Elvis Tahirovic

Titration to target dose of bisoprolol vs. carvedilol in elderly patients with heart failure: the CIBIS‐ELD trial

Various beta‐blockers with distinct pharmacological profiles are approved in heart failure, yet they remain underused and underdosed. Although potentially of major public health importance, whether one agent is superior in terms of tolerability and optimal dosing has not been investigated. The aim of this study was therefore to compare the tolerability and clinical effects of two proven beta‐blockers in elderly patients with heart failure.

Heart rate following short‐term beta‐blocker titration predicts all‐cause mortality in elderly chronic heart failure patients: insights from the CIBIS‐ELD trial

Beta‐blockers (BBs) improve outcomes in heart failure. Results from the Cardiac Insufficiency Bisoprolol Study in Elderly (CIBIS‐ELD) trial previously demonstrated the feasibility of heart rate, not maximum dose, as a treatment goal. In this pre‐specified analysis, we investigated the prognostic value of achieved heart rate after BB optimization on long‐term mortality.

Frequency and significance of unrecognized chronic obstructive pulmonary disease in elderly patients with stable heart failure

Background and aims: Due to prolonged life-spans and modern therapeutic approaches, there has been an increase in the number of patients aged ≥65 years with chronic heart failure (CHF). The duration and quality of life in elderly patients with CHF also depend on accompanying diseases. Although frequency of chronic obstructive pulmonary disease (COPD) in patients with CHF is about 30%, it is hard to find similar data in the elderly population. COPD is defined as a spirometrically assessed ratio of a post-dilatory forced expiratory volume in the first second, divided by forced vital capacity (FEV1/FVC) <70%. The aims of our study were to assess the prevalence of previously undiagnosed COPD in outpatients (≥65 yrs) with stable CHF and to determine the effect of the combination of COPD and CHF on patients’ functional capacity as measured by a 6-minute walking test. Methods and Results: Of the 174 study patients, 126 (72.4%) were men. In 48 patients (27.6%) we found previously unrecognized COPD. They were significantly older (75.6±5.8 vs 73±4.5 years, p<0.01) and more frequently had abdominal obesity and a greater waist circumference (98.8±10.2 vs 94.9±9.1 cm, p<0.05). Patients with COPD had significantly shorter 6-min walking distance (275.5±112.9 vs 291.3±96.7 m, p<0.05). Only patient’s age had a positive prognostic association with unrecognized COPD (OR=1.16; 95% CI 1.01–1.34, p<0.01). Patients with COPD showed a significant correlation between actual/predicted FEV1 and the 6-min walking distance (r=0.39, p<0.01). Conclusions: We found a high prevalence of unrecognized COPD in elderly patients with CHF and central obesity. Chronic obstructive pulmonary disease influenced functional capacity in CHF patients, as determined by the 6-minute walking test. Closer co-operation between pulmonologists and cardiologists is necessary to optimize management of this large proportion of CHF patients.

Effect of beta blockade on natriuretic peptides and copeptin in elderly patients with heart failure and preserved or reduced ejection fraction: Results from the CIBIS-ELD trial☆ , ☆☆

BACKGROUND We sought to investigate the effect of beta-blocker (BB) up-titration on serum levels of NT-proBNP and copeptin in patients with heart failure (HF) with reduced (HFREF) or preserved ejection fraction (HFPEF). METHODS Serial measurements of NT-proBNP and copeptin were obtained after initiation of BB up-titration in 219 elderly patients with HFREF or HFPEF. RESULTS After initial increasing trend of NT-proBNP at 6 weeks in HFREF patients, there was a subsequent decrease at 12 weeks of BB treatment up-titration (p=0.003), while no difference was found compared to baseline levels. In contrast to NT-proBNP, there was a continuous decreasing trend of copeptin in HFREF patients (at 12 weeks: p=0.026). In HFPEF patients, NT-proBNP significantly decreased (p=0.043) compared to copeptin after 12 weeks of BB up-titration. CONCLUSIONS After 12 weeks of BB optimization copeptin might reflect successful up-titration faster than NT-proBNP in HFREF, while the opposite was found in patients with HFPEF.

Should procalcitonin be measured routinely in acute decompensated heart failure

AIM To elucidate the prognostic role of procalcitonin (PCT) in patients with acute decompensated heart failure (ADHF) without clinical signs of infection at admission. MATERIALS & METHODS Serial measurements of PCT and NT-proBNP were performed in 168 patients, aged 68 ± 10 years with ADHF followed by 3-month outcome evaluation. RESULTS Cox regression analysis demonstrated significant predictive value of baseline PCT for all-cause death/hospitalization (area under the curve: 0.67; p = 0.013) at 90th day. The patients with persistently elevated PCT or with an increase during the first 72 h of hospitalization had the worst prognosis (p = 0.0002). CONCLUSION Baseline and serial in-hospital measurements of PCT have significant prognostic properties for 3-month all-cause mortality/hospitalization in patients with ADHF without clinical signs of infection at admission.

Beta blockers therapy is associated with improved left ventricular systolic function and sustained exercise capacity in elderly patients with heart failure. CIBIS-ELD sub-study

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.

Determinants of Change in Quality of Life in the Cardiac Insufficiency Bisoprolol Study in Elderly (CIBIS-ELD)☆

OBJECTIVE Little is known about parameters that lead to improvement in QoL in individual patients. We analysed the data of the Cardiac Insufficiency Bisoprolol Study in Elderly (CIBIS-ELD) in order to answer the question of how and to what extent change in health-related QoL during up-titration with bisoprolol vs. carvedilol is influenced by clinical and psychosocial factors in elderly patients with heart failure. METHODS This is a QoL analysis of CIBIS-ELD, an investigator-initiated multi-center randomised phase III trial in elderly patients (65 years or older) with moderate to severe heart failure. Clinical parameters such as New York Heart Association functional class, heart rate, left ventricular ejection fraction (LVEF), 6-min walk distance, as well as the physical and psychosocial component scores on the short-form QoL health survey (SF36) and depression were recorded at baseline and at the final study visit. RESULTS Full baseline and follow-up QoL data were available for 589 patients (292 in the bisoprolol and 297 in the carvedilol group). Mean physical and psychosocial QoL improved significantly during treatment. In regression analyses, changes in both SF36 component scores from baseline to follow-up were mainly predicted by baseline QoL and depression as well as change in depression over time. Changes in cardiac severity markers were significantly weaker predictors. CONCLUSION Mean QoL increased during up-titration of bisoprolol and carvedilol. Both baseline depression and improvement in depression over time are associated with greater improvement in QoL more strongly than changes in cardiac severity measures.

Self-rated health predicts adverse events during beta-blocker treatment: The CIBIS-ELD randomised trial analysis ☆

BACKGROUND Self-rated health (SRH) predicts outcome in patients with heart failure. Beta-blockers are known to improve health-related quality of life and reduce mortality in such patients. We aimed to evaluate the relation between SRH and adverse events during titration of beta-blockers in elderly patients with heart failure. METHODS The cardiac insufficiency bisoprolol study in the elderly (CIBIS-ELD) is a multicentre, double-blind trial, in which 883 patients aged ≥ 65 years with chronic heart failure (73 ± 6 years, 38% women, left ventricular ejection fraction [LVEF] 42% ± 14%) were randomised to bisoprolol or carvedilol. SRH was assessed at baseline and after 12 weeks, using a 5-grade descriptive scale: excellent, very good, good, fair, and poor. RESULTS Median SRH at baseline and follow-up was good, but more patients reported fair/poor SRH at baseline (36% vs. 30%, p = 0.012). Women, beta-blocker-naïve patients, patients in NYHA class III/IV and those with PHQ-9 score ≥ 12 were more likely to report fair/poor baseline SRH (p < 0.001 for all). During follow-up, SRH improved in 34% of patients and worsened in 8% (p < 0.001). Adverse events were experienced by 64% patients and 38% experienced > 1 adverse event or serious adverse event, with higher prevalence in lower SRH categories. In a multivariate logistic regression model, SRH, age, distance achieved on the 6-min walk test and LVEF >45% predicted adverse events (p < 0.05 for all). CONCLUSIONS SRH is an independent predictor of adverse events during titration of beta-blockers and correlates with the proportion and number of adverse events per patient.

A Novel Lipid Biomarker Panel for the Detection of Heart Failure with Reduced Ejection Fraction.

OBJECTIVES In this study we aimed to identify novel metabolomic biomarkers suitable for improved diagnosis of heart failure with reduced ejection fraction (HFrEF). METHODS We prospectively recruited 887 individuals consisting of HFrEF patients with either ischemic (ICMP, n = 257) or nonischemic cardiomyopathy (NICMP, n = 269), healthy controls (n = 327), and patients with pulmonary diseases (n = 34). A single-center identification (n = 238) was followed by a multicenter confirmation study (n = 649). Plasma samples from the single-center study were subjected to metabolite profiling analysis to identify metabolomic features with potential as HFrEF biomarkers. A dedicated analytical protocol was developed for the routine analysis of selected metabolic features in the multicenter cohort. RESULTS In the single-center study, 92 of 181 metabolomic features with known chemical identity (51%) were significantly changed in HFrEF patients compared to healthy controls (P <0.05). Three specific metabolomic features belonging to the lipid classes of sphingomyelins, triglycerides, and phosphatidylcholines were selected as the cardiac lipid panel (CLP) and analyzed in the multicenter study using the dedicated analytical protocol. The combination of the CLP with N-terminal pro-B-type natriuretic peptide (NT-proBNP) distinguished HFrEF patients from healthy controls with an area under the curve (AUC) of 0.97 (sensitivity 80.2%, specificity 97.6%) and was significantly superior compared to NT-proBNP alone (AUC = 0.93, sensitivity 81.7%, specificity 88.1%, P <0.001), even in the subgroups with mildly reduced left ventricular EF (0.94 vs 0.87; P <0.001) and asymptomatic patients (0.95 vs 0.91; P <0.05). CONCLUSIONS The new metabolomic biomarker panel has the potential to improve HFrEF detection, even in mild and asymptomatic stages. The observed changes further indicate lipid alterations in the setting of HFrEF.

Poor self-rated health predicts mortality in patients with stable chronic heart failure

Aims: In heart failure, a holistic approach incorporating the patient’s perspective is vital for prognosis and treatment. Self-rated health has strong associations with adverse events and short-term mortality risk, but long-term data are limited. We investigated the predictive value of two consecutive self-rated health assessments with regard to long-term mortality in a large, well characterised sample of elderly patients with stable chronic heart failure. Methods and results: We measured self-rated health by asking ‘In general, would you say your health is: 1, excellent; 2, very good; 3, good; 4, fair; 5, poor?’ twice: at baseline and the end of a 12-week beta-blocker up-titration period in the CIBIS-ELD trial. Mortality was assessed in an observational follow-up after 2–4 years. A total of 720 patients (mean left ventricular ejection fraction 45±12%, mean age 73±5 years, 36% women) rated their health at both time points. During long-term follow-up, 144 patients died (all-cause mortality 20%). Fair/poor self-rated health in at least one of the two reports was associated with increased mortality (hazard ratio 1.42 per level; 95% confidence interval 1.16–1.75; P<0.001). It remained independently significant in multiple Cox regression analysis, adjusted for N-terminal pro B-type natriuretic peptide (NTproBNP), heart rate and other risk prediction covariates. Self-rated health by one level worse was as predictive for mortality as a 1.9-fold increase in NTproBNP. Conclusion: Poor self-rated health predicts mortality in our long-term follow-up of patients with stable chronic heart failure, even after adjustment for established risk predictors. We encourage clinicians to capture patient-reported self-rated health routinely as an easy to assess, clinically meaningful measure and pay extra attention when self-rated health is poor.