AIMS:Pilot studies indicate that immunoadsorption with subsequent IgG substitution (IA/IgG) induces beneficial effects in patients with dilated cardiomyopathy (DCM) and heart failure. This placebo-controlled study investigates whether IA/IgG treatment enhances left ventricular (LV) systolic function as compared to a control group receiving pseudo-treatment. METHODS:This multicentre, randomized, double-blind, parallel-group trial aims to include 200 patients with heart failure due to DCM (LV ejection fraction [LVEF] <40%) on optimized guideline-directed heart failure medication. Participants are randomly assigned in a 1:1 ratio to IA/IgG using protein-A columns, or to pseudo-immunoadsorption followed by an intravenous infusion without IgG. Follow-up visits take place by telephone after 1 and 3 months and at the study centres after 6, 12 and 24 months. The primary efficacy endpoint is the change in LVEF from baseline to 6 months determined by contrast echocardiography, analysed at a core lab. In addition, LV end-diastolic and end-systolic volumes will be analysed as secondary endpoints over the entire study period to assess whether IA/IgG affects LV remodelling. As main secondary outcome, a composite of all-cause death, cardiac resuscitation, hospitalization for heart failure, and need for cardiac surgery to improve myocardial pump function will be evaluated after 24 months. In addition, exploratory outcomes as well as safety endpoints related to the treatment will be assessed throughout the whole study period. CONCLUSION:IASO-DCM is a randomized study which will provide comprehensive insights into the effects of immunoadsorption with subsequent IgG substitution in patients with DCM.

Métodos Dos 11.900 pacientes hospitalizados com ICFEr (FE ≤45%) identificados ao se relacionar o registro OPTIMIZEHF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) com dados do Medicare, 3.499 receberam digoxina pré-internação, que foi interrompida em 721 pacientes. Utilizando escores de propensão para interrupção da digoxina, estimados para cada um dos 3.499 pacientes, foi composta uma coorte pareada de 698 duplas de pacientes, equilibradas em relação a 50 características basais (média de idade, 76 anos; FE média, 28%; 41% do sexo feminino; 13% afroamericanos; 65% em uso de betabloqueadores).

BACKGROUND:The deleterious effects of discontinuation of digoxin on outcomes in ambulatory patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) receiving angiotensin-converting enzyme inhibitors are well-documented. OBJECTIVES:The authors sought to determine the relationship between digoxin discontinuation and outcomes in hospitalized patients with HFrEF receiving more contemporary guideline-directed medical therapies including beta-blockers and mineralocorticoid receptor antagonists. METHODS:Of the 11,900 hospitalized patients with HFrEF (EF ≤45%) in the Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry, 3,499 received pre-admission digoxin, which was discontinued in 721 patients. Using propensity scores for digoxin discontinuation, estimated for each of the 3,499 patients, a matched cohort of 698 pairs of patients, balanced on 50 baseline characteristics (mean age 76 years; mean EF 28%; 41% women; 13% African American; 65% on beta-blockers) was assembled. RESULTS:Four-year post-discharge, digoxin discontinuation was associated with significantly higher risks of HF readmission (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.05 to 1.39; p = 0.007), all-cause readmission (HR: 1.16; 95% CI: 1.04 to 1.31; p = 0.010), and the combined endpoint of HF readmission or all-cause mortality (HR: 1.20; 95% CI: 1.07 to 1.34; p = 0.002), but not all-cause mortality (HR: 1.09; 95% CI: 0.97 to 1.24; p = 0.163). Discontinuation of digoxin was associated with a significantly higher risk of all 4 outcomes at 6 months and 1 year post-discharge. At 30 days, digoxin discontinuation was associated with higher risks of all-cause mortality (HR: 1.80; 95% CI: 1.26 to 2.57; p = 0.001) and the combined endpoint (HR: 1.36; 95% CI: 1.09 to 1.71; p = 0.007), but not of HF readmission (HR: 1.19; 95% CI: 0.90 to 1.59; p = 0.226) or all-cause readmission (HR: 1.03; 95% CI: 0.84 to 1.26; p = 0.778). CONCLUSIONS:Among hospitalized older patients with HFrEF on more contemporary guideline-directed medical therapies, discontinuation of pre-admission digoxin therapy was associated with poor outcomes.

AIM We investigated if the baseline value of mid-regional pro-atrial natriuretic peptide (NP), N-terminal pro-B-type NP and copeptin may be helpful in optimizing β-blocker uptitration in elderly patients with heart failure. PATIENTS & METHODS According to the biomarkers' levels, 457 patients were divided into three subgroups and compared with each other at baseline and 3 months after. RESULTS All mid-regional pro-atrial NP and N-terminal pro-B-type NP subgroups had significant amelioration of left ventricle ejection fraction and New York Heart Association (NYHA) class after 3 months of β-blocker uptitration (p < 0.001). More prominent improvement of left ventricle ejection fraction and New York Heart Association class was observed in subgroups with lower versus higher NPs levels. CONCLUSION NPs levels, unlike copeptin levels, might be useful tool for objective selection of elderly heart failure patients who could have the greatest benefit of forced uptitration.

BackgroundDigoxin use has been associated with a lower risk of 30‐day all‐cause admission and readmission in patients with heart failure and reduced ejection fraction (HFrEF).HypothesisDigoxin use will be associated with improved outcomes in patients with HFrEF receiving β‐blockers.MethodsOf the 3076 hospitalized Medicare beneficiaries with HFrEF (EF <45%), 1046 received a discharge prescription for β‐blockers, of which 634 were not on digoxin. Of the 634, 204 received a new discharge prescription for digoxin. Propensity scores for digoxin use, estimated for each of the 634 patients, were used to assemble a matched cohort of 167 pairs of patients receiving and not receiving digoxin, balanced on 30 baseline characteristics. Matched patients (n = 334) had a mean age of 74 years and were 46% female and 30% African American.Results30‐day all‐cause readmission occurred in 15% and 27% of those receiving and not receiving digoxin, respectively (hazard ratio [HR]: 0.51, 95% confidence interval [CI]: 0.31‐0.83, P = 0.007). This beneficial association persisted during 4 years of follow‐up (HR: 0.72, 95% CI: 0.57‐0.92, P = 0.008). Digoxin use was also associated with a lower risk of the combined endpoint of all‐cause readmission or all‐cause mortality at 30 days (HR: 0.54, 95% CI: 0.34‐0.86, P = 0.009) and at 4 years (HR: 0.76, 95% CI: 0.61‐0.96, P = 0.020).ConclusionsIn hospitalized patients with HFrEF receiving β‐blockers, digoxin use was associated with a lower risk of 30‐day all‐cause readmission but not mortality, which persisted during longer follow‐up.

Finn Waagstein was born in Copenhagen in 1938. He graduated from Aarhus University Medical School in 1964. He received his cardiology training in the Sahlgrenska University Hospital at the University of Gothenburg, Sweden. He was appointed Associate Professor in 1980, and he assisted in establishing and directing the first Swedish heart transplant program. From 1990 he directed the heart failure and cardiomyopathy research programs. He is currently Professor of Cardiology and senior physician at Wallenberg Laboratory. In 2002, he was awarded the King Faisal International Prize for Medicine.

Finn Waagstein was born in Copenhagen in 1938. He graduated from Aarhus University Medical School in 1964. He received his cardiology training in the Sahlgrenska University Hospital at the University of Gothenburg, Sweden. He was appointed Associate Professor in 1980, and he assisted in establishing and directing the first Swedish heart transplant program. From 1990 he directed the heart failure and cardiomyopathy research programs. He is currently Professor of Cardiology and senior physician at Wallenberg Laboratory. In 2002, he was awarded the King Faisal International Prize for Medicine.

Chronic viral infections of the heart are considered one antecedent event leading to progressive dysfunction of the myocardium, often with an impaired prognosis due to a virus- or immune-mediated myocardial injury. Symptomatic treatment does not influence the viral cause of heart failure, and the effect of antiviral treatment has not been determined, yet.

AimWe aimed to study the relationships of loop diuretic dose with renal function and clinical outcomes in patients with chronic heart failure (HF).Methods and resultsLoop diuretic dose at baseline was recorded in patients included in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA). The relationship to change in estimated glomerular filtration rate (eGFR) over time and to the first occurrence of the composite outcome of cardiovascular (CV) death or hospitalization owing to HF was examined in propensity score matched cohorts. Of the 5011 patients, 2550, 745, and 449 were receiving >80 mg (high), 41–80 mg (medium) and ≤40 mg (low) of loop diuretics in furosemide equivalent daily dosages, respectively, which were used to assemble 229, 385, and 1045 pairs of propensity‐matched high, medium, and low dose cohorts. Compared with matched no loop diuretic groups, eGFR declined 0.3 ± 0.2, 0.3 ± 0.3 and 1.2 ± 0.5 mL/min/1.73 m2/year in the low‐, medium‐, and high‐dose groups, respectively. Compared with matched no loop diuretic groups, hazard ratios (HR) (95% confidence intervals) for outcome associated with low‐, medium‐ and high‐dose groups were 1.71 (1.41–2.06), 1.99 (1.50–2.64), and 2.94 (1.95–4.41), respectively. Higher loop diuretic dose was particularly associated with increased risk for hospitalization owing to HF: HR 4.80 (2.75–8.37), P < 0.001.ConclusionsThe use of loop diuretics was associated with a slightly greater rate of decline in eGFR, which did not vary significantly by diuretic dose.Loop diuretic dose was associated with higher risks of (CV) mortality and predominantly hospitalization owing to HF, which appeared to be higher among those receiving higher daily doses.

Background Beta-blockers improve outcomes in patients with systolic heart failure. However, it is unknown whether their initial negative inotropic effect may increase 30-day all-cause readmission, a target outcome for Medicare cost reduction and financial penalty for hospitals under the Affordable Care Act. Methods Of the 3067 Medicare beneficiaries discharged alive from 106 Alabama hospitals (1998-2001) with a primary discharge diagnosis of heart failure and ejection fraction <45%, 2202 were not previously on beta-blocker therapy, of which 383 received new discharge prescriptions for beta-blockers. Propensity scores for beta-blocker use, estimated for each of the 2202 patients, were used to assemble a matched cohort of 380 pairs of patients receiving and not receiving beta-blockers who were balanced on 36 baseline characteristics (mean age 73 years, mean ejection fraction 27%, 45% women, 33% African American). Results Beta-blocker use was not associated with 30-day all-cause readmission (hazard ratio [HR] 0.87; 95% confidence interval [CI], 0.64-1.18) or heart failure readmission (HR 0.95; 95% CI, 0.57-1.58), but was significantly associated with lower 30-day all-cause mortality (HR 0.29; 95% CI, 0.12-0.73). During 4-year postdischarge, those in the beta-blocker group had lower mortality (HR 0.81; 95% CI, 0.67-0.98) and combined outcome of all-cause mortality or all-cause readmission (HR 0.87; 95% CI, 0.74-0.97), but not with all-cause readmission (HR 0.89; 95% CI, 0.76-1.04). Conclusions Among hospitalized older patients with systolic heart failure, discharge prescription of beta-blockers was associated with lower 30-day all-cause mortality and 4-year combined death or readmission outcomes without higher 30-day readmission.

The interaction between the heart and the arterial system (ventricular-arterial coupling - VA) is an important determinant of cardiovascular performance. Vascular stiffness (Ea) and left ventricular (LV) endsystolic stiffness (Elv) augment with age and in heart failure (HF). Beta blockers (BB) are recommended therapy for patients with HF. However, data about the effects of BB on VA coupling are scarce.

BACKGROUND:The aim of our study was to examine regional differences in the demographics, etiology, risk factors, comorbidities and treatment of female patients with heart failure (HF) in the Cardiac Insufficiency BIsoprolol Study in ELDerly (CIBIS-ELD) clinical trial.METHODS AND RESULTS:One hundred and fifty-nine female patients from Germany and 169 from Southeastern (SE) Europe (Serbia, Slovenia and Montenegro) were included in this subanalysis of the CIBIS-ELD trial. Women comprised 54% of the study population in Germany and 29% in SE Europe. German patients were significantly older. The leading cause of HF was arterial hypertension in German patients, 71.7% of whom had a preserved ejection fraction. The leading etiology in SE Europe was the coronary artery disease; 67.6% of these patients had a reduced left ventricular ejection fraction (34.64 ± 7.75%). No significant differences were found in the prevalence of traditional cardiovascular risk factors between the two regions (hypertension, diabetes, hypercholesterolemia, smoking and family history of myocardial infarction). Depression, chronic obstructive pulmonary disease and malignancies were the comorbidities that were noted more frequently in the German patients, while the patients from SE Europe had a lower glomerular filtration rate. Compared with the German HF patients, the females in SE Europe received significantly more angiotensin converting enzyme inhibitors, loop diuretics and less frequently angiotensin receptor blockers and mineralocorticoid receptor antagonists.CONCLUSIONS:Significant regional differences were noted in the etiology, comorbidities and treatment of female patients with HF despite similar risk factors. Such differences should be considered in the design and implementation of future clinical trials, especially as women remain underrepresented in large trial populations.

Background Right ventricular ejection fraction (RVEF) <20% is an independent predictor of poor outcomes in patients with advanced chronic systolic heart failure (HF). The aim of this study was to examine if the adverse effect of abnormally reduced RVEF varies by the receipt of beta-blockers. Methods In the Beta-Blocker Evaluation of Survival Trial (BEST), 2708 patients with chronic advanced HF and left ventricular ejection fraction <35%, receiving standard background therapy with renin–angiotensin inhibition, digoxin, and diuretics, were randomized to receive bucindolol or placebo. Of these 2008 had data on baseline RVEF, and 14% (146/1017) and 13% (125/991) of the patients receiving bucindolol and placebo respectively had RVEF <20%. Results Among patients in the placebo group, all-cause mortality occurred in 33% and 43% of patients with RVEF ≥20% and <20% respectively (unadjusted hazard ratios {HR}, 1.33; 95% confidence intervals {CI}, 0.99–1.78; p=0.055 and adjusted HR, 0.99; 95% CI, 0.71–1.37; p=0.934). Among those receiving bucindolol, all-cause mortality occurred in 28% and 49% of patients with RVEF ≥20% and <20% respectively (unadjusted HR, 2.15; 95% CI, 1.65–2.80; p<0.001 and adjusted HR, 1.50; 95% CI, 1.08–2.07; p=0.016). These differences were statistically significant (unadjusted and adjusted p for interaction, 0.016 and 0.053 respectively). Conclusions In ambulatory patients with chronic advanced systolic HF receiving renin–angiotensin inhibition, digoxin, and diuretics, RVEF <20% had no intrinsic association with mortality. However, in those receiving additional therapy with bucindolol, RVEF <20% had a significant independent association with increased risk of mortality.

Background: Exercise capacity is critical for therapy and prognosis in patients with heart failure (HF). Effect of beta-blockers (BB) on exercise capacity in elderly patients with HF remains unclear. Objectives: To assess contribution of BB to functional capacity and left ventricular (LV) function in the elderly with HF. Design: According to the protocol of CIBIS-ELD study group, elderly patients were treated with BB during 12 weeks. In CPET subgroup, an integral part of the CIBIS ELD study group, patients were performed Doppler echocardiography and cardiopulmonary exercise testing (CPET) before BB therapy and after 12 weeks. Setting: Randomized patients with HF beta blockers naïve. Participants: thirty patients with HF aged over 65 years were included in CPET subgroup, while 847 were incorporated in CIBIS ELD study group. Results: Heart rate (HR) and systolic blood pressure (SBP) after BB significantly decreased at rest (p<0.001) and during exercise (p<0.05), with sustained level of peak VO2. Observed changes of resting HR and peak HR were closely correlated (p<0.001). Significant improvement of LV ejection fraction after BB was obtained (p=0.003) and symptoms of breathlessness were reduced (p=0.001). Left ventricular diastolic dysfunction at rest significantly contributed to exercise capacity (p=0.019). Conclusions: Beta-blockers in elderly patients with HF are related to a significant decrease of HR and SBP, improvement of systolic LV function and sustained exercise tolerance. Resting LV diastolic dysfunction is strongly associated with lower exercise capacity.

To explore the pharmacogenetic effects of the cytochrome P450 (CYP)2D6 genotype in patients with systolic heart failure treated using controlled/extended-release (CR/XL) metoprolol, this study assessed the CYP2D6 locus for the nonfunctional *4 allele (1846G>A; rs3892097) in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF; n = 605). Participants were characterized as extensive, intermediate, or poor metabolizers (EMs, IMs, or PMs, respectively), based on the presence of the CYP2D6*4 allele (EM: *1*1, 60.4%; IM: *1*4, 35.8%; and PM: *4*4, 3.8%). Plasma metoprolol concentrations were 2.1-/4.6-fold greater in the IM/PM groups as compared with the EM group (P < 0.0001). Metoprolol induced significantly lower heart rates and diastolic blood pressures during early titration, indicating a CYP2D6*4 allele dose-response effect (P < 0.05). These effects were not observed at maximal dose, suggesting a saturable effect. Genotype did not adversely affect surrogate treatment efficacy. CYP2D6 genotype modulates metoprolol pharmacokinetics/pharmacodynamics during early titration; however, the MERIT-HF-defined titration schedule remains recommended for all patients, regardless of genotype.

This pharmacogenetic substudy of the prospective, double-blind, randomized CIBIS-ELD trial determined the impact of the β1-adrenoceptor Arg189Gly polymorphism on heart-rate responses to bisoprolol or carvedilol in elderly patients with heart failure (421 with sinus rhythm, 107 with atrial fibrillation). Patients were randomized 1:1 to bisoprolol or carvedilol with a fortnightly dose-doubling scheme and guideline target doses. Patients with sinus rhythm responded essentially identically to bisoprolol and carvedilol, independent of genotype. Atrial fibrillation patients homozygous for Arg389 had a much smaller response to carvedilol than carriers of at least one Gly389 allele (mean difference 12 bpm, P < 0.00001). Carvedilol up to 2 × 12.5 mg did not reduce heart rate in Arg389Arg homozygotes at all. Interestingly, the immediate response to carvedilol did not differ between genotypes. The Arg389Gly polymorphism has a major impact on the heart-rate response to carvedilol (but not bisoprolol) in patients with heart failure plus atrial fibrillation.

Background Guideline-recommended beta-blocker (BB) target doses for patients with chronic heart failure can often not be reached. This secondary analysis of the CIBIS-ELD trial was carried out to better understand reasons for not achieving target doses. Methods Changes in heart rate (HR) and other parameters during a 12-week up-titration period in 302 BB naïve patients were evaluated in the subgroups achieving 12.5, 25, 50, and 100% of the target dose (groups 1, 2, 3, and 4, respectively). Results Achieved doses predominantly depended on baseline HR (means 68, 74, 76, and 84 bpm in groups 1–4, respectively, P<0.001). HR was consistently reduced with each dose level to 65, 63, and 62 bpm in groups 1–3 and to 71 bpm in group 4 (P<0.001). When adjusted for baseline, HR reduction achieved in group 3 was better than in group 4 (difference −5.4 bpm, P<0.05). More patients in groups 3/4 than in groups 1/2 improved in NYHA class (P=0.01). NTproBNP increased by 38% in group 4 (P<0.01) but not in the others (P<0.05 between groups). Changes in blood pressure, six-minute walk distance and self-rated health were comparable in all groups. Conclusions The desired effect of HR reduction appears to be a predominant limitation for BB up-titration. Vice versa, achieving the target dose may be a sign of insufficient response rather than successful treatment. In view of these results and the well-known importance of HR for survival, not target doses, but HR control should be given priority in BB treatment for heart failure.