Marta de Antonio

Head-to-head comparison of 2 myocardial fibrosis biomarkers for long-term heart failure risk stratification: ST2 versus galectin-3.

OBJECTIVES ST2 and galectin-3 (Gal-3) were compared head-to-head for long-term risk stratification in an ambulatory heart failure (HF) population on top of other risk factors including N-terminal pro-B-type natriuretic peptide. BACKGROUND ST2 and Gal-3 are promising biomarkers of myocardial fibrosis and remodeling in HF. METHODS This cohort study included 876 patients (median age: 70 years, median left ventricular ejection fraction: 34%). The 2 biomarkers were evaluated relative to conventional assessment (11 risk factors) plus N-terminal pro-B-type natriuretic peptide in terms of discrimination, calibration, and reclassification analysis. Endpoints were 5-year all-cause and cardiovascular mortality, and the combined all-cause death/HF hospitalization. RESULTS During a median follow-up of 4.2 years (5.9 for alive patients), 392 patients died. In bivariate analysis, Gal-3 and ST2 were independent variables for all endpoints. In multivariate analysis, only ST2 remained independently associated with cardiovascular mortality (hazard ratio: 1.27, 95% confidence interval [CI]: 1.05 to 1.53, p = 0.014). Incorporation of ST2 into a full-adjusted model for all-cause mortality (including clinical variables and N-terminal pro-B-type natriuretic peptide) improved discrimination (C-statistic: 0.77, p = 0.004) and calibration, and reclassified significantly better (integrated discrimination improvement: 1.5, 95% CI: 0.5 to 2.5, p = 0.003; net reclassification index: 9.4, 95% CI: 4.8 to 14.1, p < 0.001). Incorporation of Gal-3 showed no significant increase in discrimination or reclassification and worse calibration metrics. On direct model comparison, ST2 was superior to Gal-3. CONCLUSIONS Head-to-head comparison of fibrosis biomarkers ST2 and Gal-3 in chronic HF revealed superiority of ST2 over Gal-3 in risk stratification. The incremental predictive contribution of Gal-3 to existing clinical risk factors was trivial.

Combined use of high‐sensitivity ST2 and NTproBNP to improve the prediction of death in heart failure

To address the incremental usefulness of biomarkers from different disease pathways for predicting risk of death in heart failure (HF).

Estimated glomerular filtration rate and prognosis in heart failure: value of the Modification of Diet in Renal Disease Study-4, chronic kidney disease epidemiology collaboration, and cockroft-gault formulas.

OBJECTIVES The purpose of this study was to assess the value of estimated glomerular filtration rate (eGFR) calculated by different formulas for predicting the risk of death in heart failure (HF) outpatients. BACKGROUND Patients with both HF and renal insufficiency have a poor prognosis. Three formulas are mostly used to assess renal function: Cockroft-Gault formula, MDRD-4 (Modification of Diet in Renal Disease Study) formula, and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The prognostic values of these formulas have not been adequately compared in HF patients. METHODS A total of 925 patients (72% men; age 69 years; interquartile range: 59 to 75.5 years) with a left ventricular ejection fraction of 31% (interquartile range: 23.5% to 39%) were studied. Follow-up was 1,202 days (interquartile range: 627.5 to 2,156.5 days). Measures of performance were evaluated using continuous data and by dividing patients into 4 subgroups according to the eGFR: ≥90, 89 to 60, <60 to 30, and <30 ml/min/1.73 m(2). RESULTS The 3 formulas correlated significantly, with the best correlation found between the MDRD-4 and CKD-EPI formulas. The 3 formulas afforded independent prognostic information over long-term follow-up. However, risk prediction was most accurate using the Cockroft-Gault formula as evaluated by Cox proportional hazards models (hazard ratio: 0.75 vs. 0.81 with the MDRD-4 formula and 0.80 with the CKD-EPI equation), area under the curve (0.67 vs. 0.62 and 0.64, respectively), and Bayesian information criterion (both analyzing eGFR as a continuous or categorical variable). Indeed, net reclassification improvement and integrated discrimination improvement using the Cockroft-Gault formula were 21% and 5.04, respectively, versus the MDRD-4 formula (the most used) and 13.1% and 3.77 respectively versus CKD-EPI equation (the more recent) (all p values <0.001). CONCLUSIONS In this ambulatory, real-life cohort of HF patients, the Cockroft-Gault formula was the most accurate of the 3 used eGFR formulas to improve the risk stratification for death.

Development of a Novel Heart Failure Risk Tool: The Barcelona Bio-Heart Failure Risk Calculator (BCN Bio-HF Calculator)

Background A combination of clinical and routine laboratory data with biomarkers reflecting different pathophysiological pathways may help to refine risk stratification in heart failure (HF). A novel calculator (BCN Bio-HF calculator) incorporating N-terminal pro B-type natriuretic peptide (NT-proBNP, a marker of myocardial stretch), high-sensitivity cardiac troponin T (hs-cTnT, a marker of myocyte injury), and high-sensitivity soluble ST2 (ST2), (reflective of myocardial fibrosis and remodeling) was developed. Methods Model performance was evaluated using discrimination, calibration, and reclassification tools for 1-, 2-, and 3-year mortality. Ten-fold cross-validation with 1000 bootstrapping was used. Results The BCN Bio-HF calculator was derived from 864 consecutive outpatients (72% men) with mean age 68.2±12 years (73%/27% New York Heart Association (NYHA) class I-II/III-IV, LVEF 36%, ischemic etiology 52.2%) and followed for a median of 3.4 years (305 deaths). After an initial evaluation of 23 variables, eight independent models were developed. The variables included in these models were age, sex, NYHA functional class, left ventricular ejection fraction, serum sodium, estimated glomerular filtration rate, hemoglobin, loop diuretic dose, β-blocker, Angiotensin converting enzyme inhibitor/Angiotensin-2 receptor blocker and statin treatments, and hs-cTnT, ST2, and NT-proBNP levels. The calculator may run with the availability of none, one, two, or the three biomarkers. The calculated risk of death was significantly changed by additive biomarker data. The average C-statistic in cross-validation analysis was 0.79. Conclusions A new HF risk-calculator that incorporates available biomarkers reflecting different pathophysiological pathways better allowed individual prediction of death at 1, 2, and 3 years.

Combined use of high-sensitivity cardiac troponin T and N-terminal pro-B type natriuretic peptide improves measurements of performance over established mortality risk factors in chronic heart failure

BACKGROUND Heart failure still maintains a high mortality. Biomarkers reflecting different pathophysiological pathways are under evaluation to better stratify the mortality risk. The objective was to assess high-sensitivity cardiac troponin T (hs-cTnT) in combination with N-terminal pro-B type natriuretic peptide (NT-proBNP) for risk stratification in a real-life cohort of ambulatory heart failure patients. METHODS We analyzed 876 consecutive patients (median age 70.3 years, median left ventricular ejection fraction 34%) treated at a heart failure unit. A combination of biomarkers reflecting myocyte injury (hs-cTnT) and myocardial stretch (NT-proBNP) was used in addition to an assessment based on established mortality risk factors (age, sex, left ventricular ejection fraction, New York Heart Association functional class, diabetes, estimated glomerular filtration rate, ischemic etiology, sodium, hemoglobin, β-blocker treatment, and angiotensin converting enzyme inhibitor or angiotensin II receptor blocker treatment). RESULTS During a median follow-up of 41.4 months, 311 patients died. In the multivariable Cox proportional hazards model, hs-cTnT and NT-proBNP were independent prognosticators (P = .003 each). The combined elevation of both biomarkers above cut-off values significantly increased the risk of death (HR 7.42 [95% CI, 5.23-10.54], P < .001). When hs-cTnT and NT-proBNP were individually included in a model with established mortality risk factors, measurements of performance significantly improved. Results obtained for hs-cTnT compared with NT-proBNP were superior according to comprehensive discrimination, calibration, and reclassification analysis (net reclassification indices of 7.7% and 1.5%, respectively). CONCLUSIONS hs-cTnT provides significant prognostic information in a real-life cohort of patients with chronic heart failure. Simultaneous addition of hs-cTnT and NT-proBNP into a model that includes established risk factors improves mortality risk stratification.

Statins in Heart Failure: The Paradox Between Large Randomized Clinical Trials and Real Life

OBJECTIVE To assess the relationship between statins and prognosis in ischemic and nonischemic patients with heart failure (HF) in a real-life cohort followed up for a long period. PATIENTS AND METHODS This prospective study included 960 patients with HF with preserved or depressed left ventricular ejection fraction (LVEF), irrespective of HF etiology, who were referred to the HF clinic of a university hospital between August 1, 2001, and December 31, 2008. The patients were followed up for a maximum of 9.1 years (median, 3.7 years), and survival in ischemic and nonischemic patients was determined. RESULTS Median age was 69 years, and median LVEF was 31%. Of the 960 patients, 532 (55.4%) had ischemic HF etiology, and most received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (846; 88.1%) and β-blockers (776; 80.8%). Patients with HF of ischemic origin were more often treated with statins (P<.001). During follow-up, 440 patients (45.8%) died. Statin therapy was associated with significantly improved survival (hazard ratio, 0.45 [95% confidence interval, 0.37-0.54]; P<.001). After adjustment for HF prognostic factors (age, sex, cholesterol level, New York Heart Association class, HF etiology, LVEF, body mass index, HF duration, atrial fibrillation, implantable cardioverter-defibrillator therapy, and medicines), statins remained significantly associated with lower mortality risk in both ischemic (P=.007) and nonischemic (P=.002) patients. CONCLUSION In contrast to results of large randomized trials, statins were independently and significantly associated with lower mortality risk in our real-life HF cohort, including patients with nonischemic HF etiology.

Combined Use of the Novel Biomarkers High-Sensitivity Troponin T and ST2 for Heart Failure Risk Stratification vs Conventional Assessment

OBJECTIVE To assess an innovative multimarker strategy for risk stratification of death in a real-life ambulatory heart failure (HF) cohort. PATIENTS AND METHODS The study included 876 consecutive outpatients (median age, 70.3 years; left ventricular ejection fraction, 34%) between May 22, 2006, and July 7, 2010, prospectively followed up in a structured HF unit. A combination of biomarkers reflecting myocardial stretch (N-terminal pro-B-type natriuretic peptide [NT-proBNP]), myocyte injury (high-sensitivity cardiac troponin T [hs-cTnT]), and ventricular fibrosis and remodeling (high-sensitivity ST2 [hs-ST2]) were added to an assessment based on established mortality risk factors (age, sex, left ventricular ejection fraction, New York Heart Association functional class, diabetes mellitus, estimated glomerular filtration rate, ischemic etiology, sodium level, hemoglobin level, and pharmacologic treatment). RESULTS During median follow-up of 41.4 months, 311 patients died. The combined addition of hs-cTnT and hs-ST2 to the model yielded good measurements of performance (C statistic, 0.789; Bayesian information criterion, 3611; integrated discrimination improvement, 4.1 [95% CI, 2.5-5.6]; and net reclassification index, 13.9% [95% CI, 6.2-21.6]). Reclassification did not significantly benefit after NT-proBNP addition into the full model; some indices even worsened with all 3 biomarkers. Separate addition of NT-proBNP provided prognostic discrimination only in the subgroup of patients with either hs-cTnT or hs-ST2 levels below the cutoff points (hazard ratio, 2.97; 95% CI, 2.24-9.39; P<.001). CONCLUSION A multimarker strategy seems useful for stratifying risk in chronic HF. However, NT-proBNP in addition to the new-generation biomarkers hs-cTnT and hs-ST2 had a limited effect on risk stratification.

The obesity paradox in heart failure: is etiology a key factor?

BACKGROUND Obesity is paradoxically associated with survival in patients with heart failure (HF). Our objective was to assess whether the relationship between body mass index (BMI) and long-term survival is associated with HF etiology (ischemic vs. non-ischemic) in a cohort of ambulatory HF patients. METHODS BMI and survival status after a median follow-up of 6.1 years (IQR 2.2-7.8) were available for 504 patients (73% men; median age 68 years [IQR 58-74]). Fifty-nine percent of patients had ischemic etiology. Median left ventricular ejection fraction (LVEF) was 30% (IQR 23-39.7%). Most patients were in NYHA functional class II (51%) or III (42%). Patients were divided into four groups according to BMI: low weight (BMI < 20.5 kg/m(2)), normal weight (BMI 20.5 to < 25.5 kg/m(2)), overweight (BMI 25.5 to < 30 kg/m(2)), and obese (BMI ≥ 30 kg/m(2)). RESULTS Mortality differed significantly across the BMI strata in non-ischemic patients (log-rank p < 0.0001) but not in ischemic patients. Using normal weight patients as a reference, hazard ratios for low weight, overweight, and obese patients were 2.08 (1.16-3.75, p = 0.014), 0.88 (0.54-1.43, p = 0.60), and 0.49 (0.28-0.86, p = 0.01), respectively, for non-ischemic patients and 1.19 (0.48-2.97, p = 0.71), 0.88 (0.61-1.27, p = 0.48), and 0.96 (0.66-1.41, p = 0.85), respectively, for ischemic patients. After adjusting for age, sex, NYHA functional class, LVEF, co-morbidities, and treatment, BMI remained an independent predictor of survival in non-ischemic patients. CONCLUSION Over long-term follow-up of ischemic and non-ischemic HF, the obesity paradox was only observed in patients with non-ischemic HF.

Depression, antidepressants, and long-term mortality in heart failure

BACKGROUND This study was designed to assess whether depression and the use of antidepressants were related to long-term mortality in heart failure. METHODS Heart failure outpatients (n=1017) from a specialized tertiary unit in Spain were prospectively studied for a median follow-up of 5.4 years (IQR 3.1-8.1). Depressive symptoms were assessed using an abbreviated version of the geriatric depression scale. Survival rates during the study period (August 2001 until December 2010) and hazard ratios (HR) for mortality were adjusted by several demographic and clinical variables. RESULTS Depressive symptoms were detected in 302 patients (29.7%) at baseline and 222 (21.8%) de novo during follow-up; 304 patients (29.9%) received at least one prescription of antidepressants, mainly selective serotonin reuptake inhibitors (92.8%); 441 patients (43.4%) died. In a multivariate Cox proportional hazard model, depression was associated with an increased all-cause (HR, 1.39; 95% CI, 1.15-1.68), but not cardiovascular, mortality risk after adjustment for several demographic and clinical confounders. The use of any antidepressant was not independently associated with mortality (HR, 0.89; 95% CI, 0.71-1.13), but benzodiazepines showed a protective role (HR, 0.70; 95% CI, 0.57-0.87). On the contrary, fluoxetine prescriptions, but not duration of fluoxetine treatment, were associated with increased mortality (HR, 1.66; 95% CI, 1.13-2.44). CONCLUSIONS Depressive symptoms are associated with long-term mortality, but the use of antidepressants and benzodiazepines is safe regarding survival in HF patients, although further research is needed considering individual antidepressants separately.

Biomarker-assist score for reverse remodeling prediction in heart failure: The ST2-R2 score

BACKGROUND Limited data exists regarding biomarker use to predict left ventricular (LV) reverse remodeling (R2). Our aim was to examine the value of soluble ST2 (ST2), N-terminal-pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and galectin-3 relative to LV-R2 in systolic heart failure (HF), and to develop a clinical score for LV-R2 prediction. METHODS R2 was defined as a) LV ejection fraction (LVEF) increase ≥15%, or b) LVEF increase ≥10% plus reduction of LV end-systolic diameter index ≥20% or LV end-systolic volume ≥40%, for 12 months. RESULTS We studied 304 patients (79.6% men, mean age 66.1 ± 12.3 years) with baseline LVEF <40%. R2 was observed in 104 patients (34.2%). In univariable logistic regression, factors associated with R2 were age (p=0.02), non-ischemic etiology of HF (p<0.001), NYHA functional class (p=0.02), baseline LVEF (p=0.005), absence of left bundle branch block (LBBB; p=0.002), ST2 (p=0.004), NT-proBNP (p=0.005), and hs-cTnT (p<0.001); HF duration achieved borderline significance (p=0.08). In multivariable analysis, ST2 remained the only biomarker associated with LV-R2. We developed the ST2-R2 score for use in clinical practice for predicting R2; variables included were ST2 <48 ng/mL, non-ischemic etiology, absence of LBBB, HF duration <12 months, baseline LVEF <24%, and β-blocker treatment. The score had an area under the curve of 0.79 in the derivation cohort and 0.73 in a separate validation cohort. CONCLUSIONS The ST2-R2 score, which includes the novel biomarker ST2 and five clinical variables, reasonably predicts LV-R2 in systolic HF patients. ST2 was the only studied biomarker that was independently associated with R2.