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The risk of ischemic events carried by different clusters of type 2 diabetes mellitus (DM) in the setting of secondary prevention is not definite and the association between DM and bleeding complications is controversial. We explored these issues in the START-ANTIPLATELET, a multicenter Italian registry including acute coronary syndrome (ACS) patients. Study outcome was 1-year incidence of the net composite endpoint including major adverse cardiovascular events (MACE) or any bleeding and its individual components across different DM strata (no DM, DM with or without insulin). Out of 951 patients, 20.0% had diabetes not on insulin and 2.5% had diabetes on insulin. The rate of the net composite endpoint was highest in patients receiving insulin (39.4 per 100 person-years vs 11.7 in diabetic patients not on insulin vs 14.0 in those without DM; p = 0.007). In DM, the higher risk of MACE was regardless of insulin use (p = 0.36). Conversely, the increase in bleeding complications was limited to patients on insulin (Hazard Ratio 2.31, 95% CI 0.93-5.71 vs no DM; p = 0.0105 across DM strata). On top of aspirin, the rates of the net composite endpoint were similar with ticagrelor/prasugrel or clopidogrel irrespective of DM status (p for interaction 0.63). In conclusion, in ACS patients, type 2 DM enhances the risk of MACE regardless of the DM cluster, whereas the propensity to bleeding related to DM seems confined to insulin-treated patients.

Optimal dual antiplatelet therapy (DAPT) strategy in high-bleeding risk (HBR) patients presenting with acute coronary syndrome remains debated. We sought to investigate the use of clopidogrel versus ticagrelor in HBR patients with acute coronary syndrome and their impact on ischemic and bleeding events at 1year. In the START-ANTIPLATELET registry (NCT02219984), consecutive patients with ≥ 1 HBR criteria were stratified by DAPT type in clopidogrel versus ticagrelor groups. The primary endpoint was net adverse clinical endpoints (NACE), defined as a composite of all-cause death, myocardial infarction, stroke, and major bleeding. Of 1209 patients with 1-year follow-up, 553 were defined at HBR, of whom 383 were considered eligible for the study as on DAPT with clopidogrel (174 or 45.4%) or ticagrelor (209 or 54.6%). Clopidogrel was more often administered in patients at increased ischemic and bleeding risk, while ticagrelor in those undergoing percutaneous coronary intervention. Mean DAPT duration was longer in the ticagrelor group. At 1year, after multivariate adjustment, no difference in NACEs was observed between patients on clopidogrel versus ticagrelor (19% vs. 11%, adjusted hazard ratio 1.27 [95% CI 0.71–2.27], p = 0.429). Age, number of HBR criteria, and mean DAPT duration were independent predictors of NACEs. In a real-world registry of patients with acute coronary syndrome, 45% were at HBR and frequently treated with clopidogrel. After adjustment for potential confounders, the duration of DAPT, but not DAPT type (stratified by clopidogrel vs. ticagrelor), was associated with the risk of ischemic and bleeding events at 1year.

Given the high prevalence of preexisting cardiovascular diseases and the increased incidence of adverse cardiovascular events in patients hospitalized for SARS-CoV-2 infection, the identification of optimal antithrombotic approaches in terms of risk/benefit ratio and outcome improvement appears crucial in this setting. In the present position paper we collected current evidence from the literature to provide practical recommendations on the management of antithrombotic therapies (antiplatelet and anticoagulant) in various clinical contexts prevalent during the SARS-CoV-2 outbreak: in-home management of oral anticoagulant therapy; interactions between drugs used in the SARS-CoV-2 infection and antithrombotic agents; in-hospital management of antithrombotic therapies; diagnosis, risk stratification and treatment of in-hospital thrombotic complications.

Human T-lymphotropic virus type 1 (HTLV-1) and other members of the Deltaretrovirus genus code for a regulatory protein named Rex that binds to the Rex-responsive element present on viral mRNAs. Rex rescues viral mRNAs from complete splicing or degradation and guides them to the cytoplasm for translation. The activity of Rex is essential for expression of viral transcripts coding for the virion components and thus represents a potential target for virus eradication. We present an overview of the functional properties of the HTLV-1 and HTLV-2 Rex proteins (Rex-1 and Rex-2), outline mechanisms controlling Rex function, and discuss similarities and differences in the sequences of Rex coded by HTLV-1, -2, -3, and -4 that may influence their molecular anatomy and functional properties.

Diabetes mellitus is an important risk factor for a first cardiovascular event and for worse outcomes after a cardiovascular event has occurred. This situation might be caused, at least in part, by the prothrombotic status observed in patients with diabetes. Therefore, contemporary antithrombotic strategies, including more potent agents or drug combinations, might provide greater clinical benefit in patients with diabetes than in those without diabetes. In this Consensus Statement, our Working Group explores the mechanisms of platelet and coagulation activity, the current debate on antiplatelet therapy in primary cardiovascular disease prevention, and the benefit of various antithrombotic approaches in secondary prevention of cardiovascular disease in patients with diabetes. While acknowledging that current data are often derived from underpowered, observational studies or subgroup analyses of larger trials, we propose antithrombotic strategies for patients with diabetes in various cardiovascular settings (primary prevention, stable coronary artery disease, acute coronary syndromes, ischaemic stroke and transient ischaemic attack, peripheral artery disease, atrial fibrillation, and venous thromboembolism). Finally, we summarize the improvements in cardiovascular outcomes observed with the latest glucose-lowering drugs, and on the basis of the available evidence, we expand and integrate current guideline recommendations on antithrombotic strategies in patients with diabetes for both primary and secondary prevention of cardiovascular disease., Patients with diabetes mellitus have a prothrombotic status that increases the risk of cardiovascular events and worsens prognosis after these events. In this Consensus Statement, the Working Group on Thrombosis of the Italian Society of Cardiology proposes antithrombotic strategies for patients with diabetes in various cardiovascular settings.

Atrial fibrillation (AF) is the most frequent sustained cardiac arrhythmia, and its prevalence is increasing, partly due to the progressive aging of the population. AF predisposes to thrombus formation in the atria and the atrial appendage through a complex interaction among local, systemic and hemodynamic factors, significantly increasing the risk for cerebral and systemic thromboembolic events. These complications have a major impact in terms of morbidity and mortality, and numerous therapeutic strategies have been proposed to reduce such risk. Systemic anticoagulation is the main strategy in the prevention of atrial and left atrial appendage thrombosis, and the advent of non-vitamin K antagonist oral anticoagulants (NOACs) has been a significant step forward, especially for safety, compared to warfarin. While prevention of atrial appendage thrombosis with NOACs has been widely explored, their role in the resolution of thrombi is less clear. The use of NOACs in this setting is largely unexplored, and some studies are underway to clarify their effectiveness. The objective of this paper is to review the literature on atrial and left atrial appendage thrombosis, describing pathophysiological mechanisms and current treatment strategies using NOACs.

Aim To analyze the prevalence and clinical implications of the eligibility criteria for prolonged dual antithrombotic therapy with ticagrelor 60 mg twice daily and/or rivaroxaban 2.5 mg twice daily in a contemporary real-world ACS registry. Methods Patients from the START-ANTIPLATELET registry ( NCT02219984 ) were stratified according to the eligibility criteria of the PEGASUS and COMPASS studies to investigate the proportion of patients eligible for prolonged dual antithrombotic therapy at discharge and after 1-year of DAPT. Net adverse clinical events (NACE), defined as all-cause death, myocardial infarction, stroke, and major bleeding, at 1 year were also evaluated and compared among groups. Results 1844 were considered for the analysis at baseline. Out of 849 event-free patients continually receiving dual antiplatelet therapy for at least 1 year, 577 (68%) and 583 (68.7%) met at least one eligibility criterion for ticagrelor and rivaroxaban, respectively. In the PEGASUS-like patients, age was the most common criterion (71% of cases). The presence ≥2 cardiovascular risk factors was the most common eligibility criterion in the COMPASS-like patients (80.8%). At 1-year follow-up, 211 (11.4%) and 119 (6.5%) patients experienced NACE and MACE, respectively. The incidence of NACEs was higher in the PEGASUS-only group (15.4% vs. 8.4%; p = 0.008) and numerically higher in the COMPASS-only group (10.9% vs. 8.4%; p = 0.299). Conclusions In a contemporary real-world ACS cohort, approximately two-thirds of patients that complete 1-year DAPT met the eligibility criteria for ticagrelor 60 mg twice daily or rivaroxaban 2.5 mg twice daily, showing a higher risk of NACEs.

Background: Peripheral arterial disease (PAD) was reported to increase the risk of new cardiovascular events in patients with acute coronary syndromes (ACS). However, most of the evidence comes from randomized clinical trials. We aimed to assess the impact of PAD on cardiovascular outcome and treatment decisions in ACS patients in a current real-life setting. Methods: START-ANTIPLATELET is a multicenter registry enrolling ACS patient. Baseline clinical characteristics and treatment at discharge were recorded and follow-up was repeated at 6-months and 1-year. PAD was defined as intermittent claudication and/or previous revascularization. Results: Among 1442 patients enrolled, 103 (7.1%) had PAD. PAD patients were older (71.8 ± 10.6vs66.2 ± 12.6 yrs., p < 0.0001), more frequently hypertensive (90.3vs68.6%, p< 0.0001), hypercholesterolemic (66vs52%, p= 0.037), diabetic (51.5vs24%, p= 0.0001), obese (28.2vs19.3%, p= 0.029) and with previous TIA (7.8vs2.8%, p= 0.005) or stroke (11.7vs3.1%, p< 0.0001). Clinical presentation and acute treatment were similar in non-PAD and PAD patients, but the latter were discharged significantly less frequently on dual antiplatelet therapy (DAPT) (68.9vs85%, p= 0.005). After a median follow-up time of 11.1 months, major cardio/cerebrovascular event-free survival [MACCE, including cardiovascular death, MI, TIA and stroke, target-vessel revascularization (TVR) and major arterial ischemic events] was significantly shorter (9.0vs11.2 months, p= 0.02; HR 3.2, 2.4–8.4) in PAD patients and net adverse cardiovascular events (NACE = MACCE plus major hemorrhages) were significantly more frequent (19.1%vs10.5%, p = 0.049). Conclusions: PAD identifies a subgroup of ACS patients at significantly increased cardiovascular risk, but these patients tend to be undertreated. Patients admitted for ACS should be screened for PAD and optimal medical therapy at discharge should be implemented.

In patients with coronavirus disease 2019 (COVID-19), the prevalence of pre-existing cardiovascular diseases is elevated. Moreover, various features, also including pro-thrombotic status, further predispose these patients to increased risk of ischemic cardiovascular events. Thus, the identification of optimal antithrombotic strategies in terms of the risk–benefit ratio and outcome improvement in this setting is crucial. However, debated issues on antithrombotic therapies in patients with COVID-19 are multiple and relevant. In this article, we provide ten questions and answers on risk stratification and antiplatelet/anticoagulant treatments in patients at risk of/with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection based on the scientific evidence gathered during the pandemic.

Available evidence on left atrial (LA) thrombus dissolution in patients with atrial fibrillation (AF) largely refers to the use of vitamin K antagonist oral anticoagulants (VKAs), showing >50% thrombus resolution over a 4-week to 12-month treatment period. Available data on non-vitamin K antagonist anticoagulants (NOACs) in this setting are limited and derive from isolated case reports or observational small-sized investigations with dabigatran, rivaroxaban or apixaban. The aim of this study was to investigate the extent of thrombus resolution with edoxaban therapy in patients with AF and LA thrombosis. We conducted a prospective, observational, open-label pilot study in seven Italian institutions. We included a total of 25 patients with non-valvular AF and LA (or left atrial appendage (LAA)) thrombosis, documented by transesophageal echocardiography (TEE). All patients received edoxaban OD treatment (n = 23 on 60 mg daily; n = 2 on 30 mg daily) and underwent TEE examination after 4 weeks. The primary endpoint was the percentage of patients with complete thrombus resolution by TEE imaging at 4 weeks. The mean age of the study population was 68.3 ± 10.8 years with a female population of 16%. AF was permanent in all cases, with a mean arrhythmia duration of 4.3 ± 1.7 years. CHA2DS2-VASc and HAS-BLED scores were 3.2 ± 1.5 and 1.9 ± 1.1, respectively. We were able to demonstrate a complete thrombus resolution in 14 patients (56%) at 4 weeks. In patients with residual atrial thrombosis (n = 11), we observed a 15.4 ± 14.9% reduction in the thrombus area from baseline. As compared with patients without thrombus dissolution, those with thrombus resolution had a numerically lower-indexed LA diameter (27.9 ± 9.3 vs 34.8 ± 16.1 mm/m2), a smaller maximum thrombus area at baseline (45.5 ± 44.6 vs 63.9 ± 43.5 mm2), a higher left ventricular ejection fraction (47.4 ± 21.0% vs 38.4 ± 20.6%) and higher maximum LAA flow velocities (26.3 ± 15.2 vs 19.3 ± 10.0 cm/s). Figures on the percentage of thrombus resolution in this study are comparable to those reported in the literature for the other OACs. We conclude that, in patients with AF, the use of edoxaban is associated with a >50% resolution of atrial thrombus at 4 weeks, similar to studies using VKAs and the other NOACs (ClinicalTrials.gov identifier number: NCT034899395).

Pituitary adenomas represent one of the key features of multiple endocrine neoplasia type 1. The gene involved in this syndrome (MEN1) is a putative tumor suppressor, that codes for a 610-amino acid nuclear protein termed 'menin'. Analyses of sporadic pituitary adenomas have so far failed to reveal MEN1 mutations or defects in MEN1 transcription in these tumors. In the present study we detected menin protein expression in a panel of normal and tumoral pituitary tissues, using a monoclonal antibody against the carboxy-terminus of menin. In the normal human pituitary gland, strong nuclear staining for menin was detectable in the majority of the endocrine cells of the anterior lobe, without a clear association with a particular hormone-producing type. In sporadic pituitary adenomas, menin expression was variable, with a high percentage of cases demonstrating a significant decrease in menin immunoreactivity when compared with the normal pituitary. Interestingly, metastatic tissues derived from one pituitary carcinoma had no detectable menin levels. Altogether, our data provide the first information regarding the status of menin expression in human normal and neoplastic pituitary as determined by immunohistochemistry (IHC).

Diabetes mellitus (DM) is an independent predictor of adverse outcomes in patients with coronary artery disease (CAD). We investigated the interaction between DM and high platelet reactivity (HPR) in determining long-term clinical outcomes after percutaneous coronary intervention (PCI). We enrolled 500 patients who were divided based on the presence of DM and HPR. Primary endpoint was the occurrence of major adverse clinical events (MACE) at 5 years. Patients with both DM and HPR showed the highest estimates of MACE (37.9%, log-rank p

The protective effect of obesity on mortality in acute coronary syndromes (ACS) patients remains debated. We aimed at evaluating the impact of obesity on ischemic and bleeding events as possible explanations to the obesity paradox in ACS patients. For the purpose of this substudy, patients enrolled in the START-ANTIPLATELET registry were stratified according to body mass index (BMI) into 3 groups: normal, BMI

Vitamin D has been suggested as a protective compound for diabetes mellitus. Several mechanisms linking vitamin D to the regulation of the immune response support a role for vitamin D in the pathogenesis of autoimmune diabetes. Epidemiological evidence and observational studies suggesting that adequate vitamin D status is related to decreased risk of developing type 1 diabetes further corroborates this concept. However, only few and mostly underpowered randomized clinical trials have been conducted to test the effectiveness of vitamin D supplementation in autoimmune diabetes, with disappointing results. Similarly, recent evidence linking vitamin D action to insulin secretion and sensitivity led to the hypothesis that this compound may play a key role in the regulation of glucose homeostasis in both pre-diabetes and overt type 2 diabetes (T2D). However, the main clinical trials evaluating the efficacy of vitamin D supplementation for the control of glucose homeostasis in people at risk for or affected by T2D have yielded inconsistent results. The aim of this review is to summarize the rationale and results of randomized clinical trials testing vitamin D and its analogs in both autoimmune and T2D.

The impact of chronic kidney disease (CKD) on residual platelet reactivity (PR) in patients undergoing percutaneous coronary intervention (PCI) is still debatable. We sought to investigate the interaction between PR and renal function and the related clinical outcomes in patients with coronary artery disease treated with PCI. Immediately before PCI, we measured PR (as P2Y12 reaction units [PRUs]) in 800 patients on clopidogrel with the VerifyNow P2Y12 assay. High PR was defined as a PRU value of ≥240 and low PR as a PRU value of ≤178. Based on a glomerular filtration rate ofor ≥60 ml/min/1.73 m2, patients were respectively grouped into those with or without moderate-to-severe CKD. Primary end point was the incidence of 30-day net adverse clinical events (NACEs). Patients with moderate-to-severe CKD (n=173, 21.6%) and those without showed similar PRU values (208±67 vs 207±75, p=0.819). Yet, NACEs were significantly higher in patients with moderate-to-severe CKD (19.7% vs 9.1%, p0.001), in terms of both ischemic (12.1% vs 7.2%, p=0.036) and bleeding events (8.7% vs 2.1%, p0.001). NACEs were significantly higher when moderate-to-severe CKD was associated with either high PR or low PR (25.4%, p for trend0.001); this association was the strongest predictor of NACE at multivariate analysis (odds ratio 3.4, 95% confidence interval 2.0 to 5.6, p0.001). In conclusion, we did not find an association between moderate-to-severe CKD and residual PR on clopidogrel. However, the association of moderate-to-severe CKD with either high or low PR was a strong determinant of adverse events after PCI.