Venous thromboembolism secondary to hospitalization for COVID-19: patient management and long-term outcomes.

Background: Venous thromboembolism (VTE) is a complication of COVID-19 in hospitalized patients. Little information is available on long-term outcomes of VTE in this population. Objectives: We aimed to compare the characteristics, management strategies, and long-term clinical outcomes between patients with COVID-19-associated VTE and patients with VTE provoked by hospitalization for other acute medical illnesses. Methods: This is an observational cohort study, with a prospective cohort of 278 patients with COVID-19-associated VTE enrolled between 2020 and 2021 and a comparison cohort of 300 patients without COVID-19 enrolled in the ongoing START2-Register between 2018 and 2020. Exclusion criteria included age <18 years, other indications to anticoagulant treatment, active cancer, recent (<3 months) major surgery, trauma, pregnancy, and participation in interventional studies. All patients were followed up for a minimum of 12 months after treatment discontinuation. Primary end point was the occurrence of venous and arterial thrombotic events. Results: Patients with VTE secondary to COVID-19 had more frequent pulmonary embolism without deep vein thrombosis than controls (83.1% vs 46.2%, P <.001), lower prevalence of chronic inflammatory disease (1.4% and 16.3%, P <.001), and history of VTE (5.0% and 19.0%, P <.001). The median duration of anticoagulant treatment (194 and 225 days, P = 0.9) and the proportion of patients who discontinued anticoagulation (78.0% and 75.0%, P = 0.4) were similar between the 2 groups. Thrombotic event rates after discontinuation were 1.5 and 2.6 per 100 patient-years, respectively (P = 0.4). Conclusion: The risk of recurrent thrombotic events in patients with COVID-19-associated VTE is low and similar to the risk observed in patients with VTE secondary to hospitalization for other medical diseases.

Hybrid Palliation for Hypoplastic Borderline Left Ventricle: One More Chance to Biventricular Repair.

Treatment options for hypoplastic borderline left ventricle (LV) are critically dependent on the development of the LV itself and include different types of univentricular palliation or biventricular repair performed at birth. Since hybrid palliation allows deferring major surgery to 4-6 months, in borderline cases, the decision can be postponed until the LV has expressed its growth potential. We aimed to evaluate anatomic modifications of borderline LV after hybrid palliation. We retrospectively reviewed data from 45 consecutive patients with hypoplastic LV who underwent hybrid palliation at birth between 2011 and 2015. Sixteen patients (mean weight 3.15 Kg) exhibited borderline LV and were considered for potential LV growth. After 5 months, five patients underwent univentricular palliation (Group 1), eight biventricular repairs (Group 2) and three died before surgery. Echocardiograms of Groups 1 and 2 were reviewed, comparing LV structures at birth and after 5 months. Although, at birth, all LV measurements were far below the normal limits, after 5 months, LV mass in Group 2 was almost normal, while in Group 1, no growth was evident. However, aortic root diameter and long axis ratio were significantly higher in Group 2 already at birth. Hybrid palliation can be positively considered as a "bridge-to-decision" for borderline LV. Echocardiography plays a key role in monitoring the growth of borderline LV.

Direct oral anticoagulants in patients with a left-sided bioprosthetic heart valve: a systematic review and meta-analysis.

To compare the efficacy/effectiveness and safety of DOACs versus VKAs in patients with a previously and newly surgically implanted BHV with or without AF. A systematic search on MEDLINE and EMBASE was performed till November 2022. Treatment effects were estimated with relative risk (RR) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed with the I2 statistic. Four randomized controlled trials (RCTs), 2 subgroup analysis from ARISTOTLE and ENGAGE-AF-TIMI 48 and 4 observational studies were included for a total of 5808 patients, 1893 on DOACs and 3915 on VKAs. AF prevalence was 98.28%. In the overall analysis, DOACs vs VKAs were associated with a RR for stroke/transient ischemic attack (TIA)/systemic embolism (SE) of 0.63 (95% CI 0.51-0.79; I2 = 0%) and a RR of major bleeding of 0.50 (95% CI 0.39-0.63; I2 = 0%) in a median follow-up of 19 months (IQR 4.5-33.4). In the 3 RCTs (DAWA, RIVER, ENAVLE), DOACs vs VKAs were associated with a RR of stroke/TIA/SE and major bleeding of 0.38 (95% CI 0.13-1.58, I2 = 0%) and of 0.68 (95% CI 0.32-1.44; I2 = 5%) respectively. In patients randomized during the first three months from valve surgery, DOACs vs VKAs were associated with a RR of stroke/TIA/SE and major bleeding of 0.54 (95% CI 0.14-2.08; I2 = 0%) and of 0.76 (95% CI 0.05-10.72; I2 = 66%). In previously implanted BHV patients with AF, DOACs showed a risk-benefit profile at least comparable to VKAs. DOACs showed a similar, even if underpowered, risk-benefit profile during the first three months after BHV implantation prevalently in patients with AF.

Oral anticoagulant management of patients with mechanical heart valves at the Salam Centre of Khartoum: Observations on quality of anticoagulation and thrombotic risk.

INTRODUCTION: Rheumatic heart disease with mechanical heart valve (MHV) replacement is common in Africa. However, MHV requires long-life anticoagulation and managing this can be challenging. METHODS AND RESULTS: We report data of a prospective observational study conducted between August 2018 and September 2019 in MHV patients in the Salam Centre for Cardiac Surgery built in Khartoum, by Emergency, an Italian Non-Governmental Organization, to evaluate the quality of anticoagulation control and the risk of thrombotic complications. RESULTS: We studied 3647 patients (median age 25.1 years; 53.9 % female). Median Time in Therapeutic Range (TTR) was 53 % (interquartile range 37 % to 67 %) and 70 thrombotic events (rate 1.8 × 100 pt-years [95 % CI 1.38-2.23]) were recorded. Among patients in the first quartile of TTR (≤37 %), we recorded 34/70 (48.6 %) of all thrombotic events (rate 3.7 × 100 pt-years [95 % CI 2.5-5.1]), with a high mortality rate (2.2 × 100 pt-years [95 % CI 1.3-3.3]). In patients with guideline-recommended TTR (≥65 %) the event rate was 0.8 × 100 pt-years for thrombotic events [95 % CI 0.3-1.5] and 0.4 × 100 pt-years for mortality [95 % CI 0.1-0.9]. Multivariable analysis showed that having a TTR in the lowest quartile (≤37 %) and being noncompliant are significantly associated with increased thrombotic risk. Aspirin use or different valve type did not influence the thrombotic risk. Almost 40 % of all thromboembolic complications could have been potentially prevented by further improving VKA management to obtain a TTR > 37 %. CONCLUSION: The thrombotic risk of MHV patients on VKAs living in a low-income country like Sudan is associated with low quality of anticoagulation control. Efforts should be made to decrease the number of non-compliant patients and to reach a guideline-recommended TTR of ≥65 %.

Anti-SARS-CoV-2 vaccination does not influence anticoagulation levels in stable long-term warfarin treatment.

BACKGROUND: Since the outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, administration of the currently available vaccines has mostly been recommended for subjects at high risk, including elderly populations on long-term oral anticoagulation therapy (OAT) with warfarin. However, there is no clear evidence of the stability of the International Normalised Ratio (INR) after vaccine administration in those subjects on long-term OAT. The present study aimed to investigate the effects of COVID-19 vaccination on anticoagulation levels in patients on long-term OAT. MATERIALS AND METHODS: INR values of patients on long-term OAT who had undergone anti-SARS-CoV-2 vaccination from January to June 2021 were monitored for a total of 90 days follow-up after the first vaccination dose. These were then compared with INR values before vaccination. The second dose, when required, was administered during follow-up. Inclusion criterion was stable long-term INR for at least 6 months before vaccination. Exclusion criteria were recent surgery, intercurrent diseases, or treatment with medication that could compromise findings in the 3 months before vaccination and during follow-up. RESULTS: No differences were observed in the anticoagulation levels before and after COVID-19 vaccination in any of the patients studied: mean INR values were 2.39 (range 2.20-2.63) before vaccination and 2.40 (range 2.16-2.76) after vaccination (p=0.5). There was no difference in anticoagulation levels in relation to age, sex, indication for OAT, or type of vaccine (p>0.5). No bleeding or thrombotic complications were documented during follow-up. DISCUSSION: These are the first data to be reported on anticoagulation levels in patients on stable OAT after COVID-19 vaccination. No influence on the quality of OAT was detected after the vaccination; no bleeding or thrombotic complications were recorded in the follow-up. No difference between the four available COVID vaccines was found. Dose adjustment was only required in a few cases, thus confirming the stability of anticoagulation levels.

Low in-hospital mortality rate in patients with COVID-19 receiving thromboprophylaxis: data from the multicentre observational START-COVID Register.

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.

Management of DOAC in Patients Undergoing Planned Surgery or Invasive Procedure: Italian Federation of Centers for the Diagnosis of Thrombotic Disorders and the Surveillance of the Antithrombotic Therapies (FCSA) Position Paper.

Patients on anticoagulant treatment are constantly increasing, with an estimated prevalence in Italy of 2% of the total population. About a quarter of the anticoagulated patients require temporary cessation of direct oral anticoagulants (DOACs) or vitamin K antagonists for a planned intervention within 2 years from anticoagulation inception. Several clinical issues about DOAC interruption remain unanswered: many questions are tentatively addressed daily by thousands of physicians worldwide through an experience-based balancing of thrombotic and bleeding risks. Among possible valuable answers, the Italian Federation of Centers for the diagnosis of thrombotic disorders and the Surveillance of the Antithrombotic therapies (FCSA) proposes some experience-based suggestions and expert opinions. In particular, FCSA provides practical guidance on the following issues: (1) multiparametric assessment of thrombotic and bleeding risks based on patients' individual and surgical risk factor, (2) testing of prothrombin time, activated partial thromboplastin time, and DOAC plasma levels before surgery or invasive procedure, (3) use of heparin, (4) restarting of full-dose DOAC after high risk bleeding surgery, (5) practical nonpharmacological suggestions to manage patients perioperatively. Finally, FCSA suggests creating a multidisciplinary "anticoagulation team" with the aim to define the optimal perioperative management of anticoagulation.

Sex-based difference in anticoagulated patients with mechanical prosthetic heart valves and long-term mortality risk.

BACKGROUND: Vitamin K antagonists (VKAs) reduce thromboembolism in patients with mechanical prosthetic heart valves (MPHV). It is unclear whether a sex-based difference in MPHV patients regarding valve site, anticoagulation quality, and mortality risk does exist. METHODS: We analysed 2111 MPHV patients from the nationwide PLECTRUM study promoted by the Italian Federation of Anticoagulation Clinics (FCSA). We analysed the site of MPHV, anticoagulation quality, as assessed by the time in therapeutic range (TiTR), and mortality risk in women and men. RESULTS: The mean age of the patients was 56.8 ± 12.3 years. Women were older with a lower prevalence of ischemic heart disease and smoking habit and a higher prevalence of atrial fibrillation at baseline. Aortic MPHV was more frequent in men (74.7% vs 43.3%, P < .001), whereas mitral (41.1% vs 17.6%, P < .001) and mitro-aortic (15.6% vs 7.7%, P < .001) MPVH in women. The association between female sex and mitral/mitro-aortic site remained at multivariable logistic regression analysis (Odds Ratio 3.623, 95% Confidence Interval [CI] 2.947-4.455, P < .001). Regarding anticoagulation quality, women showed lower mean TiTR (63.0 ± 19.4 vs 57.5 ± 19.2, P < .001), and a higher proportion of TiTR < 60% (54.9% vs 43.3%, P < .001). During a mean follow-up of 123 months (21 665 pt-years), 152 deaths occurred (0.7%/year); 83 in the aortic (0.63%/year) and 69 in the mitral/mitro-aortic (0.81%/year) group. At multivariable Cox proportional hazard regression analysis, female sex was not associated with mortality (HR 0.953, 95%CI 0.678 1.340, P = .783). CONCLUSIONS: Female sex is independently associated with mitral/mitro-aortic MPHV. Despite a lower TiTR in women, mortality risk did not differ between the two groups.

Position paper on the safety/efficacy profile of Direct Oral Anticoagulants in patients with Chronic Kidney Disease: Consensus document of Società Italiana di Nefrologia (SIN), Federazione Centri per la diagnosi della trombosi e la Sorveglianza delle terapie Antitrombotiche (FCSA) and Società Italiana per lo Studio dell'Emostasi e della Trombosi (SISET).

Direct oral anticoagulants (DOAC) are mostly prescribed to prevent cardioembolic stroke in patients with non-valvular atrial fibrillation (AF). An increasing number of guidelines recommend DOAC in AF patients with preserved renal function for the prevention of thromboembolism and an increased use of DOAC in daily practice is recorded also in elderly patients. Aging is associated with a reduction of glomerular filtration rate and impaired renal function, regardless of the cause, increases the risk of bleeding. Multiple medication use (polypharmacy) for treating superimposed co-morbidities is common in both elderly and chronic kidney disease (CKD) patients and drug-drug interaction may cause accumulation of DOAC, thereby increasing the risk of bleeding. There is uncertainty on the safety profile of DOAC in patients with CKD, particularly in those with severely impaired renal function or end stage renal disease, due to the heterogeneity of studies and the relative paucity of data. This document reports the position of three Italian scientific societies engaged in the management of patients with atrial fibrillation who are treated with DOAC and present with CKD.

Position paper on the safety/efficacy profile of direct oral anticoagulants in patients with chronic kidney disease. Consensus document from the SIN, FCSA and SISET.

Direct oral anticoagulants (DOAC) are mostly prescribed to prevent cardioembolic stroke in patients with non-valvular atrial fibrillation (AF). An increasing number of guidelines recommend DOAC in AF patients with preserved renal function for the prevention of thromboembolism, and an increased use of DOAC in daily practice has been recorded also in elderly patients. Ageing is associated with a reduction in glomerular filtration rate, and impaired renal function, regardless of the cause, increases the risk of bleeding. Multiple medication use (polypharmacy) for treating superimposed co-morbidities is common in both elderly and chronic kidney disease (CKD) patients and drug-drug interaction may cause accumulation of DOAC, thereby increasing the risk of bleeding. The safety profile of DOAC in patients with CKD has not been defined with any certainty, particularly in those with severely impaired renal function or end stage renal disease. This has been due to the heterogeneity of studies and the relative paucity of data. This document reports the position of three Italian scientific societies engaged in the management of patients with atrial fibrillation who are treated with DOAC and present with CKD.

Anticoagulation in Italian patients with venous thromboembolism and thrombophilic alterations: findings from START2 register study.

BACKGROUND: Randomised control trials have assessed the efficacy and safety of direct oral anticoagulants in the prophylaxis and treatment of venous thromboembolism (VTE). Positive but limited results have been reported in patients with inherited thrombophilia. Using an Italian, multicentre, prospective registry of consecutive patients presenting with symptomatic, acute VTE, we aimed to assess which factors are involved in making the choice of the drug that best fits the patient's risk profile in a large real-world setting of VTE patients. MATERIALS AND METHODS: We investigated 4,866 VTE patients who took oral anticoagulants in the period between 2012 and April 2018 to prevent a new thromboembolic episode. RESULTS: The large majority of patients who underwent thrombophilic screening, regardless of the results obtained, were prescribed direct oral anticoagulants rather than conventional anticoagulant therapy (p<0.001). During anticoagulation, bleeding events occurred more frequently in patients on conventional anticoagulant therapy (4.2%) than in those receiving direct oral anticoagulants (1.8%) and an increase in bleeding events was observed in patients who tested positive at the thrombophilic screening. Overall, a higher number of recurrent VTE was observed in patients not screened for thrombophilia (n=36; 1.7%) than in those screened (n=20; 0.7%; adjusted odds ratio: 2.2; 95% confidence interval: 1.2-4.1). DISCUSSION: The present data confirm previous findings from other post-marketing registries and suggest that the choice of oral anticoagulation is strongly driven by patients' characteristics and VTE manifestations. Factors leading to the prescription of thrombophilic screening may identify a patient with a lower risk of VTE recurrence during anticoagulation.

Determinants of low-quality warfarin anticoagulation in patients with mechanical prosthetic heart valves. The nationwide PLECTRUM study.

Quality of warfarin therapy in patients with a mechanical prosthetic heart valve (MPHV) has been barely investigated. We analysed determinants of low time in the therapeutic range (TiTR <60%) in 2111 patients with MPHVs from the nationwide PLECTRUM study by the Italian Federation of Anticoagulation Clinics. Overall, 48·5% of patients had a TiTR of < 60%. At logistic regression analysis, arterial hypertension (odds ratio [OR] 1·502, P < 0·001), diabetes (OR 1·732, P < 0·001), heart failure (OR 1·484, P = 0·004), mitral site (vs. aortic) (OR 1·399, P = 0·006), international normalised ratio (INR) ranges of 2·5-3·5 (OR 2·575, P < 0·001) and 3·0-4·0 (OR 8·215, P < 0·001) associated with TiTR < 60%. TiTR is substantially suboptimal in MPHV patients, particularly in higher INR ranges.

Patients with isolated pulmonary embolism in comparison to those with deep venous thrombosis. Differences in characteristics and clinical evolution.

BACKGROUND: Patients with acute pulmonary embolism (PE) often have leg deep vein thrombosis (DVT); sometimes, however, a DVT is not detected (isolated PE, I-PE). We aimed at assessing the proportion of patients with I-PE, and their characteristics and clinical evolution compared to those with DVT with/without PE (DVT/PE). METHODS: Among 3573 patients included in the START2-Register for a venous thromboembolic event, 2880 (80.6%) had DVT/PE, the remaining I-PE (19.4%). RESULTS: Patients with I-PE were older [(≥75 years, OR 1.4 (95%CI 1.13-1.69)], and more frequently females [OR 1.4 (1.19-1.67)]. Young females (aged ≤ 50 years) with an index event occurring during hormonal contraception (HC), were more prevalent in I-PE [OR 1.96 (1.26-3.03)]. At multivariate analysis, age > 75 years, female sex, heart failure, cancer and use of HC were risk factors significantly associated with I-PE, whereas thrombophilic alterations were associated with DVT/PE. During a follow-up of 4504 years (during anticoagulation), the rate of bleeding events was 1.1% patient/years and 1.0% patient/years in I-PE and DVT/PE, respectively. Venous thromboembolic events were equally prevalent in DVT/PE or I-PE (1.94% vs 0.86%, ns), whereas arterial complications were more prevalent in the latter group (1.01% vs 0.28%, p = 0.008). CONCLUSION: I-PE and DVT/PE have important differences. Older age, female sex, heart failure and cancer, were risk factors for I-PE; thrombophilic alterations were associated with DVT/PE. HC use was more frequent in the I-PE group. The prevalence of arterial complications was higher in patients with I-PE. Further studies, specifically designed on this issue, are warranted.

Risk of reoperation in bioprosthetic valve patients with indication for long-term anticoagulation. Results from the observational retrospective multicentre PLECTRUM study.

Objective: Several factors should be considered when a prosthetic heart valve, bioprosthetic valve (BV) or mechanical valve is to be implanted: thrombogenicity, life expectancy and the risk of reoperation. Methods: We conducted an observational retrospective multicentre study among Italian Thrombosis Centers on patients with BV on long-term vitamin K antagonist (VKA) treatment to evaluate the risk of reoperation and the rate of bleeding and thrombotic events. Results: We analysed 612 patients (median age 71.8 years) with BV on long-term VKA treatment for the presence of atrial fibrillation (AF) (78.4%) or other indications (21.6%). Thirty-four major bleeding events (rate 1.1×100 patient-years) and 29 thromboembolic events (rate 0.9×100 patient-years) were recorded, and 46 patients (rate 1.5×100 patient-years) underwent reoperation. The rate of reoperation was higher among younger patients: 32.9% in patients <60 years and 3.9% in patients ≥60 years (relative risk (RR) 3.8, 95% CI 2.1 to 7.2; p=0.0001). When patients were analysed according to age <65 or ≥65 years and <75 or ≥70 years, younger patients still were at higher risk for reoperation (RR 3.1, 95% CI 1.7 to 6.0 and 3.7, 95% CI 1.7 to 8.6, respectively). Conclusions: Our findings suggest that the threshold of 65 years for implanting a BV should be carefully evaluated, considering the high risk for reoperation and the high risk of AF occurrence with persisting need for long-term anticoagulation. The high risk for reoperation of young patients implanted with BV and the availability of a safer and easier way to conduct VKA treatment, such as the use of point-of-care devices, should be considered when the type of valve must be chosen.

Management of major bleeding and outcomes in patients treated with direct oral anticoagulants: results from the START-Event registry.

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.

The vexed question of whether or not to measure levels of direct oral anticoagulants before surgery or invasive procedures.

Direct oral anticoagulants (DOAC) possess high bioavailability, and their anticoagulant effect is more predictable than that of vitamin K antagonists, hence they do not require routine dose adjustment based on laboratory testing. However, there are circumstances when laboratory testing may be useful, including patients who need to undergo surgery or invasive procedures. Most guidelines state that patients on DOAC may safely undergo surgery/invasive procedures by stopping anticoagulation for a few days before intervention without testing if renal function is within normal limits. This review article discusses the pros and cons of measuring (or not measuring) DOAC levels before surgery/invasive procedures by a multidisciplinary team of experts with different background, including the thrombosis laboratory, clinical thrombosis, internal medicine, cardiology and nephrology. The conclusion is that measuring DOAC with dedicated tests before surgical or invasive procedures is important for patient safety. It provides the best and most direct evidence to rule in (or to rule out) clinically relevant concentrations of residual drugs. Regulatory agencies should urgently approve their use in clinical practice. Hospital administrators should make them available, and clinical laboratories should set up the relative methods and make them available to clinicians.

Intracranial hemorrhage recurrence on vitamin K antagonist: severity of the first episode and HASBLED score fail to identify high-risk patients from the CHIRONE study.

The most feared complication of vitamin K antagonists (VKAs) treatment is intracranial hemorrhage (ICH). The previously published CHIRONE Study fails to identify risk factors associated with ICH recurrence after VKAs resumption. The aim of this secondary analysis of the study is to evaluate if patients who need surgery or with severe neurological sequelae after the first episode show a higher risk of ICH recurrence. The HASBLED score was used to stratify bleeding risk and to evaluate the distribution of recurrence in relation to each class of risk. The study included 267 patients from 27 Italian centers. The treatment of the index ICH, surgical or medical was recorded; modified Rankin Scale score of 3 or more was used to define patients with severe neurological impairment; HASBLED score of 3 or more was used to identify high bleeding risk patients. During follow-up, 20 patients (7.5%) had ICH recurrence (rate of 2.56 × 100 patient-years). No difference in the type of treatment [hazard ratio = 1.5; 95% confidence interval (CI): 0.49-4.74] and neurological impairment with modified Rankin Scale 3 or more (hazard ratio = 0.9; 95% CI: 0.31-2.83) were found in relation to ICH recurrence. The mean HASBLED score was similar between the two groups (P = 0.54). In conclusion, the results of our study suggest that neither the severity of the index ICH at presentation nor the HASBLED clinical prediction rule should be used to assess the risk of recurrence in patients who need VKAs resumption after a previous ICH.

Imidazo[1,2-a]pyrazin-8-amine core for the design of new adenosine receptor antagonists: Structural exploration to target the A3 and A2A subtypes.

The imidazo[1,2-a]pyrazine ring system has been chosen as a new decorable core skeleton for the design of novel adenosine receptor (AR) antagonists targeting either the human (h) A3 or the hA2A receptor subtype. The N8-(hetero)arylcarboxyamido substituted compounds 4-14 and 21-30, bearing a 6-phenyl moiety or not, respectively, show good hA3 receptor affinity and selectivity versus the other ARs. In contrast, the 8-amino-6-(hetero)aryl substituted derivatives designed for targeting the hA2A receptor subtype (compounds 31-38) and also the 6-phenyl analogues 18-20 do not bind the hA2A AR, or show hA1 or balanced hA1/hA2A AR affinity in the micromolar range. Molecular docking of the new hA3 antagonists was carried out to depict their hypothetical binding mode to our refined model of the hA3 receptor. Some derivatives were evaluated for their fluorescent potentiality and showed some fluorescent emission properties. One of the most active hA3 antagonists herein reported, i.e. the 2,6-diphenyl-8-(3-pyridoylamino)imidazo[1,2-a]pyrazine 29, tested in a rat model of cerebral ischemia, delayed the occurrence of anoxic depolarization caused by oxygen and glucose deprivation in the hippocampus and allowed disrupted synaptic activity to recover.

Clinical history and antithrombotic treatment of incidentally detected splanchnic vein thrombosis: a multicentre, international prospective registry.

BACKGROUND: Little information is available about the clinical history of patients with incidentally detected splanchnic vein thrombosis and its therapeutic management remains controversial. The aim of this study was to assess the risk factors, therapeutic strategies, and long-term outcomes of incidentally detected splanchnic vein thrombosis. METHODS: We analysed data from patients with incidentally detected splanchnic vein thrombosis who were enrolled in an international, multicentre, prospective cohort study of splanchnic vein thrombosis between 2008 and 2012. The study was done at 31 centres in 11 countries (Italy, South Korea, Germany, Canada, Belgium, the Netherlands, Brazil, USA, France, Israel, UK). Information about demographic characteristics, risk factors, and treatment was collected. The study outcomes during the 2-year follow-up were major bleeding (International Society on Thrombosis and Haemostasis definition plus the need for hospital admission), thrombotic events (venous or arterial thromboses), and mortality. The primary analysis period was from the diagnosis of incidentally detected splanchnic vein thrombosis until the first adjudicated clinical outcome or the end of follow-up. FINDINGS: Between May 2, 2008, and Jan 30, 2012, we enrolled 177 patients with incidentally detected splanchnic vein thrombosis (median age 57 years [IQR 49-66], 118 [67%] men, 138 [78%] patients with portal vein thrombosis). The most common underlying diseases were liver cirrhosis (82 [46%] patients) and solid cancer (62 [35%] patients). Anticoagulant treatment was prescribed to 109 (62%) patients. Median duration of anticoagulation was 6 months (IQR 5-12) for patients who received parenteral anticoagulants alone and 24 months (IQR 12-24) for patients treated with vitamin K antagonists. During a median follow-up of 2 years (IQR 1-2), the incidence of major bleeding was 3·3 events (95% CI 1·7-6·3) per 100 patient-years and the incidence of thrombotic events was 8·0 events (95% CI 5·2-12·1) per 100 patient-years. On-treatment incidence was 3·2 events (95% CI 1·2-8·4) per 100 patient-years for major bleeding and 3·9 events (95% CI 1·6-9·5) per 100 patient-years for thrombotic events. In multivariate analysis, anticoagulant treatment as a time-dependent variable reduced the incidence of thrombotic events (hazard ratio 0·85, 95% CI 0·76-0·96) without increasing the risk of major bleeding (p>0·05). In patients with clinically suspected splanchnic vein thrombosis, the incidence of major bleeding was 3·9 events (95% CI 2·6-5·7) per 100 patient-years and the incidence of thrombotic events was 7·0 events (95% CI 5·2-9·3) per 100 patient-years. INTERPRETATION: Our results show that the prognosis of incidentally detected splanchnic vein thrombosis is similar to that of clinically suspected splanchnic vein thrombosis and suggest that similar treatment strategies should be applied. FUNDING: Pfizer Canada research grant.