Sergio Manzano-Fernández

Red blood cell distribution width predicts long-term outcome regardless of anaemia status in acute heart failure patients

To study the long‐term prognostic value of red blood cell distribution width (RDW) in patients hospitalized with acute heart failure (AHF) and to compare the value of this measurement with haemoglobin levels and anaemia status.

Soluble ST2, high-sensitivity troponin T- and N-terminal pro-B-type natriuretic peptide: complementary role for risk stratification in acutely decompensated heart failure.

To investigate the use of biomarkers providing independent information regarding physiology in acutely decompensated heart failure (ADHF) for assessment of risk.

Usefulness of soluble concentrations of interleukin family member ST2 as predictor of mortality in patients with acutely decompensated heart failure relative to left ventricular ejection fraction.

The aim of the present study was to determine whether the risk of mortality associated with the concentration of soluble ST2 (sST2) differs in patients with acutely decompensated heart failure with preserved ejection fraction (HFpEF) compared to patients with systolic heart failure. We prospectively enrolled 447 patients with acutely decompensated heart failure. Blood samples were collected at presentation to determine the sST2 concentration. HFpEF was defined as symptoms or signs of acutely decompensated heart failure and left ventricular ejection fraction of ≥50% on the echocardiogram. The patients were followed up for 1 year, and the vital status was obtained for all. The sST2 concentrations were greater in the patients with systolic heart failure (n = 250) than in those with HFpEF (n = 197) at 0.55 versus 0.38 ng/ml (p <0.001). Receiver operating characteristic curve analyses showed different cutoff point values for sST2 for the prediction of 1-year mortality in patients with HFpEF (>0.35 ng/ml) and systolic heart failure (>0.56 mg//ml). These cutoff points had similar prognostic accuracy (area under the curve of 0.69 vs 0.73; p >0.05). In the adjusted analyses that included amino terminal B-type natriuretic peptide concentrations, elevated sST2 concentrations were associated with a greater mortality risk in both populations (HFpEF, per ng/ml, hazard ratio 1.41, 95% confidence interval 1.14 to 1.76, p = 0.002; and systolic heart failure, per ng/ml, hazard ratio 1.20, 95% confidence interval 1.10 to 1.32, p <0.001). The determination of the sST2 concentration improved the clinical risk prediction compared to amino terminal B-type natriuretic peptide, as assessed by both the improved C-statistic and an improvement in the net reclassification index and integrated discrimination improvement analyses. In conclusion, in the present multicenter study, sST2 concentrations were lower in patients with HfpEF; however, sST2 remained an independent predictor of mortality, regardless of the left ventricular ejection fraction.

The HAS-BLED Score Has Better Prediction Accuracy for Major Bleeding Than CHADS2 or CHA2DS2-VASc Scores in Anticoagulated Patients With Atrial Fibrillation

OBJECTIVES The aim of this study was to test the hypothesis that a specific bleeding risk score, HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly), was better at predicting major bleeding compared with CHADS2 (congestive heart failure, hypertension, 75 years of age or older, diabetes mellitus, and previous stroke or transient ischemic attack) and CHA2DS2-VASc (congestive heart failure, hypertension, 75 years of age and older, diabetes mellitus, previous stroke or transient ischemic attack, vascular disease, 65 to 74 years of age, female) in anticoagulated atrial fibrillation (AF) patients. BACKGROUND The CHADS2 and CHA2DS2-VASc scores are well-validated stroke risk prediction scores for AF, but are also associated with increased bleeding and mortality. METHODS We recruited 1,370 consecutive AF patients (49% male; median age, 76 years) receiving oral anticoagulation therapy from our outpatient anticoagulation clinic, all of whom were receiving acenocoumarol and had an international normalized ratio between 2.0 and 3.0 during the preceding 6 months. During follow-up, major bleeding events were identified by the 2005 International Society on Thrombosis and Haemostasis criteria. Model performance was evaluated by calculating the C-statistic, and the improvement in predictive accuracy was evaluated by calculating the net reclassification improvement and integrated discrimination improvement. RESULTS After a median follow-up of 996 (range, 802 to 1,254) days, 114 patients (3.0%/year) presented with a major bleeding event; 31 of these events were intracranial hemorrhages (0.8%/year). Based on the C-statistic, HAS-BLED had a model performance superior to that of both CHADS2 and CHA2DS2-VASc (both p < 0.001). Both net reclassification improvement and integrated discrimination improvement analyses also show that HAS-BLED was more accurately associated with major bleeding compared with CHADS2 and CHA2DS2-VASc scores. CONCLUSIONS In anticoagulated AF patients, a validated specific bleeding risk score, HAS-BLED, should be used for assessing major bleeding. The practice of using CHADS2 and CHA2DS2-VASc as a measure of high bleeding risk should be discouraged, given its inferior predictive performance compared with the HAS-BLED score.

Complementary Prognostic Value of Cystatin C, N-Terminal Pro-B-Type Natriuretic Peptide and Cardiac Troponin T in Patients With Acute Heart Failure

The aims of this study were to compare the prognostic value of cystatin C over creatinine and the Modification of Diet in Renal Disease (MDRD) equation and to evaluate whether it provides complementary information to cardiac biomarkers in the risk stratification of an unselected cohort of patients with acute heart failure. Consecutive hospitalized patients with established diagnoses of acute heart failure were prospectively studied. Blood samples were collected on hospital arrival to determine cystatin C, cardiac troponin T, and N-terminal-pro-brain natriuretic peptide. Clinical follow-up was obtained, and the occurrence of mortality and/or heart failure readmission was registered. One hundred thirty-eight patients (median age 74 years, interquartile range 67 to 80; 54% men) were studied. During a median follow-up period of 261 days (interquartile range 161 to 449), 60 patients (43.5%) presented with adverse events. After multivariate adjustment, cystatin C, N-terminal-pro-brain natriuretic peptide, cardiac troponin T, New York Heart Association functional class III or IV, and diabetes mellitus were identified as independent predictors of mortality and/or heart failure readmission. In contrast to creatinine and the MDRD equation, the highest cystatin C tertile (>1.50 mg/L) was a significant independent risk factor for adverse events (hazard ratio 3.08, 95% confidence interval 1.54 to 6.14, p = 0.004). A multimarker approach combining cardiac troponin T, N-terminal-pro-brain natriuretic peptide, and cystatin C improved risk stratification further, showing that patients with 2 (hazard ratio 2.37, 95% confidence interval 1.10 to 5.71) or 3 (hazard ratio 3.64, 95% confidence interval 1.55 to 8.56) elevated biomarkers had a higher risk for adverse events than patients with no elevated biomarkers (p for trend = 0.015). In conclusion, in this unselected cohort, cystatin C was a stronger predictor of adverse events than conventional measures of kidney function. In addition, cystatin C offered complementary prognostic information to cardiac biomarkers and could help clinicians perform more accurate risk stratification of patients with acute heart failure.

Does chronic kidney disease improve the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification risk scores for atrial fibrillation?

Chronic Kidney Disease (CKD) constitutes an adverse risk factor in chronic anticoagulated atrial fibrillation (AF) patients, being related to adverse cardiovascular events, mortality and major bleeds. It is unclear if CKD adds independent prognostic information to stroke risk stratification schemes, as the risk factor components of the CHADS2 and CHA2DS2-VASc scores are themselves related to renal dysfunction. The aim of our study was to determine if CKD independently improves the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification scores in AF. We recruited consecutive patients (n=978) patients (49% male; median age 76) with permanent or paroxysmal AF on oral anticoagulants with acenocoumarol, from our out-patient anticoagulation clinic. After a median follow-up of 875 (IQR 706-1059) days, we recorded stroke/transient ischaemic attack (TIA), peripheral embolism, vascular events (acute coronary syndrome, acute heart failure and cardiac death) and all-cause mortality. During follow-up, 113 patients (4.82%/year) experienced an adverse cardiovascular event, of which 39 (1.66%/year) were strokes, 43 (1.83%/year) had an acute coronary syndrome and 32 (1.37%/year) had acute heart failure. Also, 102 patients (4.35%/year) died during the following up, 31 of them (1.32%/year) as a result of a thrombotic event. Based on c-statistics and the integrated discrimination improvement (IDI), CKD did not improve the prediction for stroke/systemic embolism, thrombotic events and all-cause mortality using the CHADS2 and CHA2DS2-VASc scores. In conclusion, evaluating renal function in AF patients is important as CKD would confer a poor overall prognosis in terms of thromboembolic events and all-cause mortality. Adding CKD to the CHADS2 and CHA2DS2-VASc stroke risk scores did not independently add predictive information.

Renal Impairment in a “Real-Life” Cohort of Anticoagulated Patients With Atrial Fibrillation (Implications for Thromboembolism and Bleeding)

Renal dysfunction is highly prevalent among patients with atrial fibrillation (AF) and confers an increased risk of thrombotic and bleeding complications. We evaluated the effect of renal function on prognosis in anticoagulated patients with AF and assessed the changes in renal function during a long-term follow-up period. We recruited 978 consecutive stable anticoagulated patients with AF from our outpatient anticoagulation clinic (international normalized ratio 2.0 to 3.0 within the previous 6 months). The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease equation at inclusion and 2 years of follow-up. Adverse events were recorded during follow-up (thrombotic/vascular events, major bleeding episodes, and mortality). Longitudinal changes in renal function were analyzed in 886 patients (90.6%). At baseline, the median eGFR using the Modification of Diet in Renal Disease equation was 70.24 ml/min/1.73 m(2) (interquartile range 46.79 to 72.52). During follow-up, a low eGFR was associated with thrombotic/vascular events, with every 30 ml/min/1.73 m(2) eGFR decrease (hazard ratio 1.42, 95% confidence interval [CI] 1.11 to 1.83, p = 0.006), bleeding (hazard ratio 1.44, 95% CI 1.08 to 1.94, p = 0.015), and mortality (hazard ratio 1.47, 95% CI 1.13 to 1.91, p = 0.004). After excluding patients with a baseline eGFR <30 ml/min/1.73 m(2), the mean eGFR in our cohort decreased >10 ml/min/1.73 m(2) in 181 patients (21%) during the follow-up period. The variables associated with severe renal impairment during follow-up were heart failure (odds ratio 3.58, 95% CI 1.36 to 9.42, p = 0.010), basal eGFR (odds ratio 6.34, 95% CI 2.44 to 16.50, p <0.001), and CHADS2 (Congestive heart failure, Hypertension, Age >75 years, Diabetes mellitus, and previous Stroke or transient ischemic attack [doubled]) score (odds ratio 1.63, 95% CI 1.19 to 2.23, p = 0.003). In conclusion, the presence of impaired renal function was closely related to thrombotic/vascular events, bleeding, and mortality in anticoagulated patients with AF. During follow-up, 1/5 of the patients had significant impairment in renal function. Importantly, normal or mild renal dysfunction at baseline did not exclude the subsequent development of severe renal dysfunction during the follow-up period.

β-trace protein and cystatin C as predictors of long-term outcomes in patients with acute heart failure.

OBJECTIVES The purpose of this study was to evaluate the prognostic importance of novel markers of renal dysfunction among patients with acutely destabilized heart failure (ADHF). BACKGROUND β-trace protein (BTP) and cystatin C are newer biomarkers for renal dysfunction; the prognostic importance of these tests, particularly BTP, relative to standard measures of renal function remains unclear. METHODS A total of 220 consecutive hospitalized patients with ADHF were prospectively studied. Blood samples were collected on presentation. In-hospital worsening renal function, as well as mortality and/or heart failure (HF) hospitalization, over a median follow-up period of 500 days was examined as a function of BTP or cystatin C concentrations; results were compared with creatinine, estimated glomerular filtration rate, and blood urea nitrogen. RESULTS Neither BTP nor cystatin C was associated with worsening renal function during the index hospitalization. A total of 116 patients (53%) either died or were hospitalized for HF during follow-up. Those with adverse outcomes had higher BTP (1.04 mg/l [range 0.80 to 1.49 mg/l] vs. 0.88 mg/l [range 0.68 to 1.17 mg/l], p = 0.003) and cystatin C (1.29 mg/l [range 1.00 to 1.71 mg/l] vs. 1.03 mg/l [range 0.86 to 1.43 mg/l], p = 0.001). After multivariable adjustment, both BTP (hazard ratio: 1.41, 95% confidence interval: 1.06 to 1.88; p = 0.018) and cystatin C (hazard ratio: 1.50, 95% confidence interval: 1.13 to 2.01; p = 0.006) were significant predictors of death/HF hospitalization, whereas serum creatinine, estimated glomerular filtration rate, and blood urea nitrogen were no longer significant. In patients with an estimated glomerular filtration rate >60 ml/min/1.73 m(2), elevated concentrations of BTP and cystatin C were still associated with significantly higher risk of adverse clinical events (p < 0.05). Net reclassification index analysis suggested cystatin C and BTP deliver comparable information regarding prognosis. CONCLUSIONS Among patients hospitalized with ADHF, BTP and cystatin C predict risk of death and/or HF hospitalization and are superior to standard measures of renal function for this indication.

Small-size circulating microparticles in acute coronary syndromes: relevance to fibrinolytic status, reparative markers and outcomes.

BACKGROUND Recent evidence suggests that circulating microparticles (MPs) contribute to inflammation, coagulation and vascular injury. Majority of MPs have usually not been included into prior analyses due their small size and limited resolution of conventional equipment. Our aim was to assess levels of MPs of different cellular origin sized below 0.5 μm polystyrene beads, denoted as small-size microparticles (sMP), their relation to markers of cardiovascular repair and their impact on prognosis in patients with acute coronary syndromes (ACS). METHODS In a cross-sectional study, we initially compared levels of sMP between patients with ST-segment elevation myocardial infarction (STEMI, n = 50), non-STEMI (n = 47), stable coronary artery disease (CAD, n = 40) and healthy individuals (HC, n = 40). In a separate study, the prognostic value of sMP was assessed in patients with non-STEMI (n = 160). Annexin V-binding sMP (sAMP), platelet CD42b(+) sMPs (sPMP), endothelial CD144(+) sMP (sEMP) and monocyte CD14(+) sMP (sMMP) were quantified using high resolution flow cytometry. Endothelial progenitor cells (EPCs) and monocyte expression of scavenger receptors was quantified by flow cytometry. Fibrinolytic factors were measured by ELISA. RESULTS Counts of sAMP and sEMP were lower in STEMI after PCI (p < 0.001 and p = 0.025, respectively) but not in non-STEMI vs. CAD. sAMP was positively correlated with EPCs in non-STEMI (p < 0.001). Likewise, plasminogen activators negatively correlated with sAMP in non-STEMI and STEMI (p = 0.02 and p = 0.002, respectively). In non-STEMI patients, sEMP and sMMP were independently predictive for future admissions related to heart failure (p = 0.034 and 0.013, respectively) and sPMP for major bleedings (p = 0.002). The sAMP/EPCs ratio was higher in patients (before PCI) compared to STEMI patients. CONCLUSIONS Small-size MPs could be potentially implicated in the modulation of the post-ACS reparative response to injury, with prognostic implications. Besides, the sAMP/EPCs ratio could reflect a change in the apoptotic/reparative potential, being a putative indicator for vascular repair.

Should We Recommend Oral Anticoagulation Therapy in Patients With Atrial Fibrillation Undergoing Coronary Artery Stenting With a High HAS-BLED Bleeding Risk Score?

Background— Recent European guidelines for the management of atrial fibrillation recommend oral anticoagulation (OAC) in patients with CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥75 years, diabetes, history of previous stroke, vascular disease, age 65–74 years, and sex category [female]) ≥1. The HAS-BLED score (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly [>65 years], Drugs/alcohol concomitantly) has been suggested to assess bleeding risk in patients with atrial fibrillation (score ≥3 indicates high risk of bleeding). Despite the guidelines, this approach has never been tested in a cohort of patients with atrial fibrillation undergoing percutaneous coronary intervention with stent implantation. Methods and Results— We studied 590 consecutive patients with atrial fibrillation undergoing percutaneous coronary intervention/stenting and CHA2DS2-VASC score >1 (ie, OAC recommended). We compared patients with low-intermediate bleeding risk (HAS-BLED 0–2) and high risk (HAS-BLED ≥3), the relation between CHA2DS2-VASC and HAS-BLED, and the benefit and risks of the use of OAC in patients with high bleeding risk. The development of any bleeding episode, thromboembolism, mortality, cardiac events, and the composite major adverse cardiac events (ie, death, acute myocardial infarction, and/or target lesion revascularization) end point was recorded as well as the composite major adverse events (ie, major adverse cardiac events, major bleeding, or thromboembolism) end point at 1-year follow-up. Of the study cohort, 420 (71%) had a HAS-BLED score ≥3, and patients who were on OAC at discharge had lower mortality rate (9.3% versus 20.1%; P<0.01) and major adverse cardiac events (13.0% versus 26.4%; P<0.01) but with a similar major adverse event (20.5% versus 27.6%; P=0.11) and higher major bleeding rate (11.8% versus 4.0%; P<0.01). In a Cox multivariable analysis in patients with HAS-BLED ≥3, predictors of increased death were chronic renal failure and heart failure (both P<0.05), whereas OAC at discharge was associated with a reduced death rate (P<0.01). Predictors of major bleeding were chronic renal failure and the use of drug-eluting stents (both P<0.05). Conclusions— Most patients with atrial fibrillation undergoing percutaneous coronary intervention/stenting have a high risk for major bleeding (HAS-BLED score ≥3). Even in these patients, OAC improves prognosis in these patients (reduced mortality and major adverse cardiac events) with an increase in major bleeding.