Cost Effectiveness of Anticoagulation in Acute Coronary Syndromes

Background: The benefit of unfractionated heparin (UFH) added to aspirin in patients with acute coronary syndromes (ACS) was described more than 20 years ago. Ever since, a wide variety of anticoagulant drugs have become available for clinical use, including low-molecular-weight heparins (LMWH), direct thrombin inhibitors and selective factor Xa inhibitors. Objective: The aim of this study was to critically review the available evidence on the cost and incremental cost effectiveness of anticoagulants in patients with ACS. Methods: Studies were identified using specialist databases (UK NHS Economic Evaluation Database [NHS EED] and Cost-Effectiveness Analysis [CEA] Registry), PubMed and the reference lists of recovered articles. Only studies based on randomized controlled trials were considered for inclusion. Finally, 22 studies were included in the review. Results: Enoxaparin is the only LMWH that has been shown to reduce the risk of death or myocardial infarction in patients with non-ST-elevation ACS (NSTE-ACS). In economic studies based on the ESSENCE trial conducted in the late 1990s, enoxaparin was consistently associated with a lower risk of coronary events, a reduction in the number of revascularization procedures and a lower cost per patient than UFH. However, these results refer to patients managed conservatively, with little use of thienopyridines and glycoprotein IIb/IIIa inhibitors, and the results are difficult to extrapolate to moderate-to-high-risk patients managed with the present day early invasive strategy. Available studies of LMWH in ACS with persistent elevation of ST-segment (STE-ACS) are limited to patients treated with thrombolysis. In this scenario, enoxaparin was shown to be a dominant alternative compared with UFH in a study based on the ASSENT-3 study and was considered an economically attractive alternative in three studies based on the ExTRACT-TIMI 25 study. However, these results should be interpreted cautiously due to the heterogeneity of the supportive randomized trials and the possible underestimation of bleeding costs. The effectiveness and safety of bivalirudin, a direct thrombin inhibitor, were evaluated in the ACUITY study (NSTE-ACS patients managed invasively) and the HORIZONS-AMI study (STE acute myocardial infarction patients planned for primary percutaneous coronary intervention). Bivalirudin monotherapy was not inferior to heparin plus a glycoprotein IIb/IIIa inhibitor and reduced the risk of major bleeding. The economic evaluations based on these studies suggest that bivalirudin is an attractive alternative to heparin plus a glycoprotein-IIb/IIIa inhibitor. In the OASIS-5 trial, compared with enoxaparin, fondaparinux reduced the mortality in patients with NSTE-ACS, probably because of a reduced risk of bleeding. In three economic evaluations of fondaparinux versus enoxaparin based on this trial, fondaparinux was the dominant strategy in two of them, and still economically attractive in a third. Taken as a whole, the usefulness of economic studies of anticoagulants in patients with ACS is undermined by the quality of the evidence about their effectiveness and safety; the narrow spectrum of the analysed scenarios; the lack of economic evaluations based on systematic reviews; the limitations of sensitivity analyses reported by the available economic evaluations; and their substantial risk of commercial bias. Conclusions: The available studies suggest that enoxaparin is an economically attractive alternative compared with UFH in patients with NSTE-ACS treated conservatively and STE-ACS patients treated with thrombolysis. Bivalirudin in patients with ACS treated invasively is cost effective compared with heparin plus a glycoprotein IIb/IIIa inhibitor. In patients with NSTE-ACS, fondaparinux is cost effective compared with enoxaparin. The usefulness of these results for decision making in contemporary clinical practice is limited due to problems of internal and external validity

GRACE Score Validation in Predicting Hospital Mortality: Analysis of the Role of Sex

Background: The GRACE (Global Registry of Acute Coronary Events) risk score is recommended for risk stratification in acute coronary syndrome (ACS). It does not include sex, a variable strongly associated with ACS prognosis. The aim of this study was to examine if sex adds prognostic information to the GRACE score in a contemporary population. Materials and Methods: Analysis of discrimination and calibration of GRACE score in the validation population, derived from the ARIAM-SEMICYUC registry (2012-2015). Outcome was hospital mortality. The uniformity of fit of the score was tested in predefined subpopulations: with and without ST-segment elevation myocardial infarction (STEMI and NSTEMI). Results: A total of 9781 patients were included: 4598 with NSTEMI (28% women) and 5183 with STEMI (23% women). Discriminative capacity of the GRACE score was significantly lower in women with STEMI compared to men (area under the receiver operating characteristic curve [AUC] 0.82, 95% CI 0.78-0.86 vs. AUC 0.90, 95% CI 0.88-0.92, p = 0.0006). In multivariate analysis, female sex predicted hospital mortality independently of GRACE in STEMI (p = 0.019) but not in NSTEMI (p = 0.356) (interaction p = 0.0308). However, neither the AUC nor the net reclassification index (NRI) improved by including female sex in the STEMI subpopulation (NRI 0.0011, 95% CI -0.023 to 0.025; p = 0.928). Conclusions: Although female sex was an independent predictor of hospital mortality in the STEMI subpopulation, it does not substantially improve the discriminative ability of GRACE score

Accessibility to Reperfusion Therapy Among Women with Acute Myocardial Infarction: Impact on Hospital Mortality

Background: The available evidence about the effect of gender and/or sex on mortality differences is contradictory. Our aim is to assess the impact of gender on the access to reperfusion therapy in patients with acute coronary syndrome with ST-segment elevation (STEMI), and secondly, to analyze the effect of delay on the differences with regard to hospital mortality. Methods: A retrospective cohort study was conducted among consecutive patients with STEMI included in the ARIAM-SEMICYUC registry (2010-2013).Results: A total of 4816 patients were included (22.09% women). Women were older, presented with longer patient delay (90 vs. 75 minutes, p=0.0066), higher risk profile (GRACE>140: 75.1% vs. 56.05%, p<0.0001), and received less reperfusion therapy (68.8% vs. 74.7%, p<0.0001) with longer total reperfusion time (307 vs. 240 minutes, p<0.0001). Women received less thrombolysis (24.53% vs. 29.98%, p<0.0001) and longer door-to-needle time (85 vs. 70 minutes, p 0.0023). We found no differences regarding primary percutaneous coronary intervention or door-to-balloon time. Women also had higher hospital mortality (crude odds ratio 2.54, 95% confidence interval 1.99-3.26, p<0.0001), which persisted after controlling the effect of patient delay, age, risk (GRACE), and reperfusion (adjusted odds ratio 1.43, 95% confidence interval 1.0-2.06, p=0.0492). Using TIMI or Killip risk scores as risk estimates yielded nonsignificant results.Conclusions: Compared with men, women with STEMI have worse access to reperfusion and higher hospital mortality. The impact of the differences in accessibility on mortality gap remains uncertain

Clinical presentation of acute coronary syndrome in patients previously treated with nitrates

Aims: Several reports have suggested that nitrates limit acute ischaemic damage by a mechanism similar to preconditioning. This study aims to evaluate the effect of chronic oral nitrates on the clinical presentation and short-term outcomes of patients admitted with acute coronary syndrome (ACS).Methods: A retrospective cohort study was conducted in patients with ACS admitted to 62 acute care units from 2010 to 2011. A propensity score-matched samples analysis was performed.Results: We analysed 3171 consecutive patients, of whom 298 (9.4%) were chronically treated with nitrates. Patients previously treated with nitrates had higher comorbidity and disease severity at admission, lower prevalence of ACS with ST elevation, lower troponin elevation, higher prevalence of initial Killip class 2-4 and higher hospital mortality. The propensity score-matched analysis confirmed that previous use of nitrates is independently associated with a lower prevalence of ST-elevation ACS [odds ratio (OR) 0.53, 95% confidence interval (CI) 0.36-0.78; P = 0.0014] and a lower troponin elevation (OR 0.61, 95% CI 0.41-0.92) but not with Killip class on admission (OR 1.18, 95% CI 0.83-1.67, P = 0.3697) or mortality (OR 0.71, 95% CI 0.37-1.38, P = 0.3196).Conclusion: The results support the hypothesis that nitrates have a protective effect on acute ischaemic injury

Exploring forest structural complexity by multi-scale segmentation of VHR imagery

Forests are complex ecological systems, characterised by multiple-scale structural and dynamical patterns which are not inferable from a system description that spans only a narrow window of resolution; this makes their investigation a difficult task using standard field sampling protocols. We segment a QuickBird image covering a beech forest in an initial stage of old-growthness – showing, accordingly, a good degree of structural complexity – into three segmentation levels. We apply field-based diversity indices of tree size, spacing, species assemblage to quantify structural heterogeneity amongst forest regions delineated by segmentation. The aim of the study is to evaluate, on a statistical basis, the relationships between spectrally delineated image segments and observed spatial heterogeneity in forest structure, including gaps in the outer canopy. Results show that: some 45% of the segments generated at the coarser segmentation scale (level 1) are surrounded by structurally different neighbours; level 2 segments distinguish spatial heterogeneity in forest structure in about 63% of level 1 segments; level 3 image segments detect better canopy gaps, rather than differences in the spatial pattern of the investigated structural indices. Results support also the idea of a mixture of macro and micro structural heterogeneity within the beech forest: large size populations of trees homogeneous for the examined structural indices at the coarser segmentation level, when analysed at a finer scale, are internally heterogeneous; and vice versa. Findings from this study demonstrate that multiresolution segmentation is able to delineate scale-dependent patterns of forest structural heterogeneity, even in an initial stage of old-growth structural differentiation. This tool has therefore a potential to improve the sampling design of field surveys aimed at characterizing forest structural complexity across multiple spatio-temporal scales.L'articolo è disponibile sul sito dell'editore www.sciencedirect.co

Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis

Background: Infections due to antibiotic-resistant bacteria are threatening modern health care. However, estimating their incidence, complications, and attributable mortality is challenging. We aimed to estimate the burden of infections caused by antibiotic-resistant bacteria of public health concern in countries of the EU and European Economic Area (EEA) in 2015, measured in number of cases, attributable deaths, and disability-adjusted life-years (DALYs). Methods: We estimated the incidence of infections with 16 antibiotic resistance–bacterium combinations from European Antimicrobial Resistance Surveillance Network (EARS-Net) 2015 data that was country-corrected for population coverage. We multiplied the number of bloodstream infections (BSIs) by a conversion factor derived from the European Centre for Disease Prevention and Control point prevalence survey of health-care-associated infections in European acute care hospitals in 2011–12 to estimate the number of non-BSIs. We developed disease outcome models for five types of infection on the basis of systematic reviews of the literature. Findings: From EARS-Net data collected between Jan 1, 2015, and Dec 31, 2015, we estimated 671 689 (95% uncertainty interval [UI] 583 148–763 966) infections with antibiotic-resistant bacteria, of which 63·5% (426 277 of 671 689) were associated with health care. These infections accounted for an estimated 33 110 (28 480–38 430) attributable deaths and 874 541 (768 837–989 068) DALYs. The burden for the EU and EEA was highest in infants (aged <1 year) and people aged 65 years or older, had increased since 2007, and was highest in Italy and Greece. Interpretation: Our results present the health burden of five types of infection with antibiotic-resistant bacteria expressed, for the first time, in DALYs. The estimated burden of infections with antibiotic-resistant bacteria in the EU and EEA is substantial compared with that of other infectious diseases, and has increased since 2007. Our burden estimates provide useful information for public health decision-makers prioritising interventions for infectious diseases

Uso de estrategia invasiva precoz en pacientes diabéticos con síndrome coronario agudo sin elevación del ST

Fundamento y objetivos: La estrategia invasiva reduce la mortalidad de los pacientes con síndrome coronario agudo sin elevación del ST (SCASEST) de alto riesgo, entre los que se incluyen los pacientes diabéticos. Sin embargo, diversas publicaciones han puesto de manifiesto una infrautilización de esta estrategia invasiva en estos pacientes. El objetivo de este estudio es conocer las características de los pacientes diabéticos que se tratan de forma conservadora, e identificar determinantes del uso de una u otra estrategia. Paciente y métodos: Estudio de cohortes retrospectivo, realizado en diabéticos con SCASEST incluidos en los cortes anuales de 2010 y 2011 en el registro ARIAM- EMICYUC. Se realizó un análisis bruto y ajustado mediante regresión logística no condicional. Resultados: Se han analizado 531 pacientes diabéticos, de los cuales 264 (49,7%) recibieron estrategia invasiva. Los pacientes diabéticos que se tratan de forma conservadora son un subgrupo caracterizado por su mayor edad y comorbilidad cardiovascular, mayor riesgo hemorrágico y ausencia de electrocardiograma (ECG) de alto riesgo. Se identifican como variables predictoras independientes asociadas al tratamiento conservador, el ECG de bajo riesgo, el Killip al ingreso superior a 1, alto riesgo hemorrágico y el tratamiento previo con clopidogrel. Conclusiones: El temor a las complicaciones hemorrágicas o la presencia de lesiones coronarias avanzadas podrían ser la causa de la infrautilización de la estrategia invasiva en los pacientes diabéticos con SCASEST.Background and objectives: In the management of non-ST-segment elevation acute coronary syndromes (NSTE-ACS), several studies have shown a reduction in mortality with the use of an invasive strategy in high-risk patients, including diabetic patients. Paradoxically, other studies have shown an under-utilization of this invasive strategy in these patients. The aim of this study is to determine the characteristics of patients managed conservatively and identify determinants of the use of invasive or conservative strategy.Patients and methods: Retrospective cohort study conducted in diabetic patients with NSTE-ACS included in the ARIAM-SEMICYUC registry (n=531) in 2010 and 2011. We performed crude and adjusted unconditional logistic regression. Results: We analyzed 531 diabetic patients, 264 (49.7%) of which received invasive strategy. Patients managed conservatively were a subgroup characterized by older age and cardiovascular comorbidity, increased risk of bleeding and the absence of high-risk electrocardiogram (ECG). In diabetic patients with NSTE-ACS, independent predictors associated with conservative strategy were low-risk ECG, initial Killip class>1, high risk of bleeding and pretreatment with clopidogrel.Conclusions: The fear of bleeding complications or advanced coronary lesions could be the cause of the underutilization of an invasive strategy in diabetic patients with NSTE-ACS

Gene Transcription and Splicing of T-Type Channels Are Evolutionarily-Conserved Strategies for Regulating Channel Expression and Gating

T-type calcium channels operate within tightly regulated biophysical constraints for supporting rhythmic firing in the brain, heart and secretory organs of invertebrates and vertebrates. The snail T-type gene, LCav3 from Lymnaea stagnalis, possesses alternative, tandem donor splice sites enabling a choice of a large exon 8b (201 aa) or a short exon 25c (9 aa) in cytoplasmic linkers, similar to mammalian homologs. Inclusion of optional 25c exons in the III–IV linker of T-type channels speeds up kinetics and causes hyperpolarizing shifts in both activation and steady-state inactivation of macroscopic currents. The abundant variant lacking exon 25c is the workhorse of embryonic Cav3 channels, whose high density and right-shifted activation and availability curves are expected to increase pace-making and allow the channels to contribute more significantly to cellular excitation in prenatal tissue. Presence of brain-enriched, optional exon 8b conserved with mammalian Cav3.1 and encompassing the proximal half of the I–II linker, imparts a ∼50% reduction in total and surface-expressed LCav3 channel protein, which accounts for reduced whole-cell calcium currents of +8b variants in HEK cells. Evolutionarily conserved optional exons in cytoplasmic linkers of Cav3 channels regulate expression (exon 8b) and a battery of biophysical properties (exon 25c) for tuning specialized firing patterns in different tissues and throughout development

Predictores del uso de la estrategia invasiva precoz en mujeres con síndrome coronario agudo sin elevación de ST

Objetivo: Identificar los determinantes asociados a la estrategia invasiva precoz (EIP) en mujeres con síndrome coronario agudo sin elevación de ST (SCASEST). Diseño: Estudio de cohortes retrospectivo. Análisis crudo y ajustado de la realización de EIP mediante regresión logística no condicional. Ámbito: Unidades coronarias participantes en 2010-2011 en el registro ARIAM-SEMICYUC. Pacientes: Cuatrocientas cuarenta mujeres con SCASEST. Se excluyeron 16 por datos insuficientes y 58 con coronariografía electiva (> 72 h). Variables analizadas: Demográficas, factores de riesgo coronario, medicación previa, comorbilidad. Características clínicas, analíticas, hemodinámicas y electrocardiográficas del episodio. Resultados: Las mujeres tratadas conservadoramente presentaban mayor edad, mayor prevalencia de anticoagulación oral, diabetes, lesiones coronarias previas e insuficiencia cardiaca (p 80 años y el aumento de la frecuencia cardiaca son factores independientes asociados al tratamiento conservador.To identify determinants associated to an early invasive strategy in women with acute coronary syndromes without ST elevation (NSTE-ACS).Design: A retrospective cohort study was made. Crude and adjusted analysis of the performance of the early invasive strategy using logistic regression.Setting: Coronary Units enrolled in 2010 - 2011 in the ARIAM-SEMICYUC registry.Patients: A total of 440 women with NSTE-ACS were studied. Sixteen patients were excluded due to insufficient data, together with 58 patients subjected to elective coronary angiography (> 72 h).Variables analyzed: Demographic parameters, coronary risk factors, previous medication, comorbidity. Clinical, laboratory, hemodynamic and electrocardiographic data of the episode. Results: Women treated conservatively were of older age, had oral anticoagulation, diabetes, previous coronary lesions, and heart failure (p 80 years (OR 0.48, 95% CI 0.27 to 0.82, p=0.009), known coronary lesions (OR 0.47, 95% CI 0.26-0.84, p=0.011), and heart rate (OR 0.98, 95% CI 0.97-0.99, p=0.003) were independently associated to conservative treatment. Smoking (OR 2.50, 95% CI 1.20 to 5.19, p=0.013) and high-risk electrocardiogram (OR 2.96, 95% CI 1.72 to 4.97, p 80 years and increased heart rate were independent factors associated to conservative treatment

Estrategia invasiva de rutina en el síndrome coronario agudo sin elevación del segmento ST con disfunción renal. Resultados del registro ARIAM-SEMICYUC

Objetivo: Evaluar la utilización y efectividad de la estrategia invasiva de rutina (EIR) en pacientes con síndrome coronario agudo sin elevación de ST con disfunción renal en el mundo real. Métodos: Estudio de cohortes retrospectivo basado en el registro ARIAM-SEMICYUC (años 2011- 2014). Se consideró que había disfunción renal cuando el GFR (Cockroft-Gault) era menor de 60 ml/min (disfunción moderada) o de 30 ml/min (disfunción grave). Se excluyeron los pacientes en los que la coronariografía precoz (< 72 h) se debió a shock cardiogénico o isquemia recurrente. El desenlace primario fue la mortalidad hospitalaria. El control del confounding se realizó mediante un análisis de propensión. Resultados: Se analizan 4.279 pacientes, de los cuales un 26% tenía disfunción renal moderada y un 5% disfunción grave. Los pacientes con disfunción renal presentaron una mayor gravedad y comorbilidad, una mayor mortalidad hospitalaria (8,6 frente a 1,8%) y una menor utilización de la EIR (40 frente a 52%). Las OR ajustadas mediante emparejamiento para pacientes sin/con disfunción renal fueron de 0,38 (intervalo de confianza al 95% [IC95%] de 0,17 a 0,81) y 0,52 (IC95% de 0,32 a 0,87), respectivamente (p de interacción 0,4779). El impacto de la EIR (diferencia de riesgos ajustada) fue mayor en el grupo con disfunción renal (−5,1%, IC95% entre −8,1 y −2,1, frente a −1,6%, IC95% entre −2,6 y −0,6, p de interacción = 0,0335). Tampoco se detectó interacción significativa respecto a los demás enlaces considerados (mortalidad en UCI o a los 30 días, riesgo combinado de muerte o infarto, fracaso renal agudo o hemorragias moderadas/graves). Conclusiones: Los resultados evidencian que la efectividad de la EIR es similar en pacientes con función renal normal o reducida y alertan sobre una infrautilización de esta estrategia en estos últimos.Objective: To evaluate the use and effectiveness of a routine invasive strategy (RIS) in patients with acute coronary syndrome without persistent ST-segment elevation with renal dysfunction in the real world scenario. Methods: A retrospective cohort study based on the ARIAM-SEMICYUC Registry (2011-2014) was carried out. Renal dysfunction was defined as GFR (Cockroft-Gault)<60ml/min (moderate dysfunction) or<30ml/min (severe dysfunction). Patients in which early angiography (<72h) was performed due to cardiogenic shock or recurrent myocardial ischemia were excluded. The primary endpoint was hospital mortality. Confounding factors were controlled using propensity score analysis. Results: A total of 4,279 patients were analyzed, of which 26% had moderate renal dysfunction and 5% severe dysfunction. Patients with renal dysfunction had greater severity and comorbidity, higher hospital mortality (8.6 vs. 1.8%), and lesser use of the RIS (40 vs. 52%). The adjusted OR for mortality in patients without/with renal dysfunction were 0.38 (95% confidence interval [95%CI] 0.17 to 0.81) and 0.52 (95%CI 0.32 to 0.87), respectively (interaction P-value=.4779). The impact (adjusted risk difference) of RIS was higher in the group with renal dysfunction (-5.1%, 95%CI -8.1 to -2.1 vs. -1.6%, 95%CI -2.6 to -0.6; interaction P-value=.0335). No significant interaction was detected for the other endpoints considered (ICU mortality, 30-day mortality, myocardial infarction, acute renal failure or moderate/severe bleeding).Conclusions: The results suggest that the effectiveness of IRS is similar in patients with normal or abnormal renal function, and alert to the under-utilization of this strategy in such patients