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Abstract Background Novel circulating biomarkers may help in understanding the underlying mechanisms of atrial fibrillation (AF), a challenge for AF management and prevention of cardiovascular (CV) events. Whether glycosylation affects the prognostic value of N-terminal pro-B type natriuretic peptide (NT-proBNP) in AF is still unknown. Objectives To test how deglycosylated total NT-proBNP, NT-proBNP and a panel of biomarkers are associated with: (1) recurrent AF, (2) first hospitalization for CV reasons. Methods A total of 382 patients of the GISSI-AF trial in sinus rhythm with a history of AF, echocardiographic variables, total NT-proBNP, NT-proBNP and nine additional biomarkers [Total N-terminal pro-B type natriuretic peptide (Total NT proBNP), N-terminal pro-B type natriuretic peptide (NTproBNP), Angiopoietin 2 (Ang2), Bone morphogenic protein-10 (BMP10), Dickkopf-related protein-3 (DKK3), Endothelial cell specific molecule-1 (ESM1), Fatty acid-binding protein 3 (FABP3), Fibroblast growth factor 23 (FGF23), Growth differentiation factor-15 (GDF15), Insulin-like growth factor-binding protein-7 (IGFBP7) and Myosin binding protein C3 (MYPBC3)]. were assayed at baseline, 6 and 12 months under blind conditions in a laboratory at Roche Diagnostics, Penzberg, Germany. The associations between circulating biomarkers and AF at the 6- and 12-month visits, and their predictive value, were assessed in multivariable models with logistic regression analysis and Cox proportional hazards regression analysis. Biomarkers associations were modelled for 1SD increase in their level. Results Over a median follow-up of 365 days, 203/382 patients (53.1%) had at least one recurrence of AF and 16.3% were hospitalized for CV reasons. Total NT-proBNP, NT-proBNP, Ang2 and BMP10 showed the strongest associations with ongoing AF. Natriuretic peptides also predicted recurrent AF (total NT-proBNP: HR:1.19[1.04–1.36], p = 0.026; NT-proBNP: HR:1.19[1.06–1.35], p = 0.016; Ang2: HR:1.07[0.95–1.20], p = 0.283; BMP10: HR:1.09[0.96–1.25], p = 0.249) and CV hospitalization (total NT-proBNP: HR:1.57[1.29–1.90], p

Studies of adverse drug events (ADEs) are important in order not to jeopardize the positive impact of pharmacotherapy. These events have substantial impact on the population morbidity profiles, and increasing health system operating costs. Administrative databases are an important source of information for public health purposes and for identifying ADEs. In order to contribute to learning about ADE in hospitalized patients, this study examined the potential of applying ICD-10 (10th revision of the International Classification of Diseases) codes to a national database of the public health care system (SIH-SUS). The study comprised retrospective assessment of ADEs in the SIH-SUS administrative database, from 2008 to 2012. For this, a list of ICD-10 codes relating to ADEs was built. This list was built up by examining lists drawn up by other authors identified by bibliographic search in the MEDLINE and LILACS and consultations with experts. In Brazil, 55,604,537 hospital admissions were recorded in the SIH-SUS, between 2008 and 2012, of which 273,440 (0.49%) were related to at least one ADE. The proportions and rates seem to hold constant over the study period. Fourteen out of 20 most frequent ADEs were identified in codes relating to mental disorders. Intoxications figure as the second most frequently recorded group of ADEs in the SIH-SUS, comprising 76,866 hospitalizations. Monitoring of ADEs in administrative databases using ICD-10 codes is feasible, even in countries with information systems under construction, and can be an innovative tool to complement drug surveillance strategies in place in Brazil, as well as in others countries.

BackgroundThe independent prognostic impact of diabetes mellitus (DM) and prediabetes mellitus (pre‐DM) on survival outcomes in patients with chronic heart failure has been investigated in observational registries and randomized, clinical trials, but the results have been often inconclusive or conflicting. We examined the independent prognostic impact of DM and pre‐DM on survival outcomes in the GISSI‐HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca‐Heart Failure) trial. Methods and ResultsWe assessed the risk of all‐cause death and the composite of all‐cause death or cardiovascular hospitalization over a median follow‐up period of 3.9 years among the 6935 chronic heart failure participants of the GISSI‐HF trial, who were stratified by presence of DM (n=2852), pre‐DM (n=2013), and non‐DM (n=2070) at baseline. Compared with non‐DM patients, those with DM had remarkably higher incidence rates of all‐cause death (34.5% versus 24.6%) and the composite end point (63.6% versus 54.7%). Conversely, both event rates were similar between non‐DM patients and those with pre‐DM. Cox regression analysis showed that DM, but not pre‐DM, was associated with an increased risk of all‐cause death (adjusted hazard ratio, 1.43; 95% CI, 1.28–1.60) and of the composite end point (adjusted hazard ratio, 1.23; 95% CI, 1.13–1.32), independently of established risk factors. In the DM subgroup, higher hemoglobin A1c was also independently associated with increased risk of both study outcomes (all‐cause death: adjusted hazard ratio, 1.21; 95% CI, 1.02–1.43; and composite end point: adjusted hazard ratio, 1.14; 95% CI, 1.01–1.29, respectively). ConclusionsPresence of DM was independently associated with poor long‐term survival outcomes in patients with chronic heart failure. Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00336336.

The increased risks of death and adverse events with erythropoiesis-stimulating agent (ESA) therapy targeting a higher hemoglobin level are established. It is uncertain whether the adverse effects of ESA therapy are related to dose and are mitigated when a fixed low ESA dose is used. We conducted a multicenter, prospective randomized open-label, blinded-endpoint (PROBE) trial to evaluate fixed low versus high dose ESA therapy on patient outcomes. We intended to recruit 2104 hemodialysis patients >18 years with anemia or receiving ESA treated at dialysis clinics in Italy. The intervention was fixed low (4000 IU epoetin alfa equivalent weekly) or high (18,000 IU epoetin alfa equivalent weekly) dose ESA for 12 months. Primary outcomes were serum transferrin, ferritin, albumin, C-reactive protein and ESA dose. Secondary outcomes were the composite of death or cardiovascular event, all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, cardiovascular hospitalization, and quality of life. Study recruitment was terminated after inclusion of 656 participants with convergence of ESA dose between groups during follow up. Fixed low dose ESA had uncertain effects on serum ferritin (delta of delta (DD) 3.9 ng/ml, 95% CI -85.0 to 92.8), transferrin (9.2 mg/dl, -6.3 to 24.8), transferrin saturation (3.7%, -5.0 to 12.3), serum albumin (-0.03 g/dl, -0.2 to 0.1), or C-reactive protein (-0.6 mg/l, -3.3 to 2.1). In addition, fixed dose therapy had inconclusive effects on the composite endpoint of mortality and cardiovascular events (hazard ratio [HR] 0.95, 95% CI 0.66 to 1.37), death (0.98, 0.64 to 1.52), nonfatal myocardial infarction (0.52, 0.18 to 1.52), nonfatal stroke (no events), hospital admission for cardiovascular causes (0.93, 0.50 to 1.72) or health-related quality of life. A fixed low ESA dose in hemodialysis patients has uncertain effects on serum parameters, mortality, cardiovascular events, and quality of life. Hemoglobin targets may be so entrenched in nephrology practice that a trial of ESA dose is no longer possible.

BACKGROUND:The widely recognized clinical and epidemiological relevance of the socioeconomic determinants of health-disease conditions is expected to be specifically critical in terms of chronic diseases in fragile populations in low-income countries. However, in the literature, there is a substantial gap between the attention directed towards the medical components of these problems and the actual adoption of strategies aimed at providing solutions for the associated socioeconomic determinants, especially in pediatric populations. We report a prospective outcome study on the independent contribution and reciprocal interaction of the medical and socioeconomic factors to the hard end-point of mortality in a cohort of children with chronic kidney disease in Nicaragua. METHODS AND FINDINGS:Every child (n = 309) diagnosed with chronic kidney disease (CKD) and referred to the tertiary unit of Pediatric Nephrology in Managua (Nicaragua) from a network of nine hospitals serving 80% of the country's pediatric population was registered between January 2005 and December 2013. The three main socioeconomic determinants evaluated were family income, living conditions and the family's level of education. Further potential determinants of the outcomes included duration of exposure to disease, CKD stage at the first visit as suggested by the KDOQI guidelines in children, the time it took the patients to reach the reference centre and rural or urban context of life. Well-defined and systematically collected medical and socioeconomic data were available for 257 children over a mean follow-up period of 2.5±2.5 years. Mortality and lost to follow-up were considered as outcome end-points both independently and in combination, because of the inevitably progressive nature of the disease. A high proportion (55%) of children presented in the advanced stages of CKD (CKD stage IV and V) at the first visit. At the end of follow-up, 145 (57%) of the 257 cohort children were alive, 47 (18%) were lost to follow-up and 65 (25%) had died. Cox regression analysis showed an independent contribution to mortality of CKD stage at diagnosis and of level of education, with overlapping HR values (HR and 95%CI: 2.66; 1.93-3.66 and 2.72; 1.71-4.33, respectively). CONCLUSIONS:The unfavourable socioeconomic and cultural background of the pediatric study cohort and the severity of kidney damage at diagnosis were the key determinants of the clinical risk conditions at baseline and of the mortality outcome. Long-term structural interventions on such backgrounds must be adopted to assure effectiveness of medical care and to assure an earlier diagnosis of CKD in these patients. The translation-extension of our results is currently underway with an agenda which includes: 1) better integration of chronic pediatric conditions into primary care strategies to promote prevention and early timely referral; 2) the consideration of socioeconomic conditions as a mandatory component of the packages of best-care; 3) the formulation and flexible adaptation of guidelines and educational programs, based on the information generated by a context-specific, epidemiological monitoring of needs and outcomes, guaranteed by an effective database.

OBJECTIVE:to develop and validate the Drug Derived Complexity Index (DDCI), a predictive model derived from drug prescriptions able to stratify the general population according to the risk of death, unplanned hospital admission, and readmission, and to compare the new predictive index with the Charlson Comorbidity Index (CCI). DESIGN:Population-based cohort study, using a record-linkage analysis of prescription databases, hospital discharge records, and the civil registry. The predictive model was developed based on prescription patterns indicative of chronic diseases, using a random sample of 50% of the population. Multivariate Cox proportional hazards regression was used to assess weights of different prescription patterns and drug classes. The predictive properties of the DDCI were confirmed in the validation cohort, represented by the other half of the population. The performance of DDCI was compared to the CCI in terms of calibration, discrimination and reclassification. SETTING:6 local health authorities with 2.0 million citizens aged 40 years or above. RESULTS:One year and overall mortality rates, unplanned hospitalization rates and hospital readmission rates progressively increased with increasing DDCI score. In the overall population, the model including age, gender and DDCI showed a high performance. DDCI predicted 1-year mortality, overall mortality and unplanned hospitalization with an accuracy of 0.851, 0.835, and 0.584, respectively. If compared to CCI, DDCI showed discrimination and reclassification properties very similar to the CCI, and improved prediction when used in combination with the CCI. CONCLUSIONS AND RELEVANCE:DDCI is a reliable prognostic index, able to stratify the entire population into homogeneous risk groups. DDCI can represent an useful tool for risk-adjustment, policy planning, and the identification of patients needing a focused approach in everyday practice.

Daria Roccatagliata1, Fausto Avanzini1, Lara Monesi1, Vittorio Caimi2, Davide Lauri1, Paolo Longoni3, Roberto Marchioli4, Massimo Tombesi2, Gianni Tognoni1, Maria Carla Roncaglioni1, on behalf of the Collaborative Group Risk and Prevention Study*1Istituto di Ricerche Farmacologiche “Mario Negri”, Milano, Italy; 2CSeRMEG Centro Studi e Ricerca in Medicina Generale, Monza, Italy; 3CoS Consorzio Sanità, Milano, Italy; 4Consorzio Mario Negri Sud, S. Maria Imbaro, Italy *A full list of investigators is reported in the AppendixObjectives: To assess the pharmacological treatment and the control of major modifiable cardiovascular risk factors in everyday practice according to the patients’ cardiovascular risk level.Methods: In a cross-sectional study general practitioners (GPs) had to identify a random sample of their patients with cardiovascular risk factors or diseases and collect essential data on the pharmacological treatment and control of hypertension, hyperlipidemia, and diabetes according to the patients’ cardiovascular risk level and history of cardiovascular disease. Participants were subjects of both sexes, aged 40–80 years, with at least one known cardiovascular risk factor or a history of cardiovascular diseases.Results: From June to December 2000, 162 Italian GPs enrolled 3120 of their patients (2470 hypertensives, 1373 hyperlipidemics, and 604 diabetics). Despite the positive association between the perceived level of global cardiovascular risk and lipid-lowering drug prescriptions in hyperlipidemic subjects (from 26% for lowest risk to 56% for highest risk p < 0.0001) or the prescription of combination therapy in hypertensives (from 41% to 70%, p < 0.0001) and diabetics (from 24% to 43%, p = 0.057), control was still inadequate in 48% of diabetics, 77% of hypertensives, and 85% of hyperlipidemics, with no increase in patients at highest risk. Trends for treatment and control were similar in patients with cardiovascular diseases.Conclusions: Even in high-risk patients, despite a tendency towards more intensive treatment, pharmacological therapy is still under used and the degree of control of blood pressure, cholesterol level and diabetes is largely unsatisfactory.Keywords: global cardiovascular risk, hypertension, hyperlipideamia, diabetes, general practice.

BACKGROUND: Combined treatment (CT) with statins and polyunsaturated fatty acids (n-3 PUFA) resulted in a reduction of death and major cardiovascular events when administered after a myocardial infarction (MI). However, recent data suggests that CT may be ineffective because patients are currently treated aggressively and the risk may not be further decreased. We aimed to study the prevalence and the results on major outcomes with CT among patients discharged with a MI in Italy. METHODOLOGY/PRINCIPAL FINDINGS: Retrospective cohort study that used linked hospital discharge, prescription databases and vital statistics containing information on 14,704 patients who were discharged for MI between 1/2003 and 12/2003 in 117 hospitals in Italy. All analyses were time-dependent and adjusted for major confounders. Sensibility and paired matched analysis were conducted to further verify main results. A total of 11,532 (78.4%) filled a prescription for a statin. Of these, 4302 (37.3%) were on CT. There were 45,528 patients/years of follow-up. As compared with statins alone, CT was associated with an adjusted higher survival rate (HR = 0.59 [0.52-0.66], p

The systematic use of aspirin and statins in patients with diabetes and no previous cardiovascular events is controversial. We sought to assess the effects of aspirin and statins on the thrombotic risk assessed by thrombin generation (TG) among patients with type II diabetes mellitus and no previous cardiovascular events.Prospective, randomized, open, blinded to events evaluation, controlled, 2×2 factorial clinical trial including 30 patients randomly allocated to aspirin 100 mg/d, atorvastatin 40 mg/d, both or none. Outcome measurements included changes in TG levels after treatment (8 to 10 weeks), assessed by a calibrated automated thrombogram. At baseline all groups had similar clinical and biochemical profiles, including TG levels. There was no interaction between aspirin and atorvastatin. Atorvastatin significantly reduced TG measured as peak TG with saline (85.09±55.34 nmol vs 153.26±75.55 nmol for atorvastatin and control groups, respectively; p = 0.018). On the other hand, aspirin had no effect on TG (121.51±81.83 nmol vs 116.85±67.66 nmol, for aspirin and control groups, respectively; p = 0.716). The effects of treatments on measurements of TG using other agonists were consistent.While waiting for data from ongoing large clinical randomized trials to definitively outline the role of aspirin in primary prevention, our study shows that among diabetic patients without previous vascular events, statins but not aspirin reduce thrombotic risk assessed by TG.ClinicalTrials.gov NCT00793754.

Coronary artery disease (CAD) is a leading cause of death world-wide, and most cases have a complex, multifactorial aetiology that includes a substantial heritable component. Identification of new genes involved in CAD may inform pathogenesis and provide new therapeutic targets. The PROCARDIS study recruited 2,658 affected sibling pairs (ASPs) with onset of CAD before age 66 y from four European countries to map susceptibility loci for CAD. ASPs were defined as having CAD phenotype if both had CAD, or myocardial infarction (MI) phenotype if both had a MI. In a first study, involving a genome-wide linkage screen, tentative loci were mapped to Chromosomes 3 and 11 with the CAD phenotype (1,464 ASPs), and to Chromosome 17 with the MI phenotype (739 ASPs). In a second study, these loci were examined with a dense panel of grid-tightening markers in an independent set of families (1,194 CAD and 344 MI ASPs). This replication study showed a significant result on Chromosome 17 (MI phenotype; p = 0.009 after adjustment for three independent replication tests). An exclusion analysis suggests that further genes of effect size lambda(sib) > 1.24 are unlikely to exist in these populations of European ancestry. To our knowledge, this is the first genome-wide linkage analysis to map, and replicate, a CAD locus. The region on Chromosome 17 provides a compelling target within which to identify novel genes underlying CAD. Understanding the genetic aetiology of CAD may lead to novel preventative and/or therapeutic strategies.

The problem of missing values has increasingly being recognized in epidemiology. New methods allow for the analysis of missing data that can provide valid estimates of epidemiological quantities of interest. The GISSI-Prevenzione study was aimed to reliably assess the long-term relationship between the consumption of foods typical of the Mediterranean diet and the risk of mortality amongst 11,323 Italians with prior myocardial infarction. Food intake frequencies were recorded repeatedly over the 4.5 years of follow-up and missing values affected each food variable at increasing rates over the course of the study. Comparisons were made between the results obtained from the analysis of the complete data and those obtained after imputing the missing data with simple imputation methods and with various implementations of the multiple imputation (MI) method. MI appeared to best address the issue of missing data on the food intake frequencies, preserving the observed distributions and relationships between variables whilst producing plausible estimates of variability. Given its theoretical properties and flexibility to different types of data, MI is more likely to provide valid estimates, compared to complete data analysis and imputation by simple methods, and is thus worthy of wider consideration amongst epidemiological researchers. [ABSTRACT FROM AUTHOR]