Percutaneous Coronary Intervention (PCI) Reprograms Circulating Extracellular Vesicles from ACS Patients Impairing Their Cardio-Protective Properties.

Extracellular vesicles (EVs) are promising therapeutic tools in the treatment of cardiovascular disorders. We have recently shown that EVs from patients with Acute Coronary Syndrome (ACS) undergoing sham pre-conditioning, before percutaneous coronary intervention (PCI) were cardio-protective, while EVs from patients experiencing remote ischemic pre-conditioning (RIPC) failed to induce protection against ischemia/reperfusion Injury (IRI). No data on EVs from ACS patients recovered after PCI are currently available. Therefore, we herein investigated the cardio-protective properties of EVs, collected after PCI from the same patients. EVs recovered from 30 patients randomly assigned (1:1) to RIPC (EV-RIPC) or sham procedures (EV-naive) (NCT02195726) were characterized by TEM, FACS and Western blot analysis and evaluated for their mRNA content. The impact of EVs on hypoxia/reoxygenation damage and IRI, as well as the cardio-protective signaling pathways, were investigated in vitro (HMEC-1 + H9c2 co-culture) and ex vivo (isolated rat heart). Both EV-naive and EV-RIPC failed to drive cardio-protection both in vitro and ex vivo. Consistently, EV treatment failed to activate the canonical cardio-protective pathways. Specifically, PCI reduced the EV-naive Dusp6 mRNA content, found to be crucial for their cardio-protective action, and upregulated some stress- and cell-cycle-related genes in EV-RIPC. We provide the first evidence that in ACS patients, PCI reprograms the EV cargo, impairing EV-naive cardio-protective properties without improving EV-RIPC functional capability.

Comment on Savioli et al. Mild Head Trauma: Is Antiplatelet Therapy a Risk Factor for Hemorrhagic Complications? Medicina 2021, 57, 357.

We read the article of Savioli G. et al. [...].

Ticagrelor versus prasugrel in acute coronary syndrome: sex-specific analysis from the RENAMI Registry.

BACKGROUND: The use of potent P2Y12 inhibitors (ticagrelor & prasugrel) in acute coronary syndrome (ACS) patients undergoing percutaneous coronary interventions (PCI) is a class I recommendation. We performed a sex-specific analysis comparing the difference in efficacy and safety outcomes between ticagrelor and prasugrel in a real-world ACS population. METHODS: Data from the multicenter REgistry of New Antiplatelets in patients with Myocardial Infarction (RENAMI) for 4424 ACS patients who underwent PCI and were treated with ticagrelor or prasugrel between 2012 to 2016 were analyzed. Mean follow-up was 17±9 months. RESULTS: After propensity score matching, there was no significant difference in the occurrence of primary endpoint of net adverse cardiac events between ticagrelor and prasugrel in men (HR: 0.94; 95% CI: 0.69-1.29; P=0.71), or women (HR: 1.17; 95% CI: 0.63-2.20; P=0.62; P interaction [sex] = 0.40). Similarly, no differences were found in the occurrence of any of the secondary endpoints (MACE, all cause death, re-infarction, stent thrombosis, BARC major bleeding and BARC any bleeding) between the two P2Y12 groups between men and women. CONCLUSIONS: In this real-world ACS population, no relative difference in efficacy or safety outcomes were found between ticagrelor and prasugrel between sexes.

Extracellular vesicles from patients with Acute Coronary Syndrome impact on ischemia-reperfusion injury.

The relevance of extracellular vesicles (EV) as mediators of cardiac damage or recovery upon Ischemia Reperfusion Injury (IRI) and Remote Ischemic PreConditioning (RIPC) is controversial. This study aimed to investigate whether serum-derived EV, recovered from patients with Acute Coronary Syndrome (ACS) and subjected to the RIPC or sham procedures, may be a suitable therapeutic approach to prevent IRI during Percutaneous-Coronary-Intervention (PCI). A double-blind, randomized, sham-controlled study (NCT02195726) has been extended, and EV were recovered from 30 patients who were randomly assigned (1:1) to undergo the RIPC- (EV-RIPC) or sham-procedures (EV-naive) before PCI. Patient-derived EV were analyzed by TEM, FACS and western blot. We found that troponin (TnT) was enriched in EV, compared to healthy subjects, regardless of diagnosis. EV-naive induced protection against IRI, both in-vitro and in the rat heart, unlike EV-RIPC. We noticed that EV-naive led to STAT-3 phosphorylation, while EV-RIPC to Erk-1/2 activation in the rat heart. Pre-treatment of the rat heart with specific STAT-3 and Erk-1/2 inhibitors led us to demonstrate that STAT-3 is crucial for EV-naive-mediated protection. In the same model, Erk-1/2 inhibition rescued STAT-3 activation and protection upon EV-RIPC treatment. 84 Human Cardiovascular Disease mRNAs were screened and DUSP6 mRNA was found enriched in patient-derived EV-naive. Indeed, DUSP6 silencing in EV-naive prevented STAT-3 phosphorylation and cardio-protection in the rat heart. This analysis of ACS-patients' EV proved: (i) EV-naive cardio-protective activity and mechanism of action; (ii) the lack of EV-RIPC-mediated cardio-protection; (iii) the properness of the in-vitro assay to predict EV effectiveness in-vivo.

Long versus short dual antiplatelet therapy in acute coronary syndrome patients treated with prasugrel or ticagrelor and coronary revascularization: Insights from the RENAMI registry.

INTRODUCTION: The benefits of short versus long-term dual antiplatelet therapy (DAPT) based on the third generation P2Y12 antagonists prasugrel or ticagrelor, in patients with acute coronary syndromes treated with percutaneous coronary intervention remain to be clearly defined due to current evidences limited to patients treated with clopidogrel. METHODS: All acute coronary syndrome patients from the REgistry of New Antiplatelets in patients with Myocardial Infarction (RENAMI) undergoing percutaneous coronary intervention and treated with aspirin, prasugrel or ticagrelor were stratified according to DAPT duration, that is, shorter than 12 months (D1 group), 12 months (D2 group) and longer than 12 months (D3 group). The three groups were compared before and after propensity score matching. Net adverse clinical events (NACEs), defined as a combination of major adverse cardiac events (MACEs) and major bleedings (including therefore all cause death, myocardial infarction and Bleeding Academic Research Consortium (BARC) 3-5 bleeding), were the primary end points, MACEs (a composite of all cause death and myocardial infarction) the secondary one. Single components of NACEs were co-secondary end points, along with BARC 2-5 bleeding, cardiovascular death and stent thrombosis. RESULTS: A total of 4424 patients from the RENAMI registry with available data on DAPT duration were included in the model. After propensity score matching, 628 patients from each group were selected. After 20 months of follow up, DAPT for 12 months and DAPT for longer than 12 months significantly reduced the risk of NACE (D1 11.6% vs. D2 6.7% vs. D3 7.2%, p = 0.003) and MACE (10% vs. 6.2% vs. 2.4%, p < 0.001) compared with DAPT for less than 12 months. These differences were driven by a reduced risk of all cause death (7.8% vs. 1.3% vs. 1.6%, p < 0.001), cardiovascular death (5.1% vs. 1.0% vs. 1.2%, p < 0.0001) and recurrent myocardial infarction (8.3% vs. 5.2% vs. 3.5%, p = 0.002). NACEs were lower with longer DAPT despite a higher risk of BARC 2-5 bleedings (4.6% vs. 5.7% vs. 6.2%, p = 0.04) and a trend towards a higher risk of BARC 3-5 bleedings (2.4% vs. 3.3% vs. 3.9%, p = 0.06). These results were not consistent for female patients and those older than 75 years old, due to an increased risk of bleedings which exceeded the reduction in myocardial infarction. CONCLUSION: In unselected real world acute coronary syndrome patients treated with percutaneous coronary intervention, DAPT with prasugrel or ticagrelor prolonged beyond 12 months markedly reduces fatal and non-fatal ischaemic events, offsetting the increased risk deriving from the higher bleeding risk. On the contrary, patients >75 years old and female ones showed a less favourable risk-benefit ratio for longer DAPT due to excess of bleedings.

Average daily ischemic versus bleeding risk in patients with ACS undergoing PCI: Insights from the BleeMACS and RENAMI registries.

BACKGROUND: The risk of recurrent ischemia and bleeding after percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) may vary during the first year of follow-up according to clinical presentation, and medical and interventional strategies. METHODS: BleeMACS and RENAMI are 2 multicenter registries enrolling patients with ACS treated with PCI and clopidogrel, prasugrel, or ticagrelor. The average daily ischemic and bleeding risks (ADIR and ADBR) in the first year after PCI were the primary end points. The difference between ADBR and ADIR was calculated to estimate the potential excess of bleeding/ischemic events in a given period or specific subgroup. RESULTS: A total of 19,826 patients were included. Overall, in the first year after PCI, the ADBR was 0.008085%, whereas ADIR was 0.008017% (P = .886). In the first 2 weeks ADIR was higher than ADBR (P = .013), especially in patients with ST-segment elevation myocardial infarction or incomplete revascularization. ADIR continued to be, albeit non-significantly, greater than ADBR up to the third month, whereas ADBR became higher, although not significantly, afterward. Patients with incomplete revascularization had an excess in ischemic risk (P = .003), whereas non-ST-segment elevation ACS patients and those on ticagrelor had an excess of bleeding (P = .012 and P = .022, respectively). CONCLUSIONS: In unselected ACS patients, ADIR and ADBR occurred at similar rates within 1 year after PCI. ADIR was greater than ADBR in the first 2 weeks, especially in ST-segment elevation myocardial infarction patients and those with incomplete revascularization. In the first year, ADIR was higher than ADBR in patients with incomplete revascularization, whereas ADBR was higher in non-ST-segment elevation ACS patients and in those discharged on ticagrelor.

Efficacy and Safety of Clopidogrel, Prasugrel and Ticagrelor in ACS Patients Treated with PCI: A Propensity Score Analysis of the RENAMI and BleeMACS Registries.

INTRODUCTION: Real-life data comparing clopidogrel, prasugrel, and ticagrelor for unselected patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) are lacking, as are data for the temporal distribution of ischemic and bleeding risks. METHODS: A total of 19,825 patients were enrolled from the RENAMI and BleeMACS registries. Both were multicenter, retrospective, observational registries including the data and outcomes of consecutive patients with ACS who underwent primary PCI and were discharged with dual antiplatelet therapy (DAPT). We evaluated the long-term outcome stratified by the different antiplatelet agents. RESULTS: A total of 14,105 patients (71.2%) were treated with clopidogrel, 2364 patients (11.9%) with prasugrel and 3356 patients (16.9%) with ticagrelor. After propensity score matching, at 1 year, prasugrel reduced the incidence of net adverse clinical events (NACE; a composite endpoint of all-cause death, myocardial infarction [MI] and Bleeding Academic Research Consortium [BARC] 3-5 bleeding) (4.2% vs.7.6%, p = 0.002) and of major adverse cardiovascular events (MACE; a composite endpoint of death and MI) compared with clopidogrel (2.6% vs. 5.2%, p = 0.007). Ticagrelor decreased rates of MACE compared with clopidogrel (2.7% vs. 6.2%, p < 0.001), but not of NACE (6.6% vs. 8.7%, p = 0.07). Ticagrelor presented similar performance in terms of MACE compared with prasugrel (2.8% vs. 2.4%, p = 0.56), with a trend towards a reduction in MI (0.2% vs. 0.4%, p = 0.56), but with higher risk of BARC 3-5 bleedings (3.8% vs. 1.7%, p = 0.04). In the daily risk analysis, clopidogrel presented a binomial distribution with a peak of ischemic risk at 3 months, which decreased towards bleedings; prasugrel had a constant equivalence between opposite risks; and ticagrelor constantly reduced recurrent MIs despite higher risk of BARC 3-5 events. CONCLUSION: In real life, ticagrelor is more effective in reducing ischemic events during the first year after ACS, despite an increased risk of major bleedings, while prasugrel assures a better balance between ischemic and bleeding recurrent events.

Comparative external validation of the PRECISE-DAPT and PARIS risk scores in 4424 acute coronary syndrome patients treated with prasugrel or ticagrelor.

BACKGROUND: The PRECISE-DAPT and PARIS risk scores (RSs) were recently developed to help clinicians at individualizing the optimal dual antiplatelet therapy duration (DAPT) after percutaneous coronary intervention (PCI). Nevertheless, external validation of these RSs it has not yet been performed in ACS (acute coronary syndrome) patients treated with prasugrel or ticagrelor in a real- world scenario. METHODS: 4424 ACS patients who underwent PCI and survived to hospital discharge, from January 2012 to December 2016 at 12 European centers, were included. PRECISE-DAPT and PARIS bleeding RS, as well as PARIS ischemic RS, were computed, and their performance at predicting major bleeding (MB; BARC type 3 or 5) and ischemic events (MI and stent thrombosis) during follow up was compared. RESULTS: After a median follow-up of 14 (interquartile range 12-20.9) months, 83 (1.88%) patients developed MB and 133 (3.0%) suffered an ischemic episode. PRECISE-DAPT performed better than PARIS bleeding RS (c-statistic = 0.653 vs. 0.593; p = .01 for comparison) in predicting MB. The RSs performance for MB prediction remained consistent in STEMI patients (c-statistic = 0.632 vs 0.575) or in those treated with prasugrel (c-statistic = 0.623 vs 0.586). PARIS ischemic RS exhibited superior discrimination in predicting ischemic complications compared to PRECISE-DAPT (c-statistic = 0.604 vs 0.568 p = .05 for comparison). CONCLUSION: Our data provide support to the use of PRECISE-DAPT in MB risk stratification for patients receiving DAPT in form of aspirin and prasugrel or ticagrelor whereas the PARIS ischemic RS has potential to complement the risk prediction with respect to ischemic events.

Ischemia Reperfusion Injury: Mechanisms of Damage/Protection and Novel Strategies for Cardiac Recovery/Regeneration.

Ischemic diseases in an aging population pose a heavy social encumbrance. Moreover, current therapeutic approaches, which aimed to prevent or minimize ischemia-induced damage, are associated with relevant costs for healthcare systems. Early reperfusion by primary percutaneous coronary intervention (PPCI) has undoubtedly improved patient's outcomes; however, the prevention of long-term complications is still an unmet need. To face these hurdles and improve patient's outcomes, novel pharmacological and interventional approaches, alone or in combination, reducing myocardium oxygen consumption or supplying blood flow via collateral vessels have been proposed. A number of clinical trials are ongoing to validate their efficacy on patient's outcomes. Alternative options, including stem cell-based therapies, have been evaluated to improve cardiac regeneration and prevent scar formation. However, due to the lack of long-term engraftment, more recently, great attention has been devoted to their paracrine mediators, including exosomes (Exo) and microvesicles (MV). Indeed, Exo and MV are both currently considered to be one of the most promising therapeutic strategies in regenerative medicine. As a matter of fact, MV and Exo that are released from stem cells of different origin have been evaluated for their healing properties in ischemia reperfusion (I/R) settings. Therefore, this review will first summarize mechanisms of cardiac damage and protection after I/R damage to track the paths through which more appropriate interventional and/or molecular-based targeted therapies should be addressed. Moreover, it will provide insights on novel non-invasive/invasive interventional strategies and on Exo-based therapies as a challenge for improving patient's long-term complications. Finally, approaches for improving Exo healing properties, and topics still unsolved to move towards Exo clinical application will be discussed.

Correction to: Real-World Data of Prasugrel vs. Ticagrelor in Acute Myocardial Infarction: Results from the RENAMI Registry.

The first author's name which previously read.

Real-World Data of Prasugrel vs. Ticagrelor in Acute Myocardial Infarction: Results from the RENAMI Registry.

BACKGROUND: Limited data are available concerning differences in clinical outcomes for real-life patients treated with ticagrelor versus prasugrel after percutaneous coronary intervention (PCI). OBJECTIVE: Our objective was to determine and compare the efficacy and safety of ticagrelor and prasugrel in a real-world population. METHODS: RENAMI was a retrospective, observational registry including the data and outcomes of consecutive patients with acute coronary syndrome (ACS) who underwent primary PCI and were discharged with dual antiplatelet therapy (DAPT) between January 2012 and January 2016. The mean follow-up period was 17 ± 9 months. In total, 11 university hospitals from six European countries participated. After propensity-score matching, there were no substantial differences in the baseline clinical and interventional features. All patients were treated with acetylsalicylic acid plus prasugrel 10 mg once daily or acetylsalicylic acid plus ticagrelor 90 mg twice daily. Mean duration of DAPT was 12.04 ± 3.4 months with prasugrel and 11.90 ± 4.1 months with ticagrelor (p = 0.47). The primary and secondary endpoints were long-term net adverse clinical events (NACE) and major adverse cardiovascular events (MACE), respectively, along with their single components. Subgroup analysis for freedom from NACE and MACE was performed according to length of DAPT and clinical presentation [ST-elevation myocardial infarction (STEMI)-ACS versus non-ST-elevation myocardial infarction (NSTEMI)-ACS]. RESULTS: In total, 4424 patients (2725 ticagrelor, 1699 prasugrel) were enrolled. After propensity-score matching, 1290 patients in each cohort were included in the analysis. At 12 months, the incidence of both NACE and MACE was lower with prasugrel (NACE: 5.3% vs. 8.5% [p = 0.001]; MACE: 5% vs. 8.1% [p =  0.001]) mainly driven by a reduction in recurrent myocardial infarction (MI) (2.4 vs. 4.0%; p = 0.029) and a lower rate of Bleeding Academic Research Consortium (BARC) 3-5 bleeding (1.5 vs. 2.9%; p = 0.011). The benefit of prasugrel was confirmed for patients with NSTEMI and for those discharged with a DAPT regimen of ≤ 12 months. Only a trend in the reduction of NACE and MACE was noted for STEMI or for those treated with longer DAPT. CONCLUSIONS: Comparison of these drugs suggested that prasugrel is safer and more efficacious than ticagrelor in combination with aspirin after NSTEMI but not STEMI. No differences were found for events occurring after 12 months. The nonrandomized design of the present research means further studies are required to support these findings.

Incidencia anual de trombosis del stent confirmadas y factores clínicos predictores en pacientes con SCA tratados con ticagrelor o prasugrel / Annual incidence of confirmed stent thrombosis and clinical predictors in patients with ACS treated with ticagrelor or prasugrel

Introducción y objetivos: Hay muy poca evidencia sobre las tasas de trombosis del stent (TS) en pacientes que reciben tratamiento antiagregante plaquetario doble (TAPD) con ticagrelor o prasugrel. El objetivo de este estudio es analizar la incidencia y predictores de la TS tras un síndrome coronario agudo en pacientes que reciben TAPD con ticagrelor frente a prasugrel. Métodos: Se utilizaron datos del registro RENAMI (REgistry of New Antiplatelet therapy in patients with acute Myocardial Infarction), y se analizó en total a 4.123 pacientes con síndrome coronario agudo dados de alta con TAPD con ticagrelor o prasugrel en 11 centros de 6 países europeos. Se consideró como evento la TS confirmada en el primer año. Se realizó un análisis de riesgos competitivos mediante un modelo de regresión de Fine y Gray, siendo la muerte el evento competitivo. Resultados: Recibieron TAPD con ticagrelor 2.604 pacientes y con prasugrel, 1.519; 41 pacientes (1,10%) presentaron TS, con incidencias acumuladas similares entre ticagrelor (1,21%) y prasugrel (0,90%). Los predictores independientes de la TS fueron: la edad (sHR = 1,03; IC95%, 1,01-1,06), la elevación del segmento ST (sHR = 2,24; IC95%, 1,22-4,14), el antecedente de infarto de miocardio (sHR = 2,56; IC95%, 1,19-5,49) y la creatinina sérica (sHR = 1,29; IC95%, 1,08-1,54). Conclusiones: La TS es infrecuente en pacientes que reciben TAPD con ticagrelor y prasugrel. La edad avanzada, la elevación del segmento ST, el antecedente de infarto y la creatinina sérica son las variables que se asocian con mayor riesgo de TS

Introduction and objectives: There is little evidence on rates of stent thrombosis (ST) in patients receiving dual antiplatelet therapy (DAPT) with ticagrelor or prasugrel. The aim of this study was to analyze the incidence and predictors of ST after an acute coronary syndrome among patients receiving DAPT with ticagrelor vs prasugrel. Methods: We used data from the RENAMI registry (REgistry of New Antiplatelet therapy in patients with acute Myocardial Infarction), analyzing a total of 4123 acute coronary syndrome patients discharged with DAPT with ticagrelor or prasugrel in 11 centers in 6 European countries. The endpoint was definite ST within the first year. A competitive risk analysis was carried out using a Fine and Gray regression model, with death being the competitive event. Results: A total of 2604 patients received DAPT with ticagrelor and 1519 with prasugrel; ST occurred in 41 patients (1.10%), with a similar cumulative incidence between ticagrelor (1.21%) and prasugrel (0.90%). The independent predictors of ST were age (sHR, 1.03; 95%CI, 1.01-1.06), ST segment elevation (sHR, 2.24; 95%CI, 1.22-4.14), previous myocardial infarction (sHR, 2.56; 95%CI, 1.19-5.49), and serum creatinine (sHR, 1.29; 95%CI, 1.08-1.54). Conclusions: Stent thrombosis is infrequent in patients receiving DAPT with ticagrelor or prasugrel. The variables associated with an increased risk of ST were advanced age, ST segment elevation, previous myocardial infarction, and serum creatinine

Utilidad de la puntuación PARIS para evaluar el equilibrio isquémico-hemorrágico con ticagrelor y prasugrel tras un síndrome coronario agudo / Usefulness of the PARIS score to evaluate the ischemic-hemorrhagic net benefit with ticagrelor and prasugrel after an acute coronary syndrome

Introducción y objetivos: La puntuación PARIS permite una estratificación combinada de los riesgos isquémico y hemorrágico de los pacientes con cardiopatía isquémica tratados con stent coronario y tratamiento antiagregante plaquetario doble (TAPD). Se desconoce su utilidad en pacientes con síndrome coronario agudo (SCA) tratados con ticagrelor o prasugrel. Se investiga este aspecto en un registro internacional. Métodos: Estudio retrospectivo multicéntrico con participación voluntaria de 11 centros de 6 países europeos. Se estudio ́a 4.310 pacientes con SCA dados de alta en TAPD con ticagrelor o prasugrel. Se definío evento isquémico como trombosis de stent o infarto de miocardio espontáneo, y evento hemorrágico según BARC (Bleeding Academic Research Consortium) tipo3 o 5. Se calculó la discriminación y la calibración para ambas vertientes de la puntuación PARIS (PARISisquémico y PARIShemorrágico). El beneficio neto isquémico-hemorrágico se obtuvo mediante la diferencia entre las probabilidades predichas de eventos isqueémicos y hemorrágicos. Resultados: Durante 17,2 ± 8,3 meses, hubo 80 eventos isquémicos (el 1,9% anual) y 66 eventos hemorrágicos (el 1,6% anual). PARISisquémico y PARIShemorrágico se asociaron con el riesgo de evetos isquémicos (sHR=1,27; IC95%, 1,16-1,39) y hemorrágicos (sHR = 1,14; IC95%, 1,01-1,30) respectivamente. La discriminación de eventos isquémicos fue discreta (índice C = 0,64) y la de eventos hemorrágicos, pobre (índice C= 0,56), con buena calibración para ambos. El beneficio neto isquémico-hemorrágico resultó negativo (más eventos hemorrágicos) en pacientes con alto riesgo hemorrágico y positivo (más eventos isquémicos) en pacientes con alto riesgo isquémico. Conclusiones: En pacientes con SCA tratados con TAPD conticagrelor o prasugrel, la escala PARIS ayuda a establecer un equilibrio apropiado del riesgo isquémico-hemorrágico

Introduction and objectives: The PARIS score allows combined stratification of ischemic and hemorrhagic risk in patients with ischemic heart disease treated with coronary stenting and dual antiplatelet therapy(DAPT). Its usefulness in patients with acute coronary syndrome (ACS) treated with ticagrelor or prasugrel is unknown. We investigated this issue in an international registry. Methods: Retrospective multicenter study with voluntary participation of 11 centers in 6 European countries. We studied 4310 patients with ACS discharged with DAPT with ticagrelor or prasugrel. Ischemic events were defined as stent thrombosis or spontaneous myocardial infarction, and hemorrhagic events as BARC (Bleeding Academic Research Consortium) type 3 or 5 bleeding. Discrimination and calibration were calculated for both PARIS scores (PARISischemic and PARIShemorrhagic). The ischemic-hemorrhagic net benefit was obtained by the difference between the predicted probabilities of ischemic and bleeding events. Results: During a period of 17.2 ± 8.3 months, there were 80 ischemic events(1.9% per year) and 66 bleeding events (1.6% per year). PARISischemic and PARIShemorrhagic scores were associated with a risk of ischemic events (sHR, 1.27; 95%CI, 1.16-1.39) and bleeding events (sHR, 1.14; 95%CI, 1.01-1.30), respectively. The discrimination for ischemic events was modest (Cindex = 0.64) and was suboptimal for hemorrhagic events (Cindex = 0.56), where as calibration was acceptable for both. The ischemic-hemorrhagic net benefit was negative (more hemorrhagic events) in patients at high hemorrhagic risk, and was positive (more ischemicevents) in patients at high ischemic risk. Conclusions: In patients with ACS treated with DAPT with ticagrelor or prasugrel, the PARIS model helps to properly evaluate the ischemic-hemorrhagic risk

Environmental and economic benefits of the recovery of materials in a municipal solid waste management system.

The main aim of this study was to perform a Life cycle assessment study as well as an economic evaluation of the recovery of recyclable materials in a municipal solid waste management system. If citizens separate erroneously waste fractions, they produce both environmental and economic damages. The environmental and economic evaluation was performed for the case study of Nola (34.349 inhabitants) in Southern Italy, with a kerbside system that assured a source separation of 62% in 2014. The economic analysis provided a quantification of the economic benefits obtainable for the population in function of the achievable percentage of source separation. The comparison among the environmental performance of four considered scenarios showed that the higher the level of source separation was, the lower the overall impacts were. This occurred because, even if the impacts of the waste collection and transport increased, they were overcome by the avoided impacts of the recycling processes. Increasing the source separation by 1% could avoid the emission of 5 kg CO2 eq. and 5 g PM10 for each single citizen. The economic and environmental indicators defined in this study provide simple and effective information useful for a wide-ranging audience in a behavioural change programme perspective.

Usefulness of the PARIS Score to Evaluate the Ischemic-hemorrhagic Net Benefit With Ticagrelor and Prasugrel After an Acute Coronary Syndrome.

INTRODUCTION AND OBJECTIVES: The PARIS score allows combined stratification of ischemic and hemorrhagic risk in patients with ischemic heart disease treated with coronary stenting and dual antiplatelet therapy (DAPT). Its usefulness in patients with acute coronary syndrome (ACS) treated with ticagrelor or prasugrel is unknown. We investigated this issue in an international registry. METHODS: Retrospective multicenter study with voluntary participation of 11 centers in 6 European countries. We studied 4310 patients with ACS discharged with DAPT with ticagrelor or prasugrel. Ischemic events were defined as stent thrombosis or spontaneous myocardial infarction, and hemorrhagic events as BARC (Bleeding Academic Research Consortium) type 3 or 5 bleeding. Discrimination and calibration were calculated for both PARIS scores (PARISischemic and PARIShemorrhagic). The ischemic-hemorrhagic net benefit was obtained by the difference between the predicted probabilities of ischemic and bleeding events. RESULTS: During a period of 17.2 ± 8.3 months, there were 80 ischemic events (1.9% per year) and 66 bleeding events (1.6% per year). PARISischemic and PARIShemorrhagic scores were associated with a risk of ischemic events (sHR, 1.27; 95%CI, 1.16-1.39) and bleeding events (sHR, 1.14; 95%CI, 1.01-1.30), respectively. The discrimination for ischemic events was modest (C index = 0.64) and was suboptimal for hemorrhagic events (C index = 0.56), whereas calibration was acceptable for both. The ischemic-hemorrhagic net benefit was negative (more hemorrhagic events) in patients at high hemorrhagic risk, and was positive (more ischemic events) in patients at high ischemic risk. CONCLUSIONS: In patients with ACS treated with DAPT with ticagrelor or prasugrel, the PARIS model helps to properly evaluate the ischemic-hemorrhagic risk.

Annual Incidence of Confirmed Stent Thrombosis and Clinical Predictors in Patients With ACS Treated With Ticagrelor or Prasugrel.

INTRODUCTION AND OBJECTIVES: There is little evidence on rates of stent thrombosis (ST) in patients receiving dual antiplatelet therapy (DAPT) with ticagrelor or prasugrel. The aim of this study was to analyze the incidence and predictors of ST after an acute coronary syndrome among patients receiving DAPT with ticagrelor vs prasugrel. METHODS: We used data from the RENAMI registry (REgistry of New Antiplatelet therapy in patients with acute Myocardial Infarction), analyzing a total of 4123 acute coronary syndrome patients discharged with DAPT with ticagrelor or prasugrel in 11 centers in 6 European countries. The endpoint was definite ST within the first year. A competitive risk analysis was carried out using a Fine and Gray regression model, with death being the competitive event. RESULTS: A total of 2604 patients received DAPT with ticagrelor and 1519 with prasugrel; ST occurred in 41 patients (1.10%), with a similar cumulative incidence between ticagrelor (1.21%) and prasugrel (0.90%). The independent predictors of ST were age (sHR, 1.03; 95%CI, 1.01-1.06), ST segment elevation (sHR, 2.24; 95%CI, 1.22-4.14), previous myocardial infarction (sHR, 2.56; 95%CI, 1.19-5.49), and serum creatinine (sHR, 1.29; 95%CI, 1.08-1.54). CONCLUSIONS: Stent thrombosis is infrequent in patients receiving DAPT with ticagrelor or prasugrel. The variables associated with an increased risk of ST were advanced age, ST segment elevation, previous myocardial infarction, and serum creatinine.

Prasugrel or ticagrelor in patients with acute coronary syndrome and diabetes: a propensity matched substudy of RENAMI.

INTRODUCTION: The safety and efficacy of prasugrel and ticagrelor in patients with diabetes mellitus presenting with acute coronary syndrome and treated with percutaneous coronary intervention remain to be assessed. METHODS: All diabetes patients admitted for acute coronary syndrome and enrolled in the REgistry of New Antiplatelets in patients with Myocardial Infarction (RENAMI) were compared before and after propensity score matching. Net adverse cardiovascular events (composite of death, stroke, myocardial infarction and BARC 3-5 bleedings) and major adverse cardiovascular events (composite of death, stroke and myocardial infarction) were the co-primary endpoints. Single components of primary endpoints were secondary endpoints. RESULTS: Among 4424 patients enrolled in RENAMI, 462 and 862 diabetes patients treated with prasugrel and ticagrelor, respectively, were considered. After propensity score matching, 386 patients from each group were selected. At 19±5 months, major adverse cardiovascular events and net adverse cardiovascular events were similar in the prasugrel and ticagrelor groups (5.4% vs. 3.4%, P=0.16 and 6.7% vs. 4.1%, P=0.11, respectively). Ticagrelor was associated with a lower risk of death and BARC 2-5 bleeding when compared to prasugrel (2.8% vs. 0.8%, P=0.031 and 6.0% vs. 2.6%, P=0.02, respectively) and a clear but not significant trend for a reduction of BARC 3-5 bleeding (2.3% vs. 0.8%, P=0.08). There were no significant differences in myocardial infarction recurrence and stent thrombosis. CONCLUSION: Diabetes patients admitted for acute coronary syndrome seem to benefit equally in terms of major adverse cardiovascular events from ticagrelor or prasugrel use. Ticagrelor was associated with a significant reduction in all-cause death and bleedings, without differences in recurrent ischaemic events, which should be confirmed in dedicated randomised controlled trials.

Incidence and predictors of bleeding in ACS patients treated with PCI and prasugrel or ticagrelor: An analysis from the RENAMI registry.

OBJECTIVES: To evaluate "real life" incidence and independent predictors of major bleeding defined in ACS patients treated with PCI and current standard antithrombotic therapy with prasugrel or ticagrelor. METHODS AND RESULTS: The RENAMI project is a multicenter retrospective observational registry enrolling 4424 patients with ACS treated with PCI and prasugrel or ticagrelor plus aspirin. Primary endpoint was MACE (major adverse cardiovascular events). Secondary endpoints included each component of MACE, cardiovascular death (CV death), recurrence of ACS (reACS) and stroke. Eighty three (1.8%) patients developed out of hospital major bleedings after 14.1 ±â€¯6.2 months. These patients had higher rates of MACE (14.5% vs 4.4%; p = 0.001) and of all-cause death (11% vs 2.1%; p < 0.001). Independent predictors of major bleeding were age >75 years (OR 2.00; 95% CI 1.18-3.41; p = 0.010) and female sex (OR 1.66; 95% CI 1.02-2.70; p = 0.041). BARC 3-5 bleeding was independently associated with all-cause mortality (OR 3.46; 95% CI 1.64-7.31; p 0.001). CONCLUSION: In ACS patients treated with PCI and ticagrelor or prasugrel, BARC 3-5 bleedings despite being uncommon negatively impacted on prognosis. Old and female patients are at increased risk, offering clinical indications for tailoring dual antiplatelet therapy.