Biomarkers in chronic and worsening heart failure patients: Results from the CIBIS-ELD trial and the MOLITOR trial

Background: With around 26 million people affected worldwide, heart failure (HF) is growing into an epidemic. Biomarkers are powerful tools for HF management, and currently natriuretic peptides (NT-proBNP and BNP) are routinely used for this purpose. However, little is known about NT-proBNP’s trajectories during therapy optimization in different HF populations. During an episode of worsening HF (WHF), NT-proBNP is often repeatedly being measured, but the relevance of its serial measurements in combination with novel biomarkers (copeptin, MR-proADN, MR-proADM, endothelin-1) has not previously been explored. Elevated high sensitivity (hs) C-reactive protein (CRP) is associated with adverse outcomes in chronic HF. Its correlation to functional capacity in HF patients is unknown. Aim: We sought to answer the following questions concerning biomarkers in HF: • What is the trajectory of NT-proBNP levels in patients with reduced (HFrEF) and preserved ejection fraction (HFpEF) during a 12-week beta-blocker titration? • When measured serial, which biomarkers are the best predictors of mortality/rehospitalization in WHF patients? • Do hs-CRP levels correlate with the changes in functional capacity during a 12-week beta-blocker titration in HF patients? Methods: The performed analyses were substudies of CIBIS-ELD and MOLITOR trials. CIBIS-ELD was a double blind, multicenter trial in elderly HF patients, randomized to bisoprolol and carvedilol. MOLITOR was a trial of 164 hospitalized patients with WHF. Copeptin, NT-proBNP, MR-proANP, MR-proADM and endothelin-1 were measured on admission, after 24, 48, and 72h, and every 72h thereafter, at discharge and follow-up visits. Results: While comparing the NT-proBNP levels between the 626 HFrEF and 250 HFpEF patients in CIBIS-ELD, it was noticed that NT-proBNP remained stable in the HFrEF population during the 12-week beta-blocker titration, and slightly increased in the HFpEF population. The difference in NT-proBNP change over 12 weeks between HFrEF and HFpEF patients was not statistically significant (P=0.13). In 164 WHF patients of the MOLITOR trial, copeptin at admission was the best predictor of 90-day mortality/rehospitalization (χ2=16.63, C-index=0.724, P<0.001). Its remeasurement at 72h increased prognostic value (χ2=23.48, C-index=0.718, P=0.00001). In 488 HF patients of the CIBIS-ELD trial, we found a correlation between hs-CRP changes and changes in functional capacity (6-minute-walk-test; P=0.002). Conclusion: The performed analyses make a contribution to the current biomarker practice in HF patients. In WHF patients, copeptin at admission with remeasurement at 72h seems to be the best predictor of 90-day mortality and rehospitalization. We showed that in chronic HF patients, changes of hs-CRP can be used to predict of functional capacity.Mit weltweit rund 26 Millionen Erkrankten entwickelt sich die Herzinsuffizienz (HF) zu einer Epidemie. Biomarker sind effektive Werkzeuge für das HF-Management und für diesen Zweck werden derzeit üblicherweise natriuretische Peptide (NT-proBNP und BNP) verwendet. Bislang ist jedoch wenig über den Verlauf von NT-proBNP-Konzentrationen während der Therapieoptimierung bei Patienten mit Herzinsuffizienz mit reduzierter und erhaltener Ejektionsfraktion bekannt. Während einer Episode einer akuten Dekompensation wird NT-proBNP meist mehrmals gemessen. Die Relevanz der seriellen Messungen in Kombination mit neuen Biomarkern (wie Copeptin, MR-proANP, MR-proADM, Endothelin-1) ist jedoch bisher wenig untersucht. Hochsensitives (hs) C-reaktives Protein (CRP) ist mit unerwünschten Ereignissen bei chronischer HF assoziiert. Die Korrelation dieses Biomarkers zur funktionellen Kapazität bei HF-Patienten ist unbekannt. Ziele: Folgende Fragen zu Biomarkern bei HF wurden im Rahmen dieser Arbeiten beantwortet: • Wie verlaufen die NT-proBNP-Konzentrationen bei Patienten mit reduzierter (HFrEF) und erhaltener Ejektionsfraktion (HFpEF) während einer 12-wöchigen Beta-Blocker-Titration? • Welche Biomarker sind die wichtigsten Prädiktoren für Mortalität/Rehospitalisierung bei akut dekompensierten HF-Patienten, wenn sie seriell gemessen werden? • Korreliert die Konzentration des hs-CRP mit den Veränderungen der funktionellen Kapazität während einer 12-wöchigen Beta-Blocker-Titration bei HF-Patienten? Methoden: Die durchgeführten Analysen waren Substudien der CIBIS-ELD Studie und der MOLITOR Studie. CIBIS-ELD war eine doppelblinde, multizentrische Studie bei älteren Patienten mit chronischer HF, die auf eine Therapie mit Bisoprolol oder Carvedilol randomisiert wurden. MOLITOR war eine Studie von 164 hospitalisierten Patienten mit akuter dekompensierter HF. Copeptin, NT-proBNP, MR-proANP, MR-proADM und Endothelin-1 wurden bei Aufnahme, nach 24h, 48h und 72h und danach alle 72 Stunden bei Entlassungs- und Follow-up-Visiten gemessen. Ergebnisse: Beim Vergleich der NT-proBNP-Konzentrationen zwischen den 626 HFrEF- und den 250 HFpEF-Patienten in CIBIS-ELD wurde festgestellt, dass NT-proBNP in der HFrEF-Population während der 12-wöchigen Beta-Blocker-Titration stabil blieb und in der HFpEF-Population leicht anstieg. Der Unterschied der NT-proBNP-Veränderungen zwischen der HFrEF- und HFpEF-Population war statistisch nicht signifikant (P=0,13). Bei 164 akut dekompensierten HF-Patienten der MOLITOR-Studie war Copeptin bei Aufnahme der beste Prädiktor für die 90-tägige Mortalität/Rehospitalisierung (χ2=16,63, C-Index=0,724, P<0,001). Die erneute Messung nach 72h erhöhte den prognostischen Wert (χ2=23,48, C-Index=0,718, P=0,00001). Bei 488 HF-Patienten der CIBIS-ELD-Studie fanden wir eine Korrelation zwischen hs-CRP-Veränderungen und Veränderungen der funktionellen Kapazität (6-Minuten-Gehtest; P=0,002). Schlussfolgerung: Die durchgeführten Analysen leisten einen Beitrag zur aktuellen Biomarkerpraxis bei HF-Patienten. Bei akut dekompensierten HF-Patienten scheint die Messung von Copeptin bei Aufnahme und nach 72 Stunde der beste Prädiktor für die 90-Tage-Mortalität und Rehospitalisierung zu sein. Wir zeigten, dass bei chronischen HF-Patienten Veränderungen des hs-CRP zur Vorhersage der funktionellen Kapazität genutzt werden können

Tolerability and feasibility of beta-blocker titration in HFpEF versus HFrEF: Insights from the CIBIS-ELD trial

OBJECTIVES: This study evaluated the tolerability and feasibility of titration of 2 distinctly acting beta-blockers (BB) in elderly heart failure patients with preserved (HFpEF) and reduced (HFrEF) left ventricular ejection fraction. BACKGROUND: Broad evidence supports the use of BB in HFrEF, whereas the evidence for beta blockade in HFpEF is uncertain. METHODS: In the CIBIS-ELD (Cardiac Insufficiency Bisoprolol Study in Elderly) trial, patients >65 years of age with HFrEF (n = 626) or HFpEF (n = 250) were randomized to bisoprolol or carvedilol. Both BB were up-titrated to the target or maximum tolerated dose. Follow-up was performed after 12 weeks. HFrEF and HFpEF patients were compared regarding tolerability and clinical effects (heart rate, blood pressure, systolic and diastolic functions, New York Heart Association functional class, 6-minute-walk distance, quality of life, and N-terminal pro-B-type natriuretic peptide). RESULTS: For both of the BBs, tolerability and daily dose at 12 weeks were similar. HFpEF patients demonstrated higher rates of dose escalation delays and treatment-related side effects. Similar HR reductions were observed in both groups (HFpEF: 6.6 beats/min; HFrEF: 6.9 beats/min, p = NS), whereas greater improvement in NYHA functional class was observed in HFrEF (HFpEF: 23% vs. HFrEF: 34%, p < 0.001). Mean E/e' and left atrial volume index did not change in either group, although E/A increased in HFpEF. CONCLUSIONS: BB tolerability was comparable between HFrEF and HFpEF. Relevant reductions of HR and blood pressure occurred in both groups. However, only HFrEF patients experienced considerable improvements in clinical parameters and Left ventricular function. Interestingly, beta-blockade had no effect on established and prognostic markers of diastolic function in either group. Long-term studies using modern diagnostic criteria for HFpEF are urgently needed to establish whether BB therapy exerts significant clinical benefit in HFpEF. (Comparison of Bisoprolol and Carvedilol in Elderly Heart Failure HF] Patients: A Randomised, Double-Blind Multicentre Study CIBIS-ELD]; ISRCTN34827306)

Depression, anxiety, and quality of life as predictors of rehospitalization in patients with chronic heart failure

Abstract Background Chronic heart failure (CHF) is a severe condition, often co-occurring with depression and anxiety, that strongly affects the quality of life (QoL) in some patients. Conversely, depressive and anxiety symptoms are associated with a 2–3 fold increase in mortality risk and were shown to act independently of typical risk factors in CHF progression. The aim of this study was to examine the impact of depression, anxiety, and QoL on the occurrence of rehospitalization within one year after discharge in CHF patients. Methods 148 CHF patients were enrolled in a 10-center, prospective, observational study. All patients completed two questionnaires, the Hospital Anxiety and Depression Scale (HADS) and the Questionnaire Short Form Health Survey 36 (SF-36) at discharge timepoint. Results It was found that demographic and clinical characteristics are not associated with rehospitalization. Still, the levels of depression correlated with gender (p ≤ 0.027) and marital status (p ≤ 0.001), while the anxiety values ​​were dependent on the occurrence of chronic obstructive pulmonary disease (COPD). However, levels of depression (HADS-Depression) and anxiety (HADS-Anxiety) did not correlate with the risk of rehospitalization. Univariate logistic regression analysis results showed that rehospitalized patients had significantly lower levels of Bodily pain (BP, p = 0.014), Vitality (VT, p = 0.005), Social Functioning (SF, p = 0.007), and General Health (GH, p = 0.002). In the multivariate model, poor GH (OR 0.966, p = 0.005) remained a significant risk factor for rehospitalization, and poor General Health is singled out as the most reliable prognostic parameter for rehospitalization (AUC = 0.665, P = 0.002). Conclusion Taken together, our results suggest that QoL assessment complements clinical prognostic markers to identify CHF patients at high risk for adverse events. Clinical Trial Registration: The study is registered under http://clinicaltrials.gov (NCT01501981, first posted on 30/12/2011), sponsored by Charité – Universitätsmedizin Berlin