Search

Therapeutic anticoagulation is indicated for a variety of circumstances and conditions in several fields of medicine to prevent or treat venous and arterial thromboembolism. According to the different mechanisms of action, the available parenteral and oral anticoagulant drugs share the common principle of hampering or blocking key steps of the coagulation cascade, which unavoidably comes at the price of an increased propensity to bleed. Hemorrhagic complications affect patient prognosis both directly and indirectly (ie, by preventing the adoption of an effective antithrombotic strategy). Inhibition of factor XI (FXI) has emerged as a strategy with the potential to uncouple the pharmacological effect and the adverse events of anticoagulant therapy. This observation is based on the differential contribution of FXI to thrombus amplification, in which it plays a major role, and hemostasis, in which it plays an ancillary role in final clot consolidation. Several agents were developed to inhibit FXI at different stages (ie, suppressing biosynthesis, preventing zymogen activation, or impeding the biological action of the active form), including antisense oligonucleotides, monoclonal antibodies, small synthetic molecules, natural peptides, and aptamers. Phase 2 studies of different classes of FXI inhibitors in orthopedic surgery suggested that dose-dependent reductions in thrombotic complications are not paralleled by dose-dependent increases in bleeding compared with low-molecular-weight heparin. Likewise, the FXI inhibitor asundexian was associated with lower rates of bleeding compared with the activated factor X inhibitor apixaban in patients with atrial fibrillation, although no evidence of a therapeutic effect on stroke prevention is available so far. FXI inhibition could also be appealing for patients with other conditions, including end-stage renal disease, noncardioembolic stroke, or acute myocardial infarction, for which other phase 2 studies have been conducted. The balance between thromboprophylaxis and bleeding achieved by FXI inhibitors needs confirmation in large-scale phase 3 clinical trials powered for clinical end points. Several of such trials are ongoing or planned to define the role of FXI inhibitors in clinical practice and to clarify which FXI inhibitor may be most suited for each clinical indication. This article reviews the rationale, pharmacology, results of medium or small phase 2 studies, and future perspectives of drugs inhibiting FXI.

Introduction Patients with chronic coronary syndrome (CCS) can initially undergo an invasive (i.e., early referral to invasive coronary angiography [ICA]) or a conservative (i.e., anatomical or functional testing before ICA) management. The ISCHEMIA trial showed no difference between these two strategies in CCS patients with moderate-to-severe ischemia. The aim of our study was to assess whether the results of the ISCHEMIA trial impacted on the management of CCS patients. Methods Trends in the management of patients with CCS in our centre, according to the ISCHEMIA trial publication date, were analyzed and patients categorized into pre-ISCHEMIA (before March 2020) and post-ISCHEMIA (from July 2020 to February 2022) groups, with an in-between blanking period of three months. The primary outcome was incidence of referral to ICA by coronary computed tomography angiography (CCTA). Secondary objectives included the incidence ischemia test-referred ICA, incidence of CCTA-referred ICA and subsequent percutaneous coronary intervention (PCI), incidence of ischemia test-referred ICA and subsequent PCI and incidence of CCTA-referred ICA without subsequent PCI. Differences between the pre-specified subpopulations (age ≥75 years, diabetes, chronic kidney disease [CKD], peripheral arterial disease [PAD], gender male, unstable angina, active smoking status, body mass index [BMI] >30, hypertension, family history of coronary artery disease [CAD], atrial fibrillation [AF], prior percutaneous coronary intervention [PCI], prior coronary artery bypass grafting [CABG]) and the general population of the study were tested using a regression analysis. Results A total of 2,365 patients were included, 487 (20.6%) and 1,878 (79.4%) in the pre-ISCHEMIA and post-ISCHEMIA groups, respectively. There were no notable between-group differences in baseline characteristics. The primary outcome occurred more frequently in the post-ISCHEMIA group (73.5% vs. 32.5%; p Conclusions In the first two years from publication, the ISCHEMIA trial significantly impacted on the decision-making algorithm for patients with CCS, increasing referral to ICA by CCTA and diminishing ICAs indicated by an ischemia test.

Background Among dual antiplatelet therapy (DAPT) modulation strategies after acute coronary syndromes (ACS), short duration of DAPT (i.e.; 3 or 6 months) received a class IIa recommendation by European guidelines. However, whether discontinuing aspirin or P2Y12 inhibitor (P2Y12-i) after this period is still a matter of debate. Aims The aim of this study was to compare the overall effects of short DAPT versus standard DAPT in patients presenting with ACS undergoing percutaneous coronary intervention in a two-arm metanalysis, and the relative merits of short DAPT followed by aspirin or P2Y12-i discontinuation in a three-node network meta-analysis using standard DAPT as common comparator. Methods Randomized trials of DAPT modulation strategies in patients with ACS undergoing PCI were identified. All-cause death was the primary outcome. Secondary outcomes included net adverse cardiovascular events (NACE), major adverse cardiovascular events (MACE), and their components. Firstly, we conducted a two-arm random-effect frequentist meta-analysis to compare short DAPT and standard DAPT. Secondly, we conducted a frequentist random-effects network metanalysis to compare the relative merits of the two short DAPT strategies. Treatments were ranked on the basis of p-scores. Results Nineteen studies encompassing 37,789 patients were included. The transitivity assumption was fulfilled. Comparing short DAPT with standard DAPT, no significant differences were noted for the primary outcome, but short DAPT significantly reduced the risk ratio (RR) for any bleeding (RR, 0.68; 95% CI, 0.58 to 0.79), major bleedings (RR, 0.57; 95% CI, 0.41 to 0.78) and minor bleeding (RR, 0.80; 95% CI, 0.64 to 0.98), without increasing the risk for ischemic events. In the three-node network metanalysis, no significant differences were noted in the primary endpoint, all secondary ischemic outcomes and minor bleeding between the three strategies. However, short DAPT followed by aspirin discontinuation significantly reduced the incidence of any bleeding (RR, 0.61; 95% CI, 0.50 to 0.75) and major bleeding (RR, 0.51; 95% CI, 0.37 to 0.70) compared with standard DAPT. The ranking evaluation revealed that short DAPT followed by aspirin discontinuation had the highest probability of being the best treatment for prevention of the primary endpoint, MACE, cardiovascular death, stroke, any bleeding and major bleeding (p-scores 0.78, 0.80, 0.85, 0.73, 0.98, 0.97, respectively), whereas standard DAPT had the highest probability of being the best treatment for prevention of myocardial infarction and stent thrombosis (p-scores 0.84 and 0.79, respectively). Conclusions In patients with ACS undergoing PCI, there was no difference in all-cause death between short DAPT regimens and standard DAPT. However, short DAPT reduced the risk of all types of bleeding, and the major driver for this effect is represented by short DAPT followed by aspirin discontinuation, which significantly reduced the risk for any bleeding and major bleeding. These data suggest that, when a short DAPT course is chosen after an ACS, discontinuing aspirin should be the strategy of choice, rather than discontinuing the P2Y12-i.

Transcatheter aortic valve implantation (TAVI) is a treatment option for patients with symptomatic severe aortic stenosis across the entire spectrum of surgical risk. TAVI conveys some risk for thrombotic complications, requiring antithrombotic drugs for their prevention. Bleeding events represent the major drawback of antithrombotic therapy, which should be carefully tailored over the individual patient's risk profile.This review aimed at exploring the rationale for the adoption of a tailored antithrombotic therapy after successful TAVI, with a description and analysis of common complications and their impact on therapy selection. In addition, we aimed at reviewing and discussing current knowledge in this area, with a main focus on the high-quality evidence supporting latest guideline recommendations. Finally, ongoing studies and future directions on antithrombotic therapy after TAVI were outlined.Initial experience with antithrombotic therapy after TAVI was derived from percutaneous coronary intervention practice. Accruing evidence in the field led to the current monotherapy paradigm, which prioritizes oral anticoagulant and single antiplatelet therapy in patients with or without an established indication for long-term anticoagulation, respectively. Future studies will investigate the role of alternative antithrombotic strategies to improve clinical outcomes of TAVI patients by minimizing both thrombotic and bleeding complications.Aortic stenosis is the most common primary valve disease requiring treatment. Transcatheter aortic valve implantation (TAVI) is a percutaneous treatment option for patients with symptomatic severe aortic stenosis across the entire spectrum of surgical risk. To prevent several complications of TAVI, antithrombotic drugs (i.e. antiplatelets or anticoagulants) are required after the intervention. The major drawback of such therapies is represented by bleeding, which makes important a careful consideration of the individual patient’s risk profile. This review article explores the rationale for the adoption of a tailored antithrombotic therapy after TAVI, with a description and analysis of common complications and their impact on therapy selection. In addition, we reviewed and discussed current knowledge in this area, with a main focus on the evidence supporting latest guideline recommendations and their potential evolution. Finally, ongoing studies and future directions on antithrombotic therapy after TAVI were presented.

Background: More than half of the patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) have multi-vessel coronary artery disease. This is associated with worse outcomes compared with single vessel disease. Whilst evidence now exists to support complete revascularisation for bystander disease the optimal timing is still debated. This study aimed to compare clinical outcomes in patients with STEMI and multi-vessel disease who underwent complete revascularisation as inpatients in comparison to patients who had staged PCI as early outpatients. Methods and results: We conducted an observational cohort study consisting of 1522 patients who underwent primary PCI with multi-vessel disease from 2012 to 2019. Exclusions included patients with cardiogenic shock and previous CABG. Patients were split into 2 groups depending on whether they had complete revascularisation performed as inpatients or as staged PCI at later outpatient dates. The primary outcome of this study was major adverse cardiac events (consisting of myocardial infarction, target vessel revascularisation and all-cause mortality). 834 (54.8%) patients underwent complete inpatient revascularisation and 688 patients (45.2%) had outpatient PCI (median 43 days post discharge). Of the inpatient group, 652 patients (78.2%) underwent complete revascularisation during the index procedure whilst 182 (21.8%) patients underwent inpatient bystander PCI in a second procedure. Overall, there were no significant differences between the groups with regards to their baseline or procedural characteristics. Over the follow-up period there was no significant difference in MACE between the cohorts ( P = .62), which persisted after multivariate adjustment (HR 1.21 [95% CI 0.72-1.96]). Furthermore, in propensity-matched analysis there was no significant difference in outcome between the groups (HR: 0.86 95% CI: 0.75-1.25). Conclusions: Our study demonstrated that the timing of bystander PCI after STEMI did not appear to have an effect on cardiovascular outcomes. We suggest that patients with multi-vessel disease can potentially be discharged promptly and undergo early outpatient bystander PCI. This could significantly reduce length of stay in hospital.

In the last decades, the increasing use of laminate materials, such as carbon fibre reinforced plastics, in several engineering applications has pushed researchers to deeply investigate their mechanical behavior, especially in consideration of the delamination process, which could affect their performance. The need for improving the capability of the current instruments in predicting some collapse or strength reduction due to hidden damages leads to the necessity to combine numerical models with experimental campaigns. The validation of the numerical models could give useful information about the mechanical response of the materials, providing predictive data about their lifetime. The purpose of the delamination tests is to collect reliable results by monitoring the delamination growth of the simulated in situ cracking and use them to validate the numerical models. In this work, an experimental campaign was carried out on high performance composite laminates with respect to the delamination mode I, subsequently, a numerical model representative of the experimental setup was built. The ANSYS Workbench Suite was used to simulate the delamination phenomena and modeFRONTIER was applied for the numerical/experimental calibration of the constitutive relationship on the basis of the delamination process, whose mechanism was implemented by means of the cohesive zone material (CZM) model.

Some of twin shaft gas turbines models of GE are equipped with Variable Area Turbine Nozzle (VATN), also called Nozzle Guide Vane (NGV) as the first stator stage of Low Pressure Turbine (LPT). By varying the throat area, VATN controls the energy split between the High Pressure Turbine (HPT) and Low Pressure Turbine, allowing higher operational flexibility and higher efficiency at partial load/speed. This flexibility is an important requirement for gas turbine in mechanical drive applications. This paper is focused on the design, development and optimization of a numerical Finite Element (FE) model of the kinematic chain implemented to actuate the variable area turbine nozzles, in order to evaluate the required force as input to size and design the actuator. The kinematic chain is composed of an arrangement of linkage components that transfer the load provided by the actuator to the VATN and achieve a desired rotation of VATN airfoil around its axis. The load provided by actuator has to balance the aerodynamic load taking into account the contribution of friction developed inside the kinematic chain. The FE model has been specifically developed to evaluate the effects of different parameters, such as manufacturing tolerances and assembly clearances, in terms of total actuation force requirement, stress/life of the components and friction distribution. The additional scope of the detailed FE model is to represent an analytical validation criterion of the results obtained through a simplified spreadsheet-based tool which aims to be a reliable and quick responding system both for new product design phase and for implemented fleet issues resolution.

The national identity of Slavic Mitteleuropa is examined by means of a new approach to different cultural paradigms, namely the historical events out of which the popular canon in music flourished at the end of eighteenth-century Poland and in nineteenth-century Bohemia, Slovenia and Croatia. This phenomenon must be analysed within a framework in which cosmopolitism and nationalism co-existed in a mix of functional and autonomous music, superseding the boundaries of subordination, adaptation and autonomy.