Prognostic value of different biomarkers for cardiovascular death in unselected older patients in the emergency department.

Risk stratification of elderly patients presenting with heart failure (HF) to an emergency department (ED) is an unmet challenge. We prospectively investigated the prognostic performance of different biomarkers in unselected older patients in the ED. We consecutively enrolled 302 non-surgical patients ⩾70 years presenting to the ED with a wide range of cardiovascular and non-cardiovascular comorbid conditions. N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-adrenomedullin (MR-proADM), mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET-1), ultrasensitive C-terminal pro-arginine-vasopressin (Copeptin-us) and high-sensitivity cardiac troponin T (hs-cTnT) were measured at admission. Two cardiologists independently adjudicated the final diagnosis of HF after reviewing all available baseline data using circulating NT-proBNP levels. A final diagnosis of HF was found in 120 (40%) of the 302 patients. All patients were followed up for cardiovascular death within the following 12 months. In order to test the prognostic performance of the investigated biomarkers we used boosting models with age and sex as mandatory covariates. Boosting is a statistical learning technique with built-in variable selection developed to obtain sparse and interpretable prediction models. Follow-up was 100% complete. During a median follow-up time of 225 days (interquartile range (IQR) 156-319 days), 30 (9.9%) of 302 patients (aged 81±6 years) had cardiovascular deaths. Of these 30 patients, 21 had HF and nine had no HF diagnosed prior to admission. The boosting model selected MR-proADM and hs-cTNT as predictors of cardiovascular deaths. The median values of MR-proADM and hs-cTnT at presentation were significantly higher in patients with cardiovascular deaths compared to surviving patients during follow-up (2.56 nmol/L (IQR 1.62-4.48) vs. 1.11 nmol/L (IQR 0.83-1.80), P<0.001 and 81 ng/L (IQR 38-340) vs. 17 ng/L (IQR 0.9-38), P=0.004). One unit increase in the log-transformed MR-proADM levels was associated with a 1.99-fold risk of death (95% confidence interval (CI) 1.61-2.45, P<0.001). The second marker, hs-cTnT, showed an increased predicted risk but was not significantly correlated to event-free survival (hazard ratio 3.22, 95% CI 0.97-10.68, P=0.056). Within different biomarkers, MR-proADM was the only predictor of cardiovascular deaths in unselected older patients presenting to the ED.

Bahrmann P ，Christ M ，Hofner B ，Bahrmann A ，Achenbach S ，Sieber CC ，Bertsch T ... -  《-》

Multiple biomarker strategy for improved diagnosis of acute heart failure in older patients presenting to the emergency department.

Biomarkers can help to identity acute heart failure (AHF) as the cause of symptoms in patients presenting to the emergency department (ED). Older patients may prove a diagnostic challenge due to co-morbidities. Therefore we prospectively investigated the diagnostic performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP) alone or in combination with other biomarkers for AHF upon admission at the ED. 302 non-surgical patients aged ≥ 70 years were consecutively enrolled upon admission to the ED. In addition to NT-proBNP, mid-regional pro-adrenomedullin (MR-proADM), mid-regional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET-1) and ultra-sensitive C-terminal pro-vasopressin (Copeptin-us) were measured at admission. Two cardiologists independently adjudicated the final diagnosis of AHF after reviewing all available baseline data excluding the biomarkers. We assessed changes in C-index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) for the multimarker approach. AHF was diagnosed in 120 (40%) patients (age 81±6 years, 64 men, 56 women). Adding MR-ADM to NT-proBNP levels improved C-index (0.84 versus 0.81; p=0.045), and yielded IDI (3.3%; p=0.002), NRI (17%, p<0.001) and continuous NRI (33.3%; p=0.002). Adding CT-proET-1 to NT-proBNP levels improved C index (0.86 versus 0.81, p=0.031), and yielded robust IDI (12.4%; p<0.001), NRI (31.3%, p<0.001) and continuous NRI (69.9%; p<0.001). No other dual or triple biomarker combination showed a significant improvement of both C-index and IDI. In older patients presenting to the ED, the addition of CT-proET-1 or MR-proADM to NT-proBNP improves diagnostic accuracy of AHF. Both dual biomarker approaches offer significant risk reclassification improvement over NT-proBNP.

Bahrmann P ，Bahrmann A ，Hofner B ，Christ M ，Achenbach S ，Sieber CC ，Bertsch T ... -  《-》

Cardiovascular biomarkers predict post-discharge re-hospitalization risk and mortality among Swedish heart failure patients.

The aim of this study was to assess the predictive role of biomarkers, associated with cardiovascular stress and its neuroendocrine response as well as renal function, in relation to mortality and risk of re-hospitalization among consecutive patients admitted because of heart failure (HF). A total of 286 patients (mean age, 75 years; 29% women) hospitalized for newly diagnosed or exacerbated HF were analysed. Associations between circulating levels of mid-regional pro-adrenomedullin (MR-proADM), copeptin, C-terminal pro-endothelin-1, N-terminal pro-brain natriuretic peptide (NT-proBNP), cystatin C, and all-cause mortality as well as risk of re-hospitalization due to cardiac causes were assessed using multivariable Cox regression models. A two-sided Bonferroni-corrected P-value of 0.05/5 = 0.010 was considered statistically significant. All biomarkers were related to echocardiographic measurements of cardiac dimensions and function. A total of 57 patients died (median follow-up time, 17 months). In the multivariable-adjusted Cox regression analyses, all biomarkers, except C-terminal pro-endothelin-1, were significantly associated with increased mortality: NT-proBNP [hazard ratio (HR) 1.85, 95% confidence interval (CI) 1.17-2.17; P = 4.0 × 10-4 ], MR-proADM (HR 1.94, 95% CI 1.36-2.75; P = 2.2 × 10-4 ), copeptin (HR 1.70, 95% CI 1.22-2.36; P = 0.002), and cystatin C (HR 2.11, 95% CI 1.56-2.86; P = 1.0 × 10-6 ). A total of 90 patients were re-hospitalized (median time to re-hospitalization, 5 months). In multivariable Cox regression analyses, NT-proBNP was the only biomarker that showed significant association with risk of re-hospitalization due to cardiac causes (HR 1.43, 95% CI 1.10-1.87; P = 0.009). Among patients hospitalized for HF, elevated plasma levels of NT-proBNP, MR-proADM, copeptin, and cystatin C are associated with higher mortality after discharge, whereas NT-proBNP is the only biomarker that predicts the risk of re-hospitalization due to cardiac causes.

Molvin J ，Jujic A ，Bachus E ，Gallo W ，Tasevska-Dinevska G ，Holm H ，Melander O ，Fedorowski A ，Magnusson M ... -  《-》

Prognostic potential of midregional pro-adrenomedullin following decompensation for systolic heart failure: comparison with cardiac natriuretic peptides.

Whereas guidelines recommend the routine use of natriuretic peptides (NPs) in heart failure (HF) care, the clinical relevance and prognostic potential of midregional pro-adrenomedullin (MR-proADM) is less well established. We aimed to compare the prognostic potential of MR-proADM after acute decompensation for systolic HF with that of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and midregional pro-atrial NP (MR-proANP), to investigate the significance of high/rising MR-proADM, and to evaluate the incremental prognostic yield of repeat measurements. The Interdisciplinary Network Heart Failure (INH) programme enrolled patients hospitalized for acute systolic HF and followed them for 18 months (100% complete). Of 1022 INH participants, 917 (68 ± 12 years, 28% female) who had biomaterials available were enrolled. High MR-proADM was associated with more impaired left ventricular function, higher comorbidity burden, lower doses of HF medications, and lower likelihood of left ventricular reverse remodelling. Compared with NPs, MR-proADM had superior prognostic significance (concordance index 0.72 for all-cause mortality), improved Cox regression models including NPs (P < 0.001), and was the only biomarker also predicting non-cardiac death (hazard ratio 1.8 vs. 1.0). In the setting of low NPs, patients with high MR-proADM experienced non-cardiac death more often. Six month MR-proADM enhanced models including baseline MR-proADM (P < 0.001) for prediction of all-cause death (net reclassification index: 0.48, 95% confidence interval 0.19-0.78). MR-proADM was found to correlate with the global disease burden in HF and proved a potent prognostic indicator, capturing the risk for both cardiac and non-cardiac death. Serial MR-proADM measurements further enhanced risk assessment, thus facilitating substantial reclassification.

Morbach C ，Marx A ，Kaspar M ，Güder G ，Brenner S ，Feldmann C ，Störk S ，Vollert JO ，Ertl G ，Angermann CE ，INH Study Group and the Competence Network Heart Failure ... -  《-》

Cardiovascular biomarkers in patients with cancer and their association with all-cause mortality.

Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer. We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint. During a median follow-up of 25 (IQR 16-31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR-proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR-proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP. Circulating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression.

Pavo N ，Raderer M ，Hülsmann M ，Neuhold S ，Adlbrecht C ，Strunk G ，Goliasch G ，Gisslinger H ，Steger GG ，Hejna M ，Köstler W ，Zöchbauer-Müller S ，Marosi C ，Kornek G ，Auerbach L ，Schneider S ，Parschalk B ，Scheithauer W ，Pirker R ，Drach J ，Zielinski C ，Pacher R ... -  《-》