A comparative study of human and zebrafish glucocorticoid receptor activities of natural and pharmaceutical steroids.

Introduction: The action of environmental steroids on the human glucocorticoid receptor (hGR) has been pointed out with the risk to impair physiological immune and metabolic processes regulated by this nuclear receptor. However, there is still a lack of mechanistic information regarding their ability to interact with GR in aquatic species. Methods: To investigate ligand activation differences between hGR and zebrafish GR (zfGR), we tested several natural and synthetic steroids using reporter cell lines expressing hGR or zfGR. Results and discussion: Almost all the glucocorticoids tested (dexamethasone, cortisol, bimedrazol, medrol, cortivazol and fluticasone) are agonists of the two receptors with similar potencies. The dissociated glucocorticoids, RU24782 and RU24858 are agonists of both zfGR and hGR but with a better potency for the latter. On the other hand, the synthetic glucocorticoid forbimenol and the mineralocorticoid aldosterone are agonist on hGR but antagonist on zfGR. The other steroids tested, androgens and progestins, are all antagonists of both GRs with equal or lower potency on zfGR than on hGR. Surprisingly, the lower efficacy and potency on zfGR of aldosterone, forbimenol and the dissociated glucocorticoids is not related to their affinity for the receptors which would suggest that it could be related to less efficacious recruitment of coactivators by zfGR compared to hGR.

Rationale and design of COLchicine On-admission to Reduce inflammation in Acute Coronary Syndrome (COLOR-ACS) study.

AIMS: The aim of the colchicine on-admission to reduce inflammation in acute coronary syndrome (COLOR-ACS) study is to evaluate the effects of the addition of short-term, low-dose colchicine to high-dose atorvastatin in limiting levels of inflammatory markers, such as high-sensitivity C-reactive protein (hs-CRP), in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS: The COLOR-ACS study is a multicenter, randomized, open-label, two-arm trial. Statin-naive patients with NSTE-ACS, scheduled for an early invasive strategy, are randomized on admission to receive standard treatment of atorvastatin 80 mg or standard treatment plus colchicine (1 mg loading dose followed by 0.5 mg/day until discharge). The main exclusion criteria are prior statin and/or colchicine treatment, current treatment with potent inhibitors of CYP3A4, P-glycoprotein or immunosuppressive drugs, known active malignancy, severe kidney, cardiac, liver disease. There is clinical and biochemical follow-up at 30 days after discharge and telephone interview at 6 months. The primary end point is the change in hs-CRP from admission to discharge. Secondary end points include: incidence of acute kidney injury; MB fraction of creatine kinase peak value; glomerular filtration rate change from baseline to 30 days; persistence of hs-CRP ≥2 mg/dl at 30 days; adverse clinical events within 30 days; tolerance to colchicine. CONCLUSION: The COLOR-ACS study will provide evidence on the efficacy of early short-term treatment with colchicine in addition to high-dose atorvastatin compared to atorvastatin alone in ACS patients. The potential anti-inflammatory action of colchicine plus atorvastatin is expected to limit hs-CRP increase with resultant clinical benefits. TRIAL REGISTRATION: ClinicalTrials.gov; NCT05250596.

Impact of hemoglobin levels at admission on outcomes among elderly patients with acute coronary syndrome treated with low-dose Prasugrel or clopidogrel: A sub-study of the ELDERLY ACS 2 trial.

Hemoglobin (Hb) levels have emerged as a useful tool for risk stratification and the prediction of outcome after myocardial infarction. We aimed at evaluating the prognostic impact of this parameter among patients in advanced age, where the larger prevalence of anemia and the higher rate of comorbidities could directly impact on the cardiovascular risk. METHODS: All the patients in the ELDERLY-2 trial, were included in this analysis and stratified according to the values of hemoglobin at admission. The primary endpoint of this study was cardiovascular mortality within one year. The secondary endpoints were all-cause mortality, MI, Bleeding Academic Research Consortium (BARC) type 2-3 or 5 bleeding, any stroke, re-hospitalization for cardiovascular event or stent thrombosis (probable or definite) within 12 months after index admission. RESULTS: We included in our analysis 1364 patients, divided in quartiles of Hb values (<12.2; 12.2-13.39; 13.44-14.49; ≥ 4.5 g/dl). At a mean follow- up of 330.4 ± 99.9 days cardiovascular mortality was increased in patients with lower Hb (HR[95%CI] = 0.76 [0.59-0.97], p = 0.03). Results were no more significant after correction for baseline differences (adjusted HR[95%CI] = 1.22 [0.41-3.6], p = 0.16). Similar results were observed for overall mortality. At subgroup analysis, (according to Hb median values) a significant interaction was observed only with the type of antiplatelet therapy, but not with major high-risk subsets of patients. CONCLUSIONS: Among elderly patients with acute coronary syndrome managed invasively, lower hemoglobin at admission is associated with higher cardiovascular and all-cause mortality and major ischemic events, mainly explained by the higher risk profile.

Association of statin pretreatment with presentation characteristics, infarct size and outcome in older patients with acute coronary syndrome: the Elderly ACS-2 trial.

BACKGROUND: prior statin treatment has been shown to have favourable effects on short- and long-term prognosis in patients with acute coronary syndrome (ACS). There are limited data in older patients. The aim of this study was to investigate the association of previous statin therapy and presentation characteristics, infarct size and clinical outcome in older patients, with or without atherosclerotic cardiovascular disease (ASCVD), included in the Elderly-ACS 2 trial. METHODS: data on statin use pre-admission were available for 1,192 of the 1,443 patients enrolled in the original trial. Of these, 531 (44.5%) were already taking statins. Patients were stratified based on established ASCVD and statin therapy. ACS was classified as non-ST elevation or ST elevation myocardial infarction (STEMI). Infarct size was measured by peak creatine kinase MB (CK-MB). All-cause death in-hospital and within 1 year were the major end points. RESULTS: there was a significantly lower frequency of STEMI in statin patients, in both ASCVD and No-ASCVD groups. Peak CK-MB levels were lower in statin users (10 versus 25 ng/ml, P < 0.0001). There was lower all-cause death in-hospital and within 1 year for subjects with ASCVD already on statins independent of other baseline variables. There were no differences in all-cause death for No-ASCVD patients whether or not on statins. CONCLUSIONS: statin pretreatment was associated with more favourable ACS presentation and lower myocardial damage in older ACS patients both ASCVD and No-ASCVD. The incidence of all-cause death (in-hospital and within 1 year) was significantly lower in the statin treated ASCVD patients.

Prognostic value of natriuretic peptides and restrictive filling pattern before surgical ventricular restoration.

OBJECTIVE: Both increased natriuretic peptide levels and restrictive filling pattern (RFP) are important risk predictors in patients with heart failure. The aim of this study was to examine the role of the combined use of natriuretic peptide and RFP for the prognostic stratification of patients with ischemic cardiomyopathy undergoing surgical ventricular restoration in the Biomarker Plus study. METHODS: A total of 186 patients (aged 64 ± 10 years) underwent echocardiographic study and N-terminal pro-B-type natriuretic peptide assay at baseline (before surgical ventricular restoration). Patients were divided into 4 groups depending on baseline diastolic filling pattern (RFP/no RFP) and N-terminal pro-B-type natriuretic peptide level (less than or greater than or equal to the upper tertile value of 2003 ŋg/L). RFP was defined as E/A ratio ≥2. All-cause death or heart failure hospitalizations within 36-month follow-up were analyzed. RESULTS: Despite similar ejection fraction, volumes, and mass, the 4 groups presented distinct clinical and structural pattern of presurgical ventricular restoration ventricular remodeling and significantly different clinical outcome after surgical unloading. During follow-up, 67 patients died or were hospitalized for heart failure (36%). High N-terminal pro-B-type natriuretic peptide levels and RFP, considered individually, were significantly associated with outcome (P < .0001). The combination of both was associated with the highest adjusted hazard of adverse events (hazard ratio, 3.63; 95% CI, 1.73-7.6; P < .0001). CONCLUSIONS: The simultaneous use of 2 markers, 1 biological and 1 echocardiographic, may allow better prognostic stratification and characterization of the distinct structural and clinical phenotypes in a population of patients with ischemic cardiomyopathy undergoing surgical ventricular restoration. This approach could be useful in the decision-making process to guide treatment choices in patients with ischemic cardiomyopathy.

Oestrogenic Activity in Girls with Signs of Precocious Puberty as Exposure Biomarker to Endocrine Disrupting Chemicals: A Pilot Study.

The relationship between endocrine disrupting chemical (EDC) exposure and Precocious Puberty (PP) was investigated in this pilot study, involving girls with signs of PP (P) and pre-pubertal girls (C). Risk factors for PP were assessed through questionnaires, while 17ß-oestradiol (E2) levels and oestrogenic activity were quantified on sera. The oestrogenic activity, expressed as E2 equivalent concentration (EEQ), was applied as EDC exposure biomarker. Questionnaires showed a low EDC knowledge, a high EDC exposure, and a potential relationship between some habits at risk for EDC exposure and PP. EEQs were similar between C and P; however, they were significantly higher in girls living in an urban environment than in girls living in a rural environment, suggesting a potential higher EDC exposure in cities. The results of this pilot study highlighted the need to raise awareness on EDCs and can be considered a starting point to clarify the relationship between EDC exposure and PP.

Tailored Versus Standard Hydration to Prevent Acute Kidney Injury After Percutaneous Coronary Intervention: Network Meta-Analysis.

Background Contrast-induced acute kidney injury (CI-AKI) is a serious complication after percutaneous coronary intervention. The mainstay of CI-AKI prevention is represented by intravenous hydration. Tailoring infusion rate to patient volume status has emerged as advantageous over fixed infusion-rate hydration strategies. Methods and Results A systematic review and network meta-analysis with a frequentist approach were conducted. A total of 8 randomized controlled trials comprising 2312 patients comparing fixed versus tailored hydration strategies to prevent CI-AKI after percutaneous coronary intervention were included in the final analysis. Tailored hydration strategies included urine flow rate-guided, central venous pressure-guided, left ventricular end-diastolic pressure-guided, and bioimpedance vector analysis-guided hydration. Primary endpoint was CI-AKI incidence. Safety endpoint was incidence of pulmonary edema. Urine flow rate-guided and central venous pressure-guided hydration were associated with a lower incidence of CI-AKI compared with fixed-rate hydration (odds ratio [OR], 0.32 [95% CI, 0.19-0.54] and OR, 0.45 [95% CI, 0.21-0.97]). No significant difference in pulmonary edema incidence was observed between the different hydration strategies. P score analysis showed that urine flow rate-guided hydration is advantageous in terms of both CI-AKI prevention and pulmonary edema incidence when compared with other approaches. Conclusions Currently available hydration strategies tailored on patients' volume status appear to offer an advantage over guideline-supported fixed-rate hydration for CI-AKI prevention after percutaneous coronary intervention. Current evidence suggests that urine flow rate-guided hydration as the most convenient strategy in terms of effectiveness and safety.

Restrictive filling pattern in ischemic cardiomyopathy: Insights after surgical ventricular restoration.

OBJECTIVE: To examine factors possibly involved in the resolution or persistence of restrictive filling pattern (RFP) after surgical ventricular restoration (SVR) in a series of patients with ischemic cardiomyopathy (ICM) and RFP. METHODS: Echocardiography was performed at baseline (pre-SVR), discharge, and follow-up in 43 patients with ICM and RFP (E/A ratio ≥2). Patients were divided into 2 groups based on E/A ratio at discharge: improved (E/A ratio <2; 22 patients) and unchanged (E/A ratio ≥2; 21 patients). RESULTS: The improved group had a significantly increased mean deceleration time (from 137 ± 22 ms to 194 ± 68 ms; P = .002) and mean A wave velocity (from 43 ± 10 cm/s to 92 ± 37 cm/s; P = .001), and decreased E/e' ratio (from 27.7 ± 9.5 to 19.2 ± 7.8; P = .01) after SVR. The unchanged group did not show any significant variations in diastolic parameters. The only significant differences at baseline between the two groups were thinner left ventricle posterior wall and lower relative wall thickness (RWT) in the unchanged group. RWT was the sole baseline parameter independently associated with persistent RFP. CONCLUSIONS: RFP was reversed after SVR in 22 of our 43 patients with ICM with a response that remained stable over time, associated with improved New York Heart Association class. RWT was the sole baseline echocardiographic parameter significantly associated with the evolution of RFP after SVR.

Estrogenic activity of biological samples as a biomarker.

Biological assays can evaluate the cumulative effect of a mixture, considering synergistic/antagonistic interactions and effects of unknown/unconsidered compounds. Therefore, their application could increase in the next years also to analyse biological samples. The aim of this review is to discuss the methodological approach and the application of estrogenic activity assays in human biological samples. 75 research articles were analysed and divided according to whether they used these assays: i) to quantify the level of estrogens and/or as a biomarker of estrogenic status ii) as a biomarker of exposure to endocrine disrupting chemicals (EDCs). For the first purpose, some authors extracted biological samples while others tested them directly without any treatment. The study of these methodologies outlined that the methodology applied influenced the specificity of analysis. The estrogenic activity biomarker was used to analyse physiological variations of estrogens, pediatric diseases, hormone-dependent diseases and estrogen suppression/enhancement after pharmaceutical treatments. For the second purpose, some authors extracted samples while others tested them directly, some authors divided endogenous estrogens from xenoestrogens while others tested samples without separation. The analysis of these methodologies outlined some limitations related to the efficiency of extraction and the incorrect separation of some compounds. The studies which applied this EDC biomarker showed that it was correlated with some EDCs, it varied according to the exposure of the population and it allowed the identification of some relationships between EDC exposure and breast cancer, type 1 diabetes and adverse health effects on children. In conclusion, the estrogenic activity of biological samples can be a useful tool: to quantify low levels of 17ß-estradiol, to assess the combined effect of endogenous estrogens and xenoestrogens, to estimate the estrogenic status providing considerable insight into physiological or pathological conditions, to evaluate EDC presence implementing the existing knowledge about EDC exposure and adverse health effects.

Residual SYNTAX Score and One-Year Outcome in Elderly Patients With Acute Coronary Syndrome.

BACKGROUND: The residual burden of coronary artery disease after percutaneous coronary intervention (PCI) has been associated with worse ischemic outcome. However, data are conflicting in elderly patients. The aim of our study was to verify the incremental value of the residual Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) score (rSS) over clinical variables and baseline SYNTAX score (bSS) in predicting 1-year mortality or cardiovascular events. METHODS: A post hoc analysis of data collected in the Elderly-ACS 2 multicenter randomized trial was performed. We included 630 patients aged > 75 years with multivessel coronary disease undergoing PCI for acute coronary syndrome (ACS). The primary outcome was a composite of death, recurrent myocardial infarction, and stroke at 1-year follow up. Change in c-statistic and standardized net benefit were used to evaluate the incremental value of the rSS. RESULTS: Event rates were significantly higher in patients with incomplete revascularization (rSS > 8). When the rSS was included in a core Cox regression model containing age, previous myocardial infarction, and ACS type, the hazard ratio for patients with score values > 8 was 2.47 (95% confidence interval, 1.51-4.06). However, the core model with rSS did not increase the c-statistic compared with the core model with the bSS (from 0.69 to 0.70) and gave little incremental value in the standardized net benefit. CONCLUSIONS: In elderly patients with ACS with multivessel disease undergoing PCI, incomplete revascularization was associated with worse outcome at 1-year follow-up. However, there was no clear incremental value of the rSS in the prediction of 1-year adverse outcome compared with a model including clinical variables and bSS.

CONTEXTE: Le fardeau résiduel de la coronaropathie après une intervention coronarienne percutanée (ICP) a été associé à de moins bons résultats sur le plan ischémique. Les données recueillies chez les patients âgés sont toutefois contradictoires. Cette étude avait donc pour objectif de valider la valeur ajoutée du score SYNTAX (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery) résiduel (SSr) par rapport aux paramètres cliniques et au score SYNTAX initial (SSi) pour prédire la mortalité à 1 an et les manifestations cardiovasculaires. MÉTHODOLOGIE: Une analyse a posteriori des données de l'étude multicentrique avec répartition aléatoire Elderly-ACS 2 a été effectuée. Pour ce faire, 630 patients âgés de plus de 75 ans, atteints d'une coronaropathie multitronculaire et ayant subi une ICP pour traiter un syndrome coronarien aigu (SCA) ont été retenus. Le critère d'évaluation principal était composé du décès, de l'infarctus du myocarde récurrent et de l'accident vasculaire cérébral (AVC) au moment du suivi à 1 an. La variation de la statistique C et le bénéfice net normalisé ont servi à évaluer la valeur ajoutée du SSr. RÉSULTATS: Les manifestations étaient significativement plus fréquentes chez les patients dont la revascularisation était incomplète (SSr > 8). Lorsque le SSr a été pris en compte dans un modèle de régression de Cox de base ayant pour facteurs l'âge, les antécédents d'infarctus du myocarde et le type de SCA, le rapport des risques instantanés pour les patients ayant un score > 8 était de 2,47 (intervalle de confiance à 95 % : 1,51-4,06). L'intégration du SSr dans le modèle de base n'a toutefois pas donné lieu à une statistique C plus élevée que celle du SSi (0,70 vs 0,69) et conférait peu de valeur ajoutée sur le plan du bénéfice net normalisé. CONCLUSIONS: Chez les patients âgés présentant un SCA et une atteinte multitronculaire, et subissant une ICP, la revascularisation incomplète a été associée à de moins bons résultats au moment du suivi à 1 an. Le SSr n'a toutefois pas été clairement associé à une valeur ajoutée pour prédire une issue défavorable à 1 an comparativement à un modèle reposant sur des paramètres cliniques et le SSi.

Impact of diabetes on clinical outcome among elderly patients with acute coronary syndrome treated with percutaneous coronary intervention: insights from the ELDERLY ACS 2 trial.

BACKGROUND: Despite recent improvements in percutaneous coronary revascularization and antithrombotic therapies for the treatment of acute coronary syndromes, the outcome is still unsatisfactory in high-risk patients, such as the elderly and patients with diabetes. The aim of the current study was to investigate the prognostic impact of diabetes on clinical outcome among patients included in the Elderly-ACS 2 trial, a randomized, open-label, blinded endpoint study carried out at 32 centers in Italy. METHODS: Our population is represented by 1443 patients included in the Elderly-ACS 2 trial. Diabetes was defined as known history of diabetes at admission. The primary endpoint of this analysis was cardiovascular mortality, while secondary endpoints were all-cause death, recurrent myocardial infarction, Bleeding Academic Research Consortium type 2 or 3 bleeding, and rehospitalization for cardiovascular event or stent thrombosis within 12 months after index admission. RESULTS: Diabetes was present in 419 (29%) out of 1443 patients. Diabetic status was significantly associated with major cardiovascular risk factors and history of previous coronary disease, presentation with non-ST segment elevation myocardial infarction (P = 0.01) more extensive coronary disease (P = 0.02), more advanced Killip class at presentation (P = 0.003), use at admission of statins (P = 0.004) and diuretics at discharge (P < 0.001). Median follow-up was 367 days (interquartile range: 337-378 days). Diabetic status was associated with an absolute increase in the rate of cardiovascular mortality as compared with patients without diabetes [5.5 vs. 3.3%, hazard ratio (HR) 1.7 (0.99-2.8), P = 0.054], particularly among those treated with clopidogrel [HR (95% confidence interval (CI)) = 1.89 (0.93-3.87), P = 0.08]. However, this difference disappeared after correction for baseline differences [Adjusted HR (95% CI) 1.1(0.4-2.9), P = 0.86]. Similar findings were observed for other secondary endpoints, except for bleeding complications, significantly more frequent in diabetic patients [HR (95% CI) 2.02 (1.14-3.6), P = 0.02; adjusted HR (95% CI) = 2.1 (1.01-4.3), P = 0.05]. No significant interaction was observed between type of dual antiplatelet therapy, diabetic status and outcome. CONCLUSION: Among elderly patients with acute coronary syndromes, diabetic status was associated with higher rates of comorbidities, more severe cardiovascular risk profile and major bleeding complications fully accounting for the absolute increase in mortality. In fact, diabetes mellitus did not emerge as an independent predictor of survival in advanced age.

A Prospective, Randomized, Open-Label Trial of Atorvastatin versus Rosuvastatin in the Prevention of Contrast-Induced Acute Kidney Injury, Worsened Renal Function at 30 Days, and Clinical Events After Acute Coronary Angiography: the PRATO-ACS-2 Study.

BACKGROUND/AIMS: Both high-dose atorvastatin and rosuvastatin have been shown to reduce contrast-induced acute kidney injury (AKI) occurrence and improve clinical outcomes in high-risk coronary patients undergoing angiographic procedures. However, there is a lack of head-to-head comparative studies on the effects of atorvastatin or rosuvastatin administered upon hospital admission in statin-naive patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS). METHODS: In this open-label, noninferiority study, we compared changes in renal function in 709 NSTE-ACS patients randomized to atorvastatin (80 mg upon admission followed by 40 mg/day) or rosuvastatin (40 mg upon admission followed by 20 mg/day). The primary end point was AKI (increase in serum creatinine ≥0.5 mg/dL or ≥25% above baseline within 72 h). Worsening renal function (WRF) (decrease of ≥25% in the glomerular filtration rate from baseline to 30 days), 30-day major adverse cardiovascular events, and 12-month myocardial infarction (MI) or death were also evaluated. RESULTS: The AKI incidence was similar in the 2 groups (i.e., 8.2% with rosuvastatin and 7.6% with atorvastatin; absolute risk difference = 0.54; 90% CI -3.9 to 2.8), satisfying the noninferiority criteria. WRF occurred in 53 (7.5%) patients, 19 (34%) of whom had developed AKI. The rates of WRF and adverse events at 30 days and at 12 months did not differ significantly between the 2 groups. Both AKI and WRF were found to be closely associated with the 12-month cardiovascular outcome irrespectively of statin choice. CONCLUSIONS: High-dose rosuvastatin or atorvastatin started upon hospital admission led to similar rates of AKI, 30-day renal function changes, and 12-month death or MI in NSTE-ACS patients who underwent an early invasive strategy (clinical trial registration: https://www.clinicaltrials.gov; unique identifier: NCT01870804).

Impact of renal dysfunction and acute kidney injury on outcome in elderly patients with acute coronary syndrome undergoing percutaneous coronary intervention.

BACKGROUND: Chronic kidney disease is common in patients admitted with acute coronary syndrome and its prevalence dramatically increases with age. Understanding the determinants of adverse outcomes in this extremely high-risk population may be useful for the development of specific treatment strategies and planning of secondary prevention modalities. AIM: The aim of this study was to assess the impact of baseline renal function and acute kidney injury on one-year outcome of elderly patients with acute coronary syndrome treated with percutaneous coronary intervention. METHODS: Patients aged 75 years and older with acute coronary syndrome undergoing successful percutaneous coronary intervention were selected among those enrolled in three Italian multicentre studies. Based on the baseline estimated glomerular filtration rate (eGFR) calculated using the Cockcroft-Gault formula ([(140-age) × body weight × 0.85 if female]/(72 × serum creatinine)* 1.73 m2 of body surface area), patients were classified as having none or mild (eGFR ≥60 ml/min/1.73 m2), moderate (eGFR 30-59 ml/min/1.73 m2) or severe (eGFR <30 ml/min/1.73 m2) renal dysfunction. Acute kidney injury was defined according to the Acute Kidney Injury Network classification. All-cause and cardiovascular mortality, non-fatal myocardial infarction, rehospitalisation for cardiovascular causes, stroke and type 2, 3 and 5 Bleeding Academic Research Consortium bleedings were analysed up to 12 months. RESULTS: A total of 1904 patients were included. Of these, 57% had moderate and 11% severe renal dysfunction. At 12 months, patients with renal dysfunction had higher rates (P < 0.001) of all-cause (4.5%, 7.5% and 17.8% in patients with none or mild, moderate and severe renal dysfunction, respectively) and cardiovascular mortality (2.8%, 5.2% and 10.2%, respectively). After multivariable adjustment, severe renal dysfunction was associated with a higher risk of all-cause (hazard ratio (HR) 2.86, 95% confidence interval (CI) 1.52-5.37, P = 0.001) and cardiovascular death (HR 3.11, 95% CI 1.41-6.83, P = 0.005), whereas non-fatal events were unaffected. Acute kidney injury incidence was significantly higher in ST-elevation myocardial infarction versus non-ST-elevation acute coronary syndrome patients (11.7% vs. 7.8%, P = 0.036) and in those with reduced baseline renal function (P < 0.001), and it was associated with increased mortality independently from baseline renal function and clinical presentation. CONCLUSIONS: Baseline renal dysfunction is highly prevalent and is associated with higher mortality in elderly acute coronary syndrome patients undergoing percutaneous coronary intervention. Acute kidney injury occurs more frequently among ST-elevation myocardial infarction patients and those with pre-existing renal dysfunction and is independently associated with one-year mortality.

Pharmacologic Prophylaxis of Contrast-Induced Nephropathy.

Different pharmacologic agents have been tested in the effort to prevent contrast-induced acute kidney injury (AKI) in the last two decades. To date, however, no individual drug has received unanimous approval for this aim. Since 2014 statins have been included as preventive treatment in the European guidelines for revascularization procedures in cardiac patients. The present update presents the latest findings in this field focusing on the changing paradigms in the definition and consequently the approach to nephroprotection that considers clinical prognosis as the major issue. We note the current shift from attention to contrast-induced AKI to contrast-associated AKI.

Impact of body mass index on clinical outcome among elderly patients with acute coronary syndrome treated with percutaneous coronary intervention: Insights from the ELDERLY ACS 2 trial.

BACKGROUND AND AIM: Elderly patients are at increased risk of hemorrhagic and thrombotic complications after an acute coronary syndrome (ACS). Frailty, comorbidities and low body weight have emerged as conditioning the prognostic impact of dual antiplatelet therapy (DAPT). The aim of the present study was to investigate the prognostic impact of body mass index (BMI) on clinical outcome among patients included in the Elderly-ACS 2 trial, a randomized, open-label, blinded endpoint study comparing low-dose (5 mg) prasugrel vs clopidogrel among elderly patients with ACS. METHODS AND RESULTS: Our population is represented by 1408 patients enrolled in the Elderly-ACS 2 trial. BMI was calculated at admission. The primary endpoint of this analysis was cardiovascular (CV) mortality. Secondary endpoints were all-cause death, recurrent MI, Bleeding Academic Research Consortium (BARC) type 2 or 3 bleeding, and re-hospitalization for cardiovascular reasons or stent thrombosis within 12 months after index admission. Patients were grouped according to median values of BMI (

Impact of renal dysfunction and acute kidney injury on outcome in elderly patients with acute coronary syndrome undergoing percutaneous coronary intervention.

BACKGROUND: Chronic kidney disease is common in patients admitted with acute coronary syndrome and its prevalence dramatically increases with age. Understanding the determinants of adverse outcomes in this extremely high-risk population may be useful for the development of specific treatment strategies and planning of secondary prevention modalities. AIM: The aim of this study was to assess the impact of baseline renal function and acute kidney injury on one-year outcome of elderly patients with acute coronary syndrome treated with percutaneous coronary intervention. METHODS: Patients aged 75 years and older with acute coronary syndrome undergoing successful percutaneous coronary intervention were selected among those enrolled in three Italian multicentre studies. Based on the baseline estimated glomerular filtration rate (eGFR) calculated using the Cockcroft-Gault formula ([(140-age) × body weight × 0.85 if female]/(72 × serum creatinine)* 1.73 m2 of body surface area), patients were classified as having none or mild (eGFR ≥60 ml/min/1.73 m2), moderate (eGFR 30-59 ml/min/1.73 m2) or severe (eGFR <30 ml/min/1.73 m2) renal dysfunction. Acute kidney injury was defined according to the Acute Kidney Injury Network classification. All-cause and cardiovascular mortality, non-fatal myocardial infarction, rehospitalisation for cardiovascular causes, stroke and type 2, 3 and 5 Bleeding Academic Research Consortium bleedings were analysed up to 12 months. RESULTS: A total of 1904 patients were included. Of these, 57% had moderate and 11% severe renal dysfunction. At 12 months, patients with renal dysfunction had higher rates (P < 0.001) of all-cause (4.5%, 7.5% and 17.8% in patients with none or mild, moderate and severe renal dysfunction, respectively) and cardiovascular mortality (2.8%, 5.2% and 10.2%, respectively). After multivariable adjustment, severe renal dysfunction was associated with a higher risk of all-cause (hazard ratio (HR) 2.86, 95% confidence interval (CI) 1.52-5.37, P = 0.001) and cardiovascular death (HR 3.11, 95% CI 1.41-6.83, P = 0.005), whereas non-fatal events were unaffected. Acute kidney injury incidence was significantly higher in ST-elevation myocardial infarction versus non-ST-elevation acute coronary syndrome patients (11.7% vs. 7.8%, P = 0.036) and in those with reduced baseline renal function (P < 0.001), and it was associated with increased mortality independently from baseline renal function and clinical presentation. CONCLUSIONS: Baseline renal dysfunction is highly prevalent and is associated with higher mortality in elderly acute coronary syndrome patients undergoing percutaneous coronary intervention. Acute kidney injury occurs more frequently among ST-elevation myocardial infarction patients and those with pre-existing renal dysfunction and is independently associated with one-year mortality.

Time Course of Ischemic and Bleeding Burden in Elderly Patients With Acute Coronary Syndromes Randomized to Low-Dose Prasugrel or Clopidogrel.

Background Elderly patients have high ischemic and bleeding rates after acute coronary syndrome; however, the occurrence of these complications over time has never been studied. This study sought to characterize average daily ischemic rates ( ADIRs ) and average daily bleeding rates ( ADBRs ) over 1 year in patients aged >74 years with acute coronary syndrome undergoing percutaneous coronary intervention who were randomized in the Elderly ACS 2 trial, comparing low-dose prasugrel (5 mg daily) with clopidogrel (75 mg daily). Methods and Results ADIRs and ADBRs were calculated as the total number of events, including recurrent events, divided by the number of patient-days of follow-up and assessed within different clinical phases: acute (0-3 days), subacute (4-30 days), and late (31-365 days). Generalized estimating equations were used to test the least squares mean differences for the pairwise comparisons of ADIRs and ADBRs and the pairwise comparison of clopidogrel versus prasugrel effects. Globally, ADIRs were 2.6 times (95% CI, 2.4-2.9) higher than ADBRs . ADIRs were significantly higher in the clopidogrel arm than in the low-dose prasugrel arm in the subacute phase ( Padj<0.001) without a difference in ADBRs ( Padj=0.35). In the late phase, ADIRs remained significantly higher with clopidogrel ( Padj<0.001), whereas ADBRs were significantly higher with low-dose prasugrel ( Padj<0.001). Conclusions Ischemic burden was greater than bleeding burden in all clinical phases of 1-year follow-up of elderly patients with acute coronary syndrome treated with percutaneous coronary intervention. Low-dose prasugrel reduced ischemic events in the subacute and chronic phases compared with clopidogrel, whereas bleeding burden was lower with clopidogrel in the late phase. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01777503.

Outcomes of Elderly Patients with ST-Elevation or Non-ST-Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.

INTRODUCTION: Acute coronary syndromes (ACS) have been classified according to the finding of ST-segment elevation on the presenting electrocardiogram, with different treatment strategies and practice guidelines. However, a comparative description of the clinical characteristics and outcomes of acute coronary syndrome elderly patients undergoing percutaneous coronary intervention during index admission has not been published so far. METHODS: Retrospective cohort study of patients enrolled in the Elderly ACS-2 multicenter randomized trial. Main outcome measures were crude cumulative incidence and cause-specific hazard ratio (cHR) of cardiovascular death, noncardiovascular death, reinfarction, and stroke. RESULTS: Of 1443 ACS patients aged >75 years (median age 80 years, interquartile range 77-84), 41% were classified as ST-elevation myocardial infarction (STEMI), and 59% had non-ST-elevation ACS (NSTEACS) (48% NSTEMI and 11% unstable angina). As compared with those with NSTEACS, STEMI patients had more favorable baseline risk factors, fewer prior cardiovascular events, and less severe coronary disease, but lower ejection fraction (45% vs 50%, P < .001). At a median follow-up of 12 months, 51 (8.6%) STEMI patients had died, vs 39 (4.6%) NSTEACS patients. After adjusting for sex, age, and previous myocardial infarction, the hazard among the STEMI group was significantly higher for cardiovascular death (cHR 1.85; 95% confidence interval [CI], 1.02-3.36), noncardiovascular death (cHR 2.10; 95% CI, 1.01-4.38), and stroke (cHR 4.8; 95% CI, 1.7-13.7). CONCLUSIONS: Despite more favorable baseline characteristics, elderly STEMI patients have worse survival and a higher risk of stroke compared with NSTEACS patients after percutaneous coronary intervention.

Bioimpedance-Guided Hydration for the Prevention of Contrast-Induced Kidney Injury: The HYDRA Study.

BACKGROUND: Intravascular volume expansion plays a major role in the prevention of contrast-induced acute kidney injury (CI-AKI). Recommended standard amounts of fluid infusion before procedures do not produce homogeneous responses in subjects with different initial hydration status. OBJECTIVES: The goal of this study was to compare the effect of standard and double intravenous (IV) infusion volumes in patients with low body fluid level, assessed by using bioimpedance vector analysis (BIVA), on the incidence of CI-AKI after elective coronary angiographic procedures. METHODS: A total of 303 patients with low BIVA level on admission were randomized to receive standard volume saline (1 ml/kg/h for 12 h before and after the procedure) or double volume saline (2 ml/kg/h). Patients (n = 715) with an optimal BIVA level received standard volume saline and were included in a prospective registry. The saline infusion was halved in all patients with an ejection fraction <40%. BIVA was repeated immediately before the angiographic procedure in all patients. CI-AKI was defined as an increase in levels of cystatin C ≥10% above baseline at 24 h after contrast administration. RESULTS: The incidence of CI-AKI was significantly lower (11.5% vs. 22.3%; p = 0.015) in patients receiving double volume saline than in those receiving standard volume saline, respectively. Before the angiographic procedure, 50% of the double volume patients achieved the optimal BIVA level compared with only 27.7% in the standard group (p = 0.0001). The findings were consistent in all the pre-specified subgroups excluding patients with a left ventricular ejection fraction <40% (p for interaction = 0.01). CONCLUSIONS: Evaluation of BIVA levels on admission in patients with stable coronary artery disease allows adjustment of intravascular volume expansion, resulting in lower CI-AKI occurrence after angiographic procedures. (Personalized Versus Standard Hydration for Prevention of CI-AKI: A Randomized Trial With Bioimpedance Analysis; NCT02225431).