Svetlana Apostolovic

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.

Incremental value of high-sensitive troponin T in addition to the revised cardiac index for peri-operative risk stratification in non-cardiac surgery.

AIMS We aimed to evaluate the incremental value of high-sensitive troponin T (hsTnT) for risk prediction prior to non-cardiac surgery in comparison with the established revised cardiac index. METHODS AND RESULTS In this prospective, international multicentre observational study, 979 patients prior to non-cardiac surgery were enrolled. The endpoints were in-hospital mortality, the combination of death, acute myocardial infarction, cardiac arrest, cardio-pulmonary resuscitation, and acute decompensated heart failure. Twenty-five patients (2.6%) deceased and 36 (3.7%) of the patients experienced the combined endpoint. Cardiac markers were elevated in those patients who died when compared with survivors (hsTnT: 21 ng/L vs. 7 ng/L; P < 0.001; NT-proBNP: 576 pg/mL vs. 166 pg/mL; P < 0.001). Applying a cut-off for hsTnT of 14 ng/L and for NT-proBNP of 300 pg/mL, those patients with elevated hsTnT had a mortality of 6.9 vs. 1.2% (P < 0.001) and with elevated NT-proBNP 4.8 vs. 1.4% (P = 0.002). The highest AUC of the ROC curve was found for hsTnT as a predictor for mortality of 0.809. In a multivariate Cox regression analyses, hsTnT was the strongest independent predictor for the combined endpoint [HR 2.6 (95% CI: 1.3-5.3); P = 0.01]. CONCLUSION High-sensitive troponin T provides strong prognostic information in patients undergoing non-cardiac surgery incremental to the widely accepted revised cardiac index.

Impact of the β1‐Adrenoceptor Arg389Gly Polymorphism on Heart‐Rate Responses to Bisoprolol and Carvedilol in Heart‐Failure Patients

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.

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.

Is target dose the treatment target? Uptitrating beta-blockers for heart failure in the elderly

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.

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.

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.