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Background: Direct oral anticoagulants (DOACs) are widely used for the treatment of venous thromboembolism (VTE) and for stroke prevention in atrial fibrillation (AF). However, evidence in obese and underweight patients is limited. We assessed the safety and effectiveness of DOACs and vitamin K antagonists (VKAs) in patients  ≥ 120 kg or ≤ 50 kg enrolled in an observational prospective cohort study, the START-Register., Methods: Adult patients started on anticoagulant therapy were followed up for a median of 1.5 years (IQR 0.6-2.8). Primary efficacy outcome was the occurrence of VTE recurrence, stroke and systemic embolism. Primary safety outcome was major bleeding (MB)., Results: 10,080 AF and VTE patients were enrolled between March 2011 and June 2021, 295 patients weighted  ≤ 50 kg and 82 patients ≥ 120 kg. Obese patients were significantly younger than underweight patients. Rates of thrombotic events were low and similar between DOACs and VKAs in underweight patients (1 event on DOACs therapy [0.9% 95% CI 0.11-5.39] and 2 on VKAs [1.1% 95% CI 0.01-47.68]) and in overweight patients (0 events on DOACs, 1 on VKAs [1.6%, 95% CI 0.11-5.79]. Two MB events occurred on DOACs (1.9%, 95% CI 0.38-6.00) and 3 on VKAs (1.6%, 95% CI 0.04-22.06) in the underweight group; 1 MB on DOACs (5.3% 95% CI 0.33-16.68) and 2 on VKAs (3.3%, 95% CI 0.02-130.77) in the overweight group., Conclusions: DOACs seem to be effective and safe also for the treatment of patients with extreme body weights, both underweight and overweight. Further prospective studies are needed to support these findings., (© 2023. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

COVID-19 infection causes respiratory pathology with severe interstitial pneumonia and extra-pulmonary complications; in particular, it may predispose to thromboembolic disease. The current guidelines recommend the use of thromboprophylaxis in patients with COVID-19, however, the optimal heparin dosage treatment is not well-established. We conducted a multicentre, Italian, retrospective, observational study on COVID-19 patients admitted to ordinary wards, to describe clinical characteristic of patients at admission, bleeding and thrombotic events occurring during hospital stay. The strategies used for thromboprophylaxis and its role on patient outcome were, also, described. 1091 patients hospitalized were included in the START-COVID-19 Register. During hospital stay, 769 (70.7%) patients were treated with antithrombotic drugs: low molecular weight heparin (the great majority enoxaparin), fondaparinux, or unfractioned heparin. These patients were more frequently affected by comorbidities, such as hypertension, atrial fibrillation, previous thromboembolism, neurological disease, and cancer with respect to patients who did not receive thromboprophylaxis. During hospital stay, 1.2% patients had a major bleeding event. All patients were treated with antithrombotic drugs; 5.4%, had venous thromboembolism [30.5% deep vein thrombosis (DVT), 66.1% pulmonary embolism (PE), and 3.4% patients had DVT + PE]. In our cohort the mortality rate was 18.3%. Heparin use was independently associated with survival in patients aged ≥ 59 years at multivariable analysis. We confirmed the high mortality rate of COVID-19 in hospitalized patients in ordinary wards. Treatment with antithrombotic drugs is significantly associated with a reduction of mortality rates especially in patients older than 59 years., (© 2021. The Author(s).)

How to prevent recurrences after a first venous thromboembolic (VTE) event in elderly patients is still an open issue, especially because of the high bleeding risk of anticoagulation in these patients. The placebo-controlled "Jason" study aims at assessing the efficacy and safety for secondary VTE prevention in elderly patients of oral Sulodexide (Vessel ® ) administration, a mixture of glycosaminoglycans (Alfasigma, Bologna, Italy) which proved effective against recurrences in a general population (SURVET study) without major bleeding (MB) complications. 1450 patients, aged ≥ 75 years, after at least 3 months of anticoagulation treatment for a first VTE episode, are double-blind randomized to receive for 12 months either sulodexide 500 lipasemic units (LSUs) twice daily, or sulodexide 250 LSU twice daily + indistinguishable placebo, or indistinguishable placebo. Primary outcomes for efficacy are the composite of death for VTE and recurrent VTE, and occurrence of MB for safety. Secondary outcomes include stroke, cardiovascular death and other thromboembolic events, and MB + clinically relevant non-MB. The first patient is scheduled to be randomized in May 2020. The study protocol has been approved by AIFA (Agenzia Italiana del Farmaco) and the Ethics Committee of the coordinating center. Written informed consent will be obtained from all patients prior to study participation. Jason study is an investigator-initiated trial, promoted by "Arianna Anticoagulazione" Foundation, Bologna, Italy, and supported by Alfasigma, Bologna, Italy. Study findings will be disseminated to participant centers, at research conferences and in peer-reviewed journals. Trial registration numbers NCT04257487; EudraCT (2019-000570-33).

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 1 year. 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 1 year, 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 1 year.

Male patients, especially the young, are at a higher risk of recurrent venous thromboembolism (RVTE) than females. Recent scientific reports show the use of D-dimer does not help predict RVTE risk in males. In the present report, we reviewed the data obtained in the DULCIS study (main report published in Blood 2014), focusing on D-dimer results recorded in non-elderly patients of both genders included in the study, and their relationship with RVTE events occurring during follow-up. Using specifically designed cutoff values for positive/negative interpretation, serial D-dimer measurements (performed during warfarin treatment and up to 3 months after discontinuation of anticoagulation) in 475 patients (males 57.3%) aged ≤ 65 years were obtained. D-dimer resulted positive in 46.3% and 30.5% of males and females, respectively (p = 0.001). Following management procedure, anticoagulation was stopped in 53.7% of males and 69.5% of females, who had persistently negative D-dimer results. The rate of subsequent recurrent events was 1.7% (95% CI 0.5-4.5%) and 0.4% (95% CI 0-2.5%) patient-years in males and females, respectively, with upper limits of confidence intervals always below the level of risk considered acceptable by international scientific societies for stopping anticoagulation (< 5%). In conclusion, using sensitive quantitative assays with specifically designed cutoff values and serial measurements during and after discontinuation of anticoagulation, D-dimer testing is useful to predict the risk of RVTE and is of help in deciding the duration of anticoagulation in both male and female adult patients aged up to 65 years.

The management of major bleeding in patients treated with direct oral anticoagulants (DOACs) is still not well established. START-Events, a branch of the START registry (Survey on anTicoagulated pAtients RegisTer) (NCT02219984), aims to describe the actual management of bleeding or recurrent thrombotic events in routine clinical practice. We here present the results of the management of bleeding patients. The START-Event registry is a prospective, observational, multicenter, international study. Baseline characteristics (demographic, clinical, risk factors) of patients, laboratory data at admission and during follow-up, site of bleeding, therapeutic strategies, and outcomes at the time of hospital discharge and after 6 months were recorded on a web-based case report form. Between January 2015 and December 2016, 117 patients with major bleeding events were enrolled. Non-valvular atrial fibrillation (NVAF) was the indication for treatment in 84% (62% males); 53 patients had intracranial bleeding (13 fatal), 42 had gastrointestinal bleeding (1 fatal), and 22 had bleeding in other sites. Therapeutic interventions for the management of bleeding were performed in 71% of patients. Therapeutic strategies with/without surgery or invasive procedures included: fluid replacement or red blood cells transfusion, prothrombin complex concentrates (3 or 4 factors), antifibrinolytic drugs, and the administration of idarucizumab. Creatinine, blood cell count, and PT/aPTT were the most frequent tests requested, while specific DOAC measurements were performed in 23% of patients. Mortality during hospitalization was 11.9%, at 6-month follow-up 15.5%. Our data confirm a high heterogeneity in the management of bleeding complications in patients treated with DOACs.

Cerebral vein thrombosis (CVT) is a rare disease usually affecting young people, especially women, with a high prevalence of thrombophilic defects. It is known that thrombophilia is associated with pregnancy complications; therefore, a high rate of complications could be expected in women with the previous CVT who become pregnant. This study examined the whole obstetric history of women who suffered from CVT to evaluate the incidence of pregnancy complications during their entire lifespan. We prospectively followed consecutive patients with CVT, limiting the analysis to females and their obstetrical history. We studied 123 pregnancies in 99 consecutive women who had a CVT; 71 women had 91 pregnancies before the CVT; 19 women had 23 pregnancies after the CVT; and nine women had a CVT related to pregnancy. All women with CVT before pregnancy were treated with LMWH at prophylactic dosage during pregnancy. No recurrent CVT, venous thromboembolic events, or death was recorded during the observed pregnancies. Ten miscarriages were recorded (rate 8.1%), with a rate similar to that expected in the general population. We confirm the favorable outcome of pregnancies in women who suffered from CVT during their entire lifespan, whether they have occurred before and after or in relation to CVT.

Recent findings suggest that patients with non-valvular atrial fibrillation (AF), in addition to having a high risk for ischemic stroke, are also at risk for myocardial infarction (MI). The aim of the study was to combine factors predicting Major Adverse Cardiovascular Events (MACE) in AF patients, including fatal/nonfatal MI, cardiac revascularization, and cardiovascular death, into a simple risk score. Predictors of MACE were obtained from a prospective observational cohort study, including 1019 AF patients taking vitamin K antagonists from the Atherothrombosis Center, of Sapienza University of Rome. Thus, we derived the 2MACE score [2 points for Metabolic Syndrome and Age ≥75, 1 point for MI/revascularization, Congestive heart failure (ejection fraction ≤40 %), thrombo-Embolism (stroke/transient ischemic attack)], ranging from 0 to 7 points. To evaluate the 2MACE score, we included an external validation cohort of 1089 anticoagulated AF patients from the Thrombosis Centre of Azienda Ospedaliero-Universitaria Careggi, Firenze, Italy. At follow-up, 111 AF patients in the internal and 68 in the external cohort experienced a MACE. The 2MACE score showed a good ability in discriminating AF patients experiencing MACE both in the internal derivation cohort, with a c-index of 0.79 [95 % Confidence Interval (CI) 0.71-0.90, p < 0.001] and in the external validation cohort (c-index 0.66, 95 % CI 0.60-0.73, p < 0.001). The overall Hazard Ratio (HR) was 1.61 (95 % CI 1.40-1.85, p < 0.001) for each additional point. A 2MACE score ≥3 had the best combination of specificity and sensitivity, with an HR of 3.92 (95 % CI 2.41-6.40, p < 0.001). The new simple 2MACE score may help identifying AF patients at risk for cardiovascular events.

Stroke prevention, achieved with oral anticoagulation therapy (OAT), is central to the management of patients with atrial fibrillation (AF). Well-managed OAT, as reflected by a long time in therapeutic range (TTR), is associated with good clinical outcomes. The SAME-TT2R2 score has been proposed to identify patients who will maintain a high average TTR on vitamin K antagonists (VKA) treatment. The objective of the study was to validate this score in a cohort of AF patients followed by an anticoagulation clinic. We applied the SAME-TT2R2 score to 1,089 patients with AF on VKAs followed by two anticoagulation clinics. The median TTR overall for the whole cohort was 73.0 %. There was a significant decline in mean (or median) TTR in relation to the SAME-TT2R2 score (p = 0.042). When the SAME-TT2R2 scores were categorized we find a TTR 74.0 % for score ≤2 and 68.0 % for score >2 (p = 0.006). The rate of major bleeding events and stroke/TIA was 1.78 × 100 patient-years (pt-yrs) and 1.26 × 100 pt-yrs, respectively. No relationship exists between the SAME-TT2R2 score and adverse events. We describe the first validation of the SAME-TT2R2 score in AF patients where, despite an overall good quality of anticoagulation, the SAME-TT2R2 score is able to identify the patients who are less likely to do well on VKA therapy if this is the chosen OAT.