in Central/Eastern European countries. The proportion of patients at target dose and ≥50% of target dose was low (27.9% and 63.3% for ACEIs, 14.8% and 51.8% for beta-blockers, 6.9% and 39.5% for ARBs, and 6.9% and 39.5% for ivabradine, respectively). It was also lower in patients most recently hospitalized (<6  vs. ≥6 months) except for beta-blockers.Conclusion: This international survey shows that adherence to guideline-recommended medications is relatively satisfactory but the dosage of recommended CHF medications is usually suboptimal. Action plans aimed at improving adherence to guidelines are required. [ABSTRACT FROM AUTHOR]

Acute right ventricular (RV) failure is a complex clinical syndrome that results from many causes. Research efforts have disproportionately focused on the failing left ventricle, but recently the need has been recognized to achieve a more comprehensive understanding of RV anatomy, physiology, and pathophysiology, and of management approaches. Right ventricular mechanics and function are altered in the setting of either pressure overload or volume overload. Failure may also result from a primary reduction of myocardial contractility owing to ischaemia, cardiomyopathy, or arrhythmia. Dysfunction leads to impaired RV filling and increased right atrial pressures. As dysfunction progresses to overt RV failure, the RV chamber becomes more spherical and tricuspid regurgitation is aggravated, a cascade leading to increasing venous congestion. Ventricular interdependence results in impaired left ventricular filling, a decrease in left ventricular stroke volume, and ultimately low cardiac output and cardiogenic shock. Identification and treatment of the underlying cause of RV failure, such as acute pulmonary embolism, acute respiratory distress syndrome, acute decompensation of chronic pulmonary hypertension, RV infarction, or arrhythmia, is the primary management strategy. Judicious fluid management, use of inotropes and vasopressors, assist devices, and a strategy focusing on RV protection for mechanical ventilation if required all play a role in the clinical care of these patients. Future research should aim to address the remaining areas of uncertainty which result from the complexity of RV haemodynamics and lack of conclusive evidence regarding RV-specific treatment approaches. [ABSTRACT FROM AUTHOR]

Takotsubo syndrome is an acute reversible heart failure syndrome that is increasingly recognized in modern cardiology practice. This Position Statement from the European Society of Cardiology Heart Failure Association provides a comprehensive review of the various clinical and pathophysiological facets of Takotsubo syndrome, including nomenclature, definition, and diagnosis, primary and secondary clinical subtypes, anatomical variants, triggers, epidemiology, pathophysiology, clinical presentation, complications, prognosis, clinical investigations, and treatment approaches. Novel structured approaches to diagnosis, risk stratification, and management are presented, with new algorithms to aid decision-making by practising clinicians. These also cover more complex areas (e.g. uncertain diagnosis and delayed presentation) and the management of complex cases with ongoing symptoms after recovery, recurrent episodes, or spontaneous presentation. The unmet needs and future directions for research in this syndrome are also discussed. [ABSTRACT FROM AUTHOR]

Aims: Hyperkalaemia in heart failure patients limits use of cardioprotective renin-angiotensin-aldosterone system inhibitors (RAASi). Sodium zirconium cyclosilicate (ZS-9) is a selective potassium ion trap, whose mechanism of action may allow for potassium binding in the upper gastrointestinal tract as early as the duodenum following oral administration. ZS-9 previously demonstrated the ability to reduce elevated potassium levels into the normal range, with a median time of normalization of 2.2 h and sustain normal potassium levels for 28 days in HARMONIZE--a Phase 3, double-blind, randomized, placebo-controlled trial. In the present study we evaluated management of serum potassium with daily ZS-9 over 28 days in heart failure patients from HARMONIZE, including those receiving RAASi therapies.Methods and Results: Heart failure patients with evidence of hyperkalaemia (serum potassium ≥5.1 mmol/L, n = 94) were treated with open-label ZS-9 for 48 h. Patients (n = 87; 60 receiving RAASi) who achieved normokalaemia (potassium 3.5-5.0 mmol/L) were randomized to daily ZS-9 (5, 10, or 15 g) or placebo for 28 days. Mean potassium and proportion of patients maintaining normokalaemia during days 8-29 post-randomization were evaluated. Despite RAASi doses being kept constant, patients on 5 g, 10 g, and 15 g ZS-9 maintained a lower potassium level (4.7 mmol/L, 4.5 mmol/L, and 4.4 mmol/L, respectively) than the placebo group (5.2 mmol/L; P<0.01 vs. each ZS-9 group); greater proportions of ZS-9 patients (83%, 89%, and 92%, respectively) maintained normokalaemia than placebo (40%; P < 0.01 vs. each ZS-9 group). The safety profile was consistent with previously reported overall study population.Conclusion: Compared with placebo, all three ZS-9 doses lowered potassium and effectively maintained normokalaemia for 28 days in heart failure patients without adjusting concomitant RAASi, while maintaining a safety profile consistent with the overall study population. [ABSTRACT FROM AUTHOR]

Aims In the Digitalis Investigation Group (DIG) trial, digoxin reduced mortality or hospitalization due to heart failure (HF) in several pre-specified high-risk subgroups of HF patients, but data on protocol-specified 2-year outcomes were not presented. In the current study, we examined the effect of digoxin on HF death or HF hospitalization and all-cause death or all-cause hospitalization in high-risk subgroups during the protocol-specified 2 years of post-randomization follow-up. Methods and results In the DIG trial, 6800 ambulatory patients with chronic HF, normal sinus rhythm, and LVEF ≤45% (mean age 64 years, 26% women, 17% non-whites) were randomized to receive digoxin or placebo. The three high-risk groups were defined as NYHA class III–IV symptoms (n = 2223), LVEF <25% (n = 2256), and cardiothoracic ratio (CTR) >55% (n = 2345). In all three high-risk subgroups, compared with patients in the placebo group, those in the digoxin group had a significant reduction in the risk of the 2-year composite endpoint of HF mortality or HF hospitalization: NYHA III–IV [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.57–0.75; P < 0.001], LVEF <25% (HR 0.61; 95% CI 0.53–0.71; P < 0.001), and CTR >55% (HR 0.65; 95% CI 0.57–0.75; P < 0.001). Digoxin-associated HRs (95% CI) for 2-year all-cause mortality or all-cause hospitalization for subgroups with NYHA III–IV, LVEF <25%, and CTR >55% were 0.88 (0.80–0.97; P = 0.012), 0.84 (0.76–0.93; P = 0.001), and 0.85 (0.77–0.94; P = 0.002), respectively. Conclusions Digoxin improves outcomes in chronic HF patients with NYHA class III–IV, LVEF <25%, or CTR >55%, and should be considered in these patients. [ABSTRACT FROM PUBLISHER]

The article focuses on the development of pharmacological therapies for the treatment of acute heart failure syndromes (AHFS). It discusses various factors attributed to therapy failure including patient heterogeneity, lack of pathophysiological understanding and flaws in the designs of AHFS studies. It also mentions that Phase III studies on drug efficacy should consider all risk boundaries. Moreover, it notes that therapy standardization requires cooperation within the scientific community.

Aims: Many chronic heart failure (CHF) patients take β-blockers. When such patients are hospitalized for decompensation, it remains unclear how ongoing β-blocker treatment will affect outcomes of acute inotrope therapy. We aimed to assess outcomes of SURVIVE patients who were on β-blocker therapy before receiving a single intravenous infusion of levosimendan or dobutamine. [ABSTRACT FROM PUBLISHER]

The increasing prevalence of heart failure poses enormous challenges for health care systems worldwide. Despite effective medical interventions that target neurohumoral activation, mortality and morbidity remain substantial. Evidence for inflammatory activation as an important pathway in disease progression in chronic heart failure has emerged in the last two decades. However, clinical trials of ‘anti-inflammatory’ therapies (such as anti-tumor necrosis factor-α approaches) have to date failed to show benefit in heart failure patients. The Heart Failure Association of the European Society of Cardiology recently organized an expert workshop to address the issue of inflammation in heart failure from a basic science, translational and clinical perspective, and to assess whether specific inflammatory pathways may yet serve as novel therapeutic targets for this condition. This consensus document represents the outcome of the workshop and defines key research questions that still need to be addressed as well as considering the requirements for future clinical trials in this area. [ABSTRACT FROM PUBLISHER]

Abstract: Objective: Functional electrical stimulation (FES) improves exercise capacity and endothelial function in chronic heart failure (CHF) patients. This study evaluates the impact of FES on quality of life and emotional stress in patients with moderate to severe CHF. Methods: Thirty patients with stable CHF (24 men; NYHA class II–III; left ventricular ejection fraction <35%) were randomly assigned (2:1) to a 6-week FES training program (n =20) or placebo (n =10). Questionnaires addressing quality of life [Kansas City Cardiomyopathy Questionnaire (KCCQ), functional and overall], and emotional stress [Zung self-rating depression scale (SDS), Beck Depression Inventory (BDI)], as well as plasma B-type natriuretic peptide (BNP) and 6-min walking distance test (6MWT) were assessed at baseline and after completion of training protocol. Results: A significant improvement in KCCQ functional (F =76.666, p <0.001), KCCQ overall (F =41.508, p <0.001), BDI (F =17.768, p <0.001) and Zung SDS (F =27.098, p <0.001) was observed in the FES group compared to placebo. Patients in the FES group had also a significant increase in 6MWT (F =19.413, p <0.001) and a trend towards reduction in plasma BNP (F =4.252, p =0.053) compared to placebo. Conclusion: FES seems to have a beneficial effect on quality of life, exercise capacity and emotional stress in patients with moderate to severe CHF. [Copyright &y& Elsevier]

Abstract: Background: Several therapies commonly used for the treatment of acute heart failure syndromes (AHFS) present some well-known limitations and have been associated with an early increase in the risk of death. There is, therefore, an unmet need for new pharmacologic agents for the early management of AHFS that may improve both short- and long-term outcomes. Aim: To review the recent evidence on emerging pharmacologic therapies in AHFS. Methods: A systematic search of peer-reviewed publications was performed on MEDLINE, EMBASE and Clinical Trials.gov from January 1990 to August 2007. The results of unpublished or ongoing trials were obtained from presentations at national and international meetings and pharmaceutical industry releases. Bibliographies from these references were also reviewed, as were additional articles identified by content experts. Results: Cumulative data from large studies and randomised trials suggest that therapies with innovative mechanisms of action may safely and effectively reduce pulmonary congestion or improve cardiac performance in AHFS patients. Conclusion: Some investigational agents for the management of AHFS are able to improve haemodynamics and/or clinical status. In spite of these promising findings, no new agent has demonstrated a clear benefit in terms of long-term clinical outcomes compared to placebo or conventional therapies. [Copyright &y& Elsevier]

Heart failure represents a primary cause of morbidity and mortality in older people and despite significant therapeutic advances, it is still characterized by important unmet needs, thus remaining a challenging field of clinical research. The recent PARADIGM-HF trial compared the novel compound LCZ696, a combination of the angiotensin receptor blocker valsartan and the neprilysin inhibitor sacubitril, versus the angiotensin-converting enzyme inhibitor enalapril in 8,442 patients with symptomatic chronic systolic heart failure. LCZ696 led to a 20% reduction in the rate of death or hospitalization for heart failure and a 16% reduction in the rate of all-cause death compared to enalapril at 3.5 years of follow-up. Despite those impressive results, the clinical application of this novel agent that requires the substitution of a cornerstone of current heart failure therapy, the angiotensin-converting enzyme inhibitors, should follow careful steps as imposed by the study design, the recruited population and the outcome in specific patient subgroups. Further insights into the effects of LCZ696 will be provided by the ongoing PARAGON-HF trial in patients with diastolic heart failure. [ABSTRACT FROM AUTHOR]

Adverse events and serious adverse events were comparable for empagliflozin versus placebo in Black patients and White patients (adverse events: Black patients: placebo 88.3%, empagliflozin 85.4%; White patients: placebo 83.6%, empagliflozin 82.9%; serious adverse events: Black patients: placebo 61.5%, empagliflozin 53.1%; White patients: placebo 51.2%, empagliflozin 48.2%); however, the placebo incidence of adverse events was higher in Black patients. Keywords: heart failure; racial groups; therapeutics EN heart failure racial groups therapeutics 101 104 4 12/29/22 20230103 NES 230103 There are disparities in both rates and outcomes of heart failure (HF) between Black patients and White patients, and important questions remain about the generalizability of conventional HF therapies, including angiotensin-converting enzyme inhibitors and -blockers, to Black patients. [Extracted from the article]

Abstract: Patients with acute heart failure syndromes (AHFS) typically present with signs and symptoms of systemic and pulmonary congestion at admission. However, elevated left ventricular (LV) filling pressures (hemodynamic congestion) may be present days or weeks before systemic and pulmonary congestion develop, resulting in hospital admission. This “hemodynamic congestion,” with or without clinical congestion, may have deleterious effects including subendocardial ischemia, alterations in LV geometry resulting in secondary mitral insufficiency, and impaired cardiac venous drainage from coronary veins resulting in diastolic dysfunction. It is possible that these hemodynamic abnormalities in addition to neurohormonal activation may contribute to LV remodeling and heart failure progression. Approximately 50% of patients admitted for AHFS are discharged with persistent symptoms and/or minimal or no weight loss in spite of the fact that the main reason for admission was clinical congestion. Accordingly, the assessment and management of pulmonary and systemic congestion in these patients require reevaluation. [Copyright &y& Elsevier]

This article comments on the PAC-Man clinical trial which showed that management with a pulmonary artery catheter did not reduce all-cause mortality in critically ill patients. The mortality rate of 69% in the PAC-Man trial was higher than anticipated, indicating that only seriously ill patients had been randomized and that the results may apply primarily to these patients. This trial stands out because of its large sample size and high participation rate. However, the delay from ICU admission to randomization raises concerns about whether earlier placement of the PAC could be beneficial. While effective therapies and interventions are much needed for critically ill patients, introducing potentially harmful interventions is an even greater concern.

Background: Iron deficiency may impair aerobic performance. This study aimed to determine whether treatment with intravenous iron (ferric carboxymaltose) would improve symptoms in patients who had heart failure, reduced left ventricular ejection fraction, and iron deficiency, either with or without anemia. Methods: We enrolled 459 patients with chronic heart failure of New York Heart Association (NYHA) functional class II or III, a left ventricular ejection fraction of 40% or less (for patients with NYHA class II) or 45% or less (for NYHA class III), iron deficiency (ferritin level <100 μg per liter or between 100 and 299 μg per liter, if the transferrin saturation was <20%), and a hemoglobin level of 95 to 135 g per liter. Patients were randomly assigned, in a 2:1 ratio, to receive 200 mg of intravenous iron (ferric carboxymaltose) or saline (placebo). The primary end points were the self-reported Patient Global Assessment and NYHA functional class, both at week 24. Secondary end points included the distance walked in 6 minutes and the health-related quality of life. Results: Among the patients receiving ferric carboxymaltose, 50% reported being much or moderately improved, as compared with 28% of patients receiving placebo, according to the Patient Global Assessment (odds ratio for improvement, 2.51; 95% confidence interval [CI], 1.75 to 3.61). Among the patients assigned to ferric carboxymaltose, 47% had an NYHA functional class I or II at week 24, as compared with 30% of patients assigned to placebo (odds ratio for improvement by one class, 2.40; 95% CI, 1.55 to 3.71). Results were similar in patients with anemia and those without anemia. Significant improvements were seen with ferric carboxymaltose in the distance on the 6-minute walk test and quality-of-life assessments. The rates of death, adverse events, and serious adverse events were similar in the two study groups. Conclusions: Treatment with intravenous ferric carboxymaltose in patients with chronic heart failure and iron deficiency, with or without anemia, improves symptoms, functional capacity, and quality of life; the side-effect profile is acceptable. (ClinicalTrials.gov number, NCT00520780.) N Engl J Med 2009;361:2436-48. [ABSTRACT FROM AUTHOR]

Abstract: Depression is a common comorbid condition in patients with coronary artery disease and a well-documented risk factor for recurrent cardiac events and mortality. The exact mechanisms underlying the interplay between depression and ischemic heart disease remain poorly understood and the same is true for the most effective depression treatment for cardiac patients. This review summarizes current knowledge regarding the prognostic role of depression in patients with coronary artery disease, the pathophysiologic pathways involved, and the effects of antidepressant therapy on cardiovascular disease outcomes. With recent evidence suggesting that selective serotonin reuptake inhibitors may improve survival after myocardial infarction in patients with depression, diagnosis and treatment of this co-morbidity may be essential for the clinical management of coronary artery disease. [Copyright &y& Elsevier]

Clinical status in heart failure is conventionally assessed by the physician's evaluation, patients' own perception of their symptoms, quality of life (QoL) tools, and a measure of functional capacity. These aspects can be measured with tools such as the New York Heart Association functional class, QoL tools such as the EuropeanQoL-5 dimension, the Kansas City Cardiomyopathy Questionnaire, patient global assessment (PGA), and by 6-minute walk test (6MWT), respectively. The ferric carboxymaltose in patients with heart failure and iron deficiency (FAIR-HF) trial demonstrated that treatment with intravenous ferric carboxymaltose in iron-deficient patients with symptomatic heart failure with reduced left ventricular function, significantly improved all 5 outcome measures. This analysis assessed the correlations between the longitudinal changes in the measures of clinical status, as measured by QoL tools and the changes in the measures of functional capacity as measured by the 6MWT. This analysis used the database from the FAIR-HF trial, which randomized 459 patients with chronic heart failure (reduced left ventricular ejection fraction) and iron deficiency, with or without anemia to ferrous carboxymaltose or placebo. The degree of correlation between QoL tools and the 6MWT was assessed at 4, 12, and 24 weeks. The data demonstrate highly significant correlations between QoL and functional capacity, as measured by the 6MWT, at all time points (p <0.001). Changes in PGA, Kansas City Cardiomyopathy Questionnaire, and EuroQoL-5D correlated increasingly over time with changes in 6MWT performance. Interestingly, the strongest correlation at 24 weeks is for the PGA, which is a simple numerical scale (r = -0.57, p <0.001). This analysis provides evidence that QoL assessment show a significant correlation with functional capacity, as measured by the 6MWT. The strength of these correlations increased over time. [ABSTRACT FROM AUTHOR]

Background: Inflammatory processes have been identified as key mediators of the deleterious effects of ischemia/reperfusion in ST-segment-elevation myocardial infarction. Colchicine is a substance with potent anti-inflammatory properties, suitable for safe use in patients with cardiovascular disease. The purpose of this study was to test the hypothesis that a short course of colchicine treatment could lead to reduced infarct size. Methods and Results: Patients presenting with ST-segment-elevation myocardial infarction ≤12 hours from pain onset (treated with primary percutaneous coronary intervention) were randomly assigned to colchicine or placebo for 5 days. The primary outcome parameter was the area under the curve of creatine kinase-myocardial brain fraction concentration. A subset of patients underwent cardiac MRI with late gadolinium enhancement 6 to 9 days after the index ST-segment-elevation myocardial infarction. One hundred fifty-one patients were included (60 in the MRI substudy). The area under the creatine kinase-myocardial brain fraction curve was 3144 (interquartile range [IQR], 1754-6940) ng·h(-1)·mL(-1) in the colchicine group in comparison with 6184 (IQR, 4456-6980) ng·h(-1)·mL(-1) in controls (P<0.001). Indexed MRI-late gadolinium enhancement-defined infarct size was 18.3 (IQR, 7.6-29.9) mL/1.73 m(2) in the colchicine group versus 23.2 (18.5-33.4) mL/1.73 m(2) in controls (P=0.019). The relative infarct size (as a proportion to left ventricular myocardial volume) was 13.0 (IQR, 8.0-25.3) % and 19.8 (IQR, 13.7-29.8) %, respectively (P=0.034). Conclusions: These results suggest a potential benefit of colchicine in ST-segment-elevation myocardial infarction, but further clinical trials are necessary to draw secure conclusions, especially considering the fact that the present study was not powered to assess clinical end points. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01936285. [ABSTRACT FROM AUTHOR]

Mitral regurgitation (MR) is one of the most prevalent valve disorders and has numerous etiologies, including primary (organic) MR, due to underlying degenerative/structural mitral valve (MV) pathology, and secondary (functional) MR, which is principally caused by global or regional left ventricular remodeling and/or severe left atrial dilation. Diagnosis and optimal management of MR requires integration of valve disease and heart failure specialists, MV cardiac surgeons, interventional cardiologists with expertise in structural heart disease, and imaging experts. The introduction of transcatheter MV therapies has highlighted the need for a consensus approach to pragmatic clinical trial design and uniform endpoint definitions to evaluate outcomes in patients with MR. The Mitral Valve Academic Research Consortium is a collaboration between leading academic research organizations and physician-scientists specializing in MV disease from the United States and Europe. Three in-person meetings were held in Virginia and New York during which 44 heart failure, valve, and imaging experts, MV surgeons and interventional cardiologists, clinical trial specialists and statisticians, and representatives from the U.S. Food and Drug Administration considered all aspects of MV pathophysiology, prognosis, and therapies, culminating in a 2-part document describing consensus recommendations for clinical trial design (Part 1) and endpoint definitions (Part 2) to guide evaluation of transcatheter and surgical therapies for MR. The adoption of these recommendations will afford robustness and consistency in the comparative effectiveness evaluation of new devices and approaches to treat MR. These principles may be useful for regulatory assessment of new transcatheter MV devices, as well as for monitoring local and regional outcomes to guide quality improvement initiatives. [ABSTRACT FROM AUTHOR]

Mitral regurgitation (MR) is one of the most prevalent valve disorders and has numerous etiologies, including primary (organic) MR, due to underlying degenerative/structural mitral valve (MV) pathology, and secondary (functional) MR, which is principally caused by global or regional left ventricular remodeling and/or severe left atrial dilation. Diagnosis and optimal management of MR requires integration of valve disease and heart failure specialists, MV cardiac surgeons, interventional cardiologists with expertise in structural heart disease, and imaging experts. The introduction of transcatheter MV therapies has highlighted the need for a consensus approach to pragmatic clinical trial design and uniform endpoint definitions to evaluate outcomes in patients with MR. The Mitral Valve Academic Research Consortium is a collaboration between leading academic research organizations and physician-scientists specializing in MV disease from the United States and Europe. Three in-person meetings were held in Virginia and New York during which 44 heart failure, valve, and imaging experts, MV surgeons and interventional cardiologists, clinical trial specialists and statisticians, and representatives from the U.S. Food and Drug Administration considered all aspects of MV pathophysiology, prognosis, and therapies, culminating in a 2-part document describing consensus recommendations for clinical trial design (Part 1) and endpoint definitions (Part 2) to guide evaluation of transcatheter and surgical therapies for MR. The adoption of these recommendations will afford robustness and consistency in the comparative effectiveness evaluation of new devices and approaches to treat MR. These principles may be useful for regulatory assessment of new transcatheter MV devices, as well as for monitoring local and regional outcomes to guide quality improvement initiatives. [ABSTRACT FROM AUTHOR]

Abstract: Aims: The role of low-dose dopamine infusion in patients with acute decompensated heart failure (ADHF) remains controversial. We aim to evaluate the efficacy and safety of high- versus low-dose furosemide with or without low-dose dopamine infusion in this patient population. Methods and results: 161 ADHF patients (78years; 46% female; ejection fraction 31%) were randomized to 8-hour continuous infusions of: a) high-dose furosemide (HDF, n=50, 20mg/h), b) low-dose furosemide and low-dose dopamine (LDFD, n=56, 5mg/h and 5μgkg−1 min−1 respectively), or c) low-dose furosemide (LDF, n=55, furosemide 5mg/h). The main outcomes were 60-day and one-year all-cause mortality (ACM) and hospitalization for HF (HHF). Dyspnea relief (Borg index), worsening renal function (WRF, rise in serum creatinine (sCr)≥0.3mg/dL), and length of stay (LOS) were also assessed. The urinary output at 2, 4, 6, 8, and 24h was not significantly different in the three groups. Neither the ACM at day 60 (4.0%, 7.1%, and 7.2%; P=0.74) or at one year (38.1%, 33.9% and 32.7%, P=0.84) nor the HHF at day 60 (22.0%, 21.4%, and 14.5%, P=0.55) or one year (60.0%, 50.0%, and 47%, P=0.40) differed between HDF, LDFD, and LDF groups, respectively. No differences in the Borg index or LOS were noted. WRF was higher in the HDF than in LDFD and LDF groups at day 1 (24% vs. 11% vs. 7%, P<0.0001) but not at sCr peak (44% vs. 38% vs. 29%, P=0.27). No significant differences in adverse events were noted. Conclusions: In ADHF patients, there were no significant differences in the in-hospital and post-discharge outcomes between high- vs. low-dose furosemide infusion; the addition of low-dose dopamine infusion was not associated with any beneficial effects. [Copyright &y& Elsevier]

The article discusses the RELAXin in Acute Heart Failure (RELAX-AHF) trial that was conducted to determine the efficacy of the serelaxin, recombinant human relaxin-2 for the treatment of acute heart failure. It claims that serelaxin is a vasoactive peptide hormone with various biological and haemodynamic effects. Based on the study results, serelaxin treatment was well tolerated and safe.

Increased oxidative and nitrosative stress are important mediators of left ventricular (LV) and vascular dysfunction in patients with chronic heart failure (CHF). This study investigated the effects of darbepoetin alfa on plasma markers of oxidative and nitrosative stress in patients with CHF with anemia. Thirty patients with CHF (LV ejection fraction [LVEF] <40%, hemoglobin <12.5 g/dl, and serum creatinine <2.5 mg/dl) were randomly assigned (1:1) to receive either a 3-month darbepoetin alfa regimen at 1.5 μg/kg every 20 days plus oral iron or placebo plus oral iron. Plasma B-type natriuretic peptide (BNP), markers of oxidative (oxidative, malondialdehyde, carbonyl proteins; antioxidative, glutathione) and nitrosative (nitrotyrosine) stress, LVEF, and 6-minute walked distance were assessed at baseline and after treatment. A significant improvement in LVEF and 6-minute walked distance was observed in only darbepoetin-treated patients. Plasma BNP (F = 14.8, p = 001), malondialdehyde (F = 9.4, p = 0.006), protein carbonyl (F = 9.2, p = 0.006), and nitrotyrosine (F = 4.4, p = 0.045) were significantly decreased, along with an increase in antioxidative glutathione (F = 4.2, p = 0.049) after darbepoetin alfa treatment. These factors were unaffected in placebo-treated patients. Darbepoetin-induced percentages of change in carbonyl protein significantly correlated with respective changes in plasma BNP (r = 0.55, p <0.05) and LVEF (r = −0.46, p <0.05). Finally, a drug-induced percentage of decrease in nitrotyrosine significantly correlated with the respective improvement in 6-minute walked distance (r = −0.63, p <0.05). In conclusion, darbepoetin alfa attenuated deleterious effects of oxidative and nitrosative stress into the cardiovascular system of anemic patients with CHF, improving also cardiac function and exercise capacity. [Copyright &y& Elsevier]

Acute heart failure syndromes (AHFS) have emerged as a leading public health problem worldwide, accounting for a substantial number of hospitalizations and a high utilization of resources. Although in-hospital mortality rates are relatively low, patients with AHFS have very high early after-discharge mortality and rehospitalization rates. The majority of patients admitted with AHFS have coronary artery disease (CAD), which independently has an adverse impact on prognosis. The initial in-hospital and after-discharge management of AHFS may be dependent on clinical presentation: AHFS in patients with underlying CAD or acute coronary syndromes (ACS) complicated by heart failure. In addition, the extent and severity of CAD and the presence of ischemia and/or stunned/hibernating myocardium should be assessed for optimal management. Although the overall management of AHFS with CAD may be similar to that in patients with ACS complicated by heart failure, for which specific guidelines exist, management of the former is less well defined. Prospective studies of the assessment and treatment of CAD in patients with AHFS are urgently needed. [Copyright &y& Elsevier]

Abstract: Aim: Endothelial activation and dysfunction may be an important contributor to chronic heart failure (CHF) progression. We sought to investigate whether the calcium sensitizer levosimendan affects beneficially endothelial function and attenuates the deleterious effects of soluble adhesion molecules in patients with advanced CHF. Methods: Twenty-six advanced CHF patients (mean New York Heart Association class, 2.6±0.3; ischemic/dilated, 18/8; mean left ventricular ejection fraction <35%) hospitalized due to syndrome worsening, were randomized (2:1) to receive either a 24-h levosimendan infusion of 0.1μg/kg/min (n =17) or placebo (n =9). Endothelial function estimated by endothelial-dependent flow-mediated dilatation of the brachial artery (FMD), as well as plasma soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1), were assessed before and 48h after therapy. Results: Baseline characteristics and medications were well balanced in the two treatment groups. A significant improvement of FMD (6.4±4.4% from 4.8±3.0%; p <0.05) with concomitant reduction of plasma concentrations of sICAM-1 (231±75pg/ml from 339±157pg/ml; p <0.05) and sVCAM-1 (1134±508pg/ml from 1386±602pg/ml; p <0.05) were observed only in levosimendan treated patients. Conclusion: Levosimendan could be an effective treatment in improving the endothelial function and reducing the detrimental adhesion molecule activation in advanced CHF patients. [Copyright &y& Elsevier]

The article focuses on publication of clinical practice guidelines related to management of heart failure patients by the American College of Cardiology (ACC), the European Society of Cardiology (ESC) and the American Heart Association (AHA). Topics include the use of angiotensin receptor-neprilysin inhibitor (ARNI), ivabradine and valsartan/sacubitril in management of the patients, aim of the associations to improve quality of life of the patients and recommendations to improve patient care.