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Current guidelines suggest a 3-month anticoagulant treatment course for isolated distal deep vein thrombosis (IDDVT), but shorter durations of treatment are frequently prescribed in clinical practice. We investigated whether a 6-week treatment with low-molecular-weight heparin (LMWH) at intermediate dosage can be an effective and safe alternative to vitamin K antagonists (VKA) in patients with IDDVT (non-inferiority trial). In a multicenter, open-label, randomized trial, 260 outpatients with symptomatic IDDVT were randomly assigned to receive either LMWH followed by VKA for 12 weeks or LMWH 1 mg/kg subcutaneously twice a day for 2 weeks followed by 1 mg/kg subcutaneously once a day for 4 weeks. The follow-up was 6 months and the primary endpoint was the composite measure of recurrent venous thromboembolism (VTE) defined as: recurrence or extension of IDDVT, proximal DVT, and pulmonary embolism (PE). The study was stopped prematurely due to slow recruiting rates. The primary efficacy outcome occurred in 14 patients receiving LMWH (10.8%) and in five patients receiving VKA (3.8%); risk difference was 0.069 (95% CI: 0.006-0.132), hazard ratio 2.8 (95% CI: 1.04-7.55). There was one PE in the VKA group and one proximal DVT in the LMWH group. IDDVT recurrence was 10.0% in the LMWH group versus 3.1% in the VKA group (p = .024). Two patients had clinically relevant bleedings (1.6%) in the LMWH group versus one (0.8%) in VKA group (p = .56). In conclusion, VKA for 12 weeks seems superior to LMWH for 6 weeks in reducing the risk of VTE recurrences in our cohort of outpatients with IDDVT., (© 2024 Wiley Periodicals LLC.)

Anticoagulation represents the first line treatment for venous thromboembolism (VTE). However, inferior vena cava (IVC) filter insertion can be considered as a possible therapeutic strategy when anticoagulant therapy is contraindicated, to avoid embolization from the lower limbs to pulmonary circulation. Other possible indications are debated among experts. Both permanent and retrievable caval filters are available in clinical practice. Retrievable filters can be removed when no longer necessary, as their use may be indicated only for a limited amount of time. Moreover, caval filter insertion is not devoid of possible complications, particularly in cases of permanent or long-dwelling filters. A multidisciplinary approach is recommended to review the appropriateness of caval filter use and to define the best timing for retrieval.

Background  Isolated distal deep vein thromboses (IDDVT) are frequently diagnosed; however, their natural history and real risk of complications are still uncertain. Though treatment is still not well standardized, international guidelines recommend no more than 3 months of anticoagulation therapy. We investigated how Italian clinicians treat IDDVT patients in their real life in our country. Methods  Baseline characteristics and clinical history of the patients enrolled in the prospective, observational, multicenter START-Register for a first IDDVT or proximal DVT (PDVT) were analyzed. Results  Overall, 412 IDDVT patients were significantly younger, with better renal function, and more frequent major transient risk factors, when compared with 1,173 PDVT patients. The anticoagulation duration was >180 days in 52.7% of IDDVT patients (70.7% in PDVT). During treatment, bleeding occurred in 5.6 and 2.8% patient-years in IDDVT and PDVT, respectively ( p  = 0082). Bleeding was more frequent in IDDVT than PDVT patients treated with warfarin (6.8 vs. 3.2 patient-years, p  = 0.0228, respectively). Thrombotic complications occurred in 1.1 and 2.4% patient-years in IDDVT and PDVT patients, respectively. Analyzing together the two groups, 66.1% of bleeds and 86.1% thrombotic complications occurred after 90 days anticoagulation treatment. Conclusion  The large majority of IDDVT patients received anticoagulation for more than 3 months. Most bleeding and thrombotic complications occurred after the first 90 days of anticoagulation therapy. These results indicate that an extended anticoagulation beyond 90 days in IDDVT patients is associated with increased risk of complications. Whether an extended treatment may lower recurrences after anticoagulation withdrawal should be assessed by specifically designed studies., Competing Interests: Conflict of Interest The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. G.P. reports consulting fees from Alfasigma SpA., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Introduction: The aim of this study in patients with acute posterior ischaemic stroke (PS) and atrial fibrillation (AF) was to evaluate (1) the risks of recurrent ischaemic event and severe bleeding and (2) these risks in relation with oral anticoagulant therapy (OAT) and its timing., Materials and Methods: Patients with PS were prospectively included; the outcome events of these patients were compared with those of patients with anterior stroke (AS) which were taken from previous registries. The primary outcome was the composite of stroke recurrence, transient ischaemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding occurring within 90 days from acute stroke., Results: A total of 2470 patients were available for the analysis: 473 (19.1%) with PS and 1997 (80.9%) with AS. Over 90 days, 213 (8.6%) primary outcome events were recorded: 175 (8.7%) in patients with AS and 38 (8.0%) in those with PS. In patients who initiated OAT within 2 days, the primary outcome occurred in 5 out of 95 patients (5.3%) with PS compared to 21 out of 373 patients (4.3%) with AS (OR 1.07; 95% CI 0.39-2.94). In patients who initiated OAT between days 3 and 7, the primary outcome occurred in 3 out of 103 patients (2.9%) with PS compared to 26 out of 490 patients (5.3%) with AS (OR 0.54; 95% CI 0.16-1.80)., Discussion: our findings suggest that, when deciding the time to initiate oral anticoagulation, the location of stroke, either anterior or posterior, does not predict the risk of outcome events., Conclusions: Patients with PS or AS and AF appear to have similar risks of ischaemic or haemorrhagic events at 90 days with no difference concerning the timing of initiation of OAT., (© European Stroke Organisation 2020.)

Background and Purpose: The optimal timing for starting oral anticoagulant after an ischemic stroke related to atrial fibrillation remains a challenge, mainly in patients treated with systemic thrombolysis or mechanical thrombectomy. We aimed at assessing the incidence of early recurrence and major bleeding in patients with acute ischemic stroke and atrial fibrillation treated with thrombolytic therapy and/or thrombectomy, who then received oral anticoagulants for secondary prevention., Methods: We combined the dataset of the RAF and the RAF-NOACs (Early Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Treated With Non-Vitamin K Oral Anticoagulants) studies, which were prospective observational studies carried out from January 2012 to March 2014 and April 2014 to June 2016, respectively. We included consecutive patients with acute ischemic stroke and atrial fibrillation treated with either vitamin K antagonists or nonvitamin K oral anticoagulants. Primary outcome was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding within 90 days from the inclusion. Treated-patients were propensity matched to untreated-patients in a 1:1 ratio after stratification by baseline clinical features., Results: A total of 2159 patients were included, 564 (26%) patients received acute reperfusion therapies. After the index event, 505 (90%) patients treated with acute reperfusion therapies and 1287 of 1595 (81%) patients untreated started oral anticoagulation. Timing of starting oral anticoagulant was similar in reperfusion-treated and untreated patients (median 7.5 versus 7.0 days, respectively). At 90 days, the primary study outcome occurred in 37 (7%) patients treated with reperfusion and in 146 (9%) untreated patients (odds ratio, 0.74 [95% CI, 0.50-1.07]). After propensity score matching, risk of primary outcome was comparable between the 2 groups (odds ratio, 1.06 [95% CI, 0.53-2.02])., Conclusions: Acute reperfusion treatment did not influence the risk of early recurrence and major bleeding in patients with atrial fibrillation-related acute ischemic stroke, who started on oral anticoagulant.

The risk of recurrence of venous thromboembolism (VTE) persists after interruption of the initial anticoagulation therapy. New evidence shows that direct oral anticoagulants are effective for extended treatment of VTE and may reduce the risk of all-cause mortality. The optimal duration of anticoagulation after VTE is, however, controversial and complicated by the need for individualised assessment and balance between thrombosis and bleeding risks. Three direct oral anticoagulants (rivaroxaban, apixaban and dabigatran) have been studied for extended treatment of VTE. Dabigatran was shown to be safer than vitamin K antagonists and similarly effective for the prevention of recurrent VTE. Dabigatran, apixaban and rivaroxaban resulted in significant decreases in the rate of recurrent symptomatic VTE when compared to placebo, without a statistically significant difference in the risk of major bleeding. The latest guidelines of the American College of Chest Physicians suggest the use of low-dose aspirin to prevent VTE recurrence in patients who want to stop anticoagulation. In the randomised, double-blind, phase 3 EINSTEIN CHOICE trial, once-daily rivaroxaban at doses of 20 mg or 10 mg and 100 mg of aspirin were compared in VTE patients for whom there was clinical equipoise for extended anticoagulation. Either a treatment dose (20 mg) or a prophylactic dose (10 mg) of rivaroxaban significantly reduced the risk of VTE recurrence without a significant increase in bleeding risk compared with aspirin. The EINSTEIN CHOICE trial included patients with provoked or unprovoked VTE. Patients with VTE provoked by minor persistent or minor transient risk factors enrolled in this trial had not-negligible VTE recurrence rates. These new findings on extended therapy suggest the possibility of anticoagulation regimens at intensities tailored to the patients' risk profiles and VTE characteristics, with a shift of the risk-benefit balance in favour of extended treatment.

Background: Venous thromboembolism (VTE) accounts for an estimated 900,000 cases per year in the US alone and constitutes a considerable burden on healthcare systems across the globe., Objective: To understand why the burden is so high, qualitative and quantitative research was carried out to gain insights from experts, guidelines and published studies on the unmet clinical needs and therapeutic strategies in VTE prevention and treatment in three populations identified as being at increased risk of VTE and in whom VTE prevention and treatment were regarded as suboptimal: pregnant women, the elderly and obese patients., Methodology: A gap analysis methodology was created to highlight unmet needs in VTE management and to discover the patient populations considered most at risk. A questionnaire was devised to guide qualitative interviews with 44 thrombosis and haemostasis experts, and a review of the literature on VTE in the specific patient groups from 2015 to 2017 was completed. This was followed by a Think Tank meeting where the results from the research were discussed., Results: This review highlights the insights gained and examines in detail the unmet needs with regard to VTE risk-assessment tools, biomarkers, patient stratification methods, and anticoagulant and dosing regimens in pregnant women, the elderly and obese patients., Conclusions: Specifically, in pregnant women at high risk of VTE, low-molecular-weight heparin (LMWH) is the therapy of choice, but it remains unclear how to use anticoagulants when VTE risk is intermediate. In elderly patients, evaluation of the benefit of VTE prophylaxis against the bleeding risk is particularly important, and a head-to-head comparison of efficacy and safety of LMWH versus direct oral anticoagulants is needed. Finally, in obese patients, lack of guidance on anticoagulant dose adjustment to body weight has emerged as a major obstacle in effective prophylaxis and treatment of VTE., Competing Interests: Competing interestsBB receives honoraria for lectures and advisory board contributions from Pfizer, LEO Pharma, Sanofi, ROVI Laboratories and Bayer Pharmaceuticals; RA received research grants from Bayer and Covidien and honoraria from Bayer, Sanofi, Pfizer and Boehringer-Ingelheim; JBW is involved with all the NOAC manufacturers (Bayer, Boehringer, Pfizer, Daiichi and Portola) and took part in the current ASH guideline panel; JD participated in advisory boards or educational activities for Bayer, Boehringer-Ingelheim, Pfizer and Sanofi and is currently chair of the Clinical Endpoint Committee, MARINER trial for Janssen Research and Development; RH is a member of the executive committee for ‘Betrixaban in the acutely medically ill population’ sponsored by Portola and was awarded a grant to University of Calgary by Portola; IE is involved in various advisory boards (Sanofi, Bayer, Pfizer, Bristol Myers Squibb, Shire, Aspen, Leo Pharma and Stago), has received research grants from Sanofi, Leo Pharma and Stago, and gives industry-sponsored lectures in symposia (Sanofi, Bayer, Pfizer, Bristol Myers Squibb, Shire, Aspen, Leo Pharma and Stago); DI and ZZ have no competing interests to report., (© The Author(s). 2019.)

Background: Assessing the impact of the environment on plant performance requires growing plants under controlled environmental conditions. Plant phenotypes are a product of genotype × environment (G × E), and the Enviratron at Iowa State University is a facility for testing under controlled conditions the effects of the environment on plant growth and development. Crop plants (including maize) can be grown to maturity in the Enviratron, and the performance of plants under different environmental conditions can be monitored 24 h per day, 7 days per week throughout the growth cycle., Results: The Enviratron is an array of custom-designed plant growth chambers that simulate different environmental conditions coupled with precise sensor-based phenotypic measurements carried out by a robotic rover. The rover has workflow instructions to periodically visit plants growing in the different chambers where it measures various growth and physiological parameters. The rover consists of an unmanned ground vehicle, an industrial robotic arm and an array of sensors including RGB, visible and near infrared (VNIR) hyperspectral, thermal, and time-of-flight (ToF) cameras, laser profilometer and pulse-amplitude modulated (PAM) fluorometer. The sensors are autonomously positioned for detecting leaves in the plant canopy, collecting various physiological measurements based on computer vision algorithms and planning motion via "eye-in-hand" movement control of the robotic arm. In particular, the automated leaf probing function that allows the precise placement of sensor probes on leaf surfaces presents a unique advantage of the Enviratron system over other types of plant phenotyping systems., Conclusions: The Enviratron offers a new level of control over plant growth parameters and optimizes positioning and timing of sensor-based phenotypic measurements. Plant phenotypes in the Enviratron are measured in situ-in that the rover takes sensors to the plants rather than moving plants to the sensors., Competing Interests: Competing interestsThe authors declare no competing interests. David Imberti, Daniel Kiekhaefer and Henry Imberti are employees of Percival Scientific, Inc., the manufacturer of the Enviratron’s plant growth chambers., (© The Author(s) 2019.)

Background and Purpose- Bridging therapy with low-molecular-weight heparin reportedly leads to a worse outcome for acute cardioembolic stroke patients because of a higher incidence of intracerebral bleeding. However, this practice is common in clinical settings. This observational study aimed to compare (1) the clinical profiles of patients receiving and not receiving bridging therapy, (2) overall group outcomes, and (3) outcomes according to the type of anticoagulant prescribed. Methods- We analyzed data of patients from the prospective RAF and RAF-NOACs studies. The primary outcome was defined as the composite of ischemic stroke, transient ischemic attack, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding observed at 90 days after the acute stroke. Results- Of 1810 patients who initiated oral anticoagulant therapy, 371 (20%) underwent bridging therapy with full-dose low-molecular-weight heparin. Older age and the presence of leukoaraiosis were inversely correlated with the use of bridging therapy. Forty-two bridged patients (11.3%) reached the combined outcome versus 72 (5.0%) of the nonbridged patients (P=0.0001). At multivariable analysis, bridging therapy was associated with the composite end point (odds ratio, 2.3; 95% CI, 1.4-3.7; P<0.0001), as well as ischemic (odds ratio, 2.2; 95% CI, 1.3-3.9; P=0.005) and hemorrhagic (odds ratio, 2.4; 95% CI, 1.2-4.9; P=0.01) end points separately. Conclusions- Our findings suggest that patients receiving low-molecular-weight heparin have a higher risk of early ischemic recurrence and hemorrhagic transformation compared with nonbridged patients.

Background: Clinical practice shows that venous thromboembolism (VTE) presents a substantial burden in medical patients, and awareness and advocacy for its primary and secondary prevention remains inadequate. Specific patient populations, such as those with cancer and the critically ill, show elevated risk for VTE, bleeding or both, and significant gaps in VTE prophylaxis and treatment exist in these groups., Objective: To present novel insights and consolidated evidence collected from experts, clinical practice guidelines and original studies on the unmet needs in thromboprophylaxis, and on the treatment of VTE in two high-risk patient groups: patients with cancer and the critically ill., Methodology: To identify specific unmet needs in the management of VTE, a methodology was designed and implemented that assessed gaps in prophylaxis and treatment of VTE through interviews with 44 experts in the field of thrombosis and haemostasis, and through a review of current guidelines and seminal studies to substantiate the insights provided by the experts. The research findings were then analysed, discussed and consolidated by a multidisciplinary group of experts., Results: The gap analysis methodology identified shortcomings in the VTE risk assessment tools, patient stratification approaches for prophylaxis, and the suboptimal use of anticoagulants for primary prophylaxis and treatment., Conclusions: Specifically, patients with cancer need better VTE risk assessment tools to tailor primary thromboprophylaxis to tumour types and disease stages, and the potential for drug-drug interactions needs to be considered. In critically ill patients, unfractionated heparin is not advised as a first-line treatment option, and the strength of evidence is increasing for direct oral anticoagulants as a treatment option over low-molecular-weight heparins., Competing Interests: Not applicable.Not applicable.BB receives honoraria for lectures and advisory board contributions from Pfizer, LEO Pharma, Sanofi, ROVI Laboratories and Bayer Pharmaceuticals; RH is a member of the executive committee for ‘Betrixaban in the acutely medically ill population’ sponsored by Portola and was awarded a grant to University of Calgary by Portola; RA received research grants from Bayer and Covidien and honoraria from Bayer, Sanofi, Pfizer and Boehringer-Ingelheim; JBW is involved with all the NOAC manufacturers (Bayer, Boehringer, Pfizer, Daiichi and Portola) and took part in the current ASH guideline panel; JD participated in advisory boards or educational activities for Bayer, Boehringer-Ingelheim, Pfizer and Sanofi, and is currently Chair of the Clinical Endpoint Committee, MARINER trial for Janssen Research and Development; IE is involved in various advisory boards (Sanofi, Bayer, Pfizer, Bristol Myers Squibb, Shire, Aspen, Leo-Pharma and Stago), has received research grants from Sanofi, Leo-Pharma and Stago, and gives industry-sponsored lectures in symposia (Sanofi, Bayer, Pfizer, Bristol Myers Squibb, Shire, Aspen, Leo-Pharma and Stago); DI and ZZ have no competing interests to report.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: The relationship between different patterns of atrial fibrillation and early recurrence after an acute ischaemic stroke is unclear., Purpose: In a prospective cohort study, we evaluated the rates of early ischaemic recurrence after an acute ischaemic stroke in patients with paroxysmal atrial fibrillation or sustained atrial fibrillation which included persistent and permanent atrial fibrillation., Methods: In patients with acute ischaemic stroke, atrial fibrillation was categorised as paroxysmal atrial fibrillation or sustained atrial fibrillation. Ischaemic recurrences were the composite of ischaemic stroke, transient ischaemic attack and symptomatic systemic embolism occurring within 90 days from acute index stroke., Results: A total of 2150 patients (1155 females, 53.7%) were enrolled: 930 (43.3%) had paroxysmal atrial fibrillation and 1220 (56.7%) sustained atrial fibrillation. During the 90-day follow-up, 111 ischaemic recurrences were observed in 107 patients: 31 in patients with paroxysmal atrial fibrillation (3.3%) and 76 with sustained atrial fibrillation (6.2%) (hazard ratio (HR) 1.86 (95% CI 1.24-2.81)). Patients with sustained atrial fibrillation were on average older, more likely to have diabetes mellitus, hypertension, history of stroke/ transient ischaemic attack, congestive heart failure, atrial enlargement, high baseline NIHSS-score and implanted pacemaker. After adjustment by Cox proportional hazard model, sustained atrial fibrillation was not associated with early ischaemic recurrences (adjusted HR 1.23 (95% CI 0.74-2.04))., Conclusions: After acute ischaemic stroke, patients with sustained atrial fibrillation had a higher rate of early ischaemic recurrence than patients with paroxysmal atrial fibrillation. After adjustment for relevant risk factors, sustained atrial fibrillation was not associated with a significantly higher risk of recurrence, thus suggesting that the risk profile associated with atrial fibrillation, rather than its pattern, is determinant for recurrence.

Objectives: This multicentre study aimed to investigate the overall mortality of combined pulmonary fibrosis and emphysema (CPFE) in systemic sclerosis (SSc) and to compare CPFE-SSc characteristics with those of other SSc subtypes (with interstitial lung disease-ILD, emphysema or neither)., Methods: Chest CTs, anamnestic data, immunological profile and pulmonary function tests of patients with SSc were retrospectively collected. Each chest CT underwent a semiquantitative assessment blindly performed by three radiologists. Patients were clustered in four groups: SSc-CPFE, SSc-ILD, SSc-emphysema and other-SSc (without ILD nor emphysema). The overall mortality of these groups was calculated by Kaplan-Meier method and compared with the stratified log-rank test; Kruskal-Wallis test, t-Student test and χ² test assessed the differences between groups. P<0.05 was considered statistically significant., Results: We enrolled 470 patients (1959 patient-year); 15.5 % (73/470) died during the follow-up. Compared with the SSc-ILD and other-SSc, in SSc-CPFE there was a higher prevalence of males, lower anticentromere antibodies prevalence and a more reduced pulmonary function (p<0.05). The Kaplan-Meier survival analysis demonstrates a significantly worse survival in patients with SSc-CPFE (HR vs SSc-ILD, vs SSc-emphysema and vs other-SSc, respectively 1.6 (CI 0.5 to 5.2), 1.6 (CI 0.7 to 3.8) and 2.8 (CI 1.2 to 6.6)., Conclusions: CPFE increases the mortality risk in SSc along with a highly impaired lung function. These findings strengthen the importance to take into account emphysema in patients with SSc with ILD., Competing Interests: Competing interests: None declared.

Background In patients with acute ischemic stroke and atrial fibrillation, early anticoagulation prevents ischemic recurrence but with the risk of hemorrhagic transformation ( HT ). The aims of this study were to evaluate in consecutive patients with acute stroke and atrial fibrillation (1) the incidence of early HT, (2) the time to initiation of anticoagulation in patients with HT , (3) the association of HT with ischemic recurrences, and (4) the association of HT with clinical outcome at 90 days. Methods and Results HT was diagnosed by a second brain computed tomographic scan performed 24 to 72 hours after stroke onset. The incidence of ischemic recurrences as well as mortality or disability (modified Rankin Scale scores >2) were evaluated at 90 days. Ischemic recurrences were the composite of ischemic stroke, transient ischemic attack, or systemic embolism. Among the 2183 patients included in the study, 241 (11.0%) had HT . Patients with and without HT initiated anticoagulant therapy after a mean 23.3 and 11.6 days, respectively, from index stroke. At 90 days, 4.6% (95% confidence interval, 2.3-8.0) of the patients with HT had ischemic recurrences compared with 4.9% (95% confidence interval, 4.0-6.0) of those without HT ; 53.1% of patients with  HT were deceased or disabled compared with 35.8% of those without HT . On multivariable analysis, HT was associated with mortality or disability (odds ratio, 1.71; 95% confidence interval, 1.24-2.35). Conclusions In patients with HT , anticoagulation was initiated about 12 days later than patients without HT . This delay was not associated with increased detection of ischemic recurrence. HT was associated with increased mortality or disability.

Two large randomized controlled trials examined the efficacy and safety of rivaroxaban for the treatment of venous thromboembolism (VTE). The aim of this epidemiological study was to analyze a cohort of Italian patients affected by VTE who were treated with rivaroxaban in clinical practice. The data were collected by physicians using an online electronic questionnaire. The study was performed during a 6-month period from January to June 2014. We analyzed the clinical characteristics, risk factors for VTE, comorbidities, diagnostic techniques, and treatments in the whole population and in the subgroups with deep vein thrombosis (DVT) only, pulmonary embolism (PE) only, and DVT+PE. Overall, 75.9% of patients were affected by DVT; 20% of patients had DVT and PE; and 4.8% of patients had only PE. Approximately 90% of patients were symptomatic upon diagnosis, and 46.3% of patients required hospitalization. More than half of the patients switched to rivaroxaban after receiving another anticoagulant therapy. The main reasons for changing treatment included difficulties in managing vitamin K antagonists, patient choice, and prothrombin time-international normalized ratio (PT-INR) instability. The switch to rivaroxaban occurred after a mean of 1.8 PT-INR measurements. Clinical characteristic were overall similar to those of patients enrolled in prior clinical trials evaluating the safety and efficacy of rivaroxaban.

Objective: In this multicentre study, we aimed to evaluate the capacity of a computer-assisted automated QCT method to identify patients with SSc-associated interstitial lung disease (SSc-ILD) with high mortality risk according to validated composite clinical indexes (ILD-Gender, Age, Physiology index and du Bois index)., Methods: Chest CT, anamnestic data and pulmonary function tests of 146 patients with SSc were retrospectively collected, and the ILD-Gender, Age, Physiology score and DuBois index were calculated. Each chest CT underwent an operator-independent quantitative assessment performed with a free medical image viewer (Horos). The correlation between clinical prediction models and QCT parameters was tested. A value of P < 0.05 was considered statistically significant., Results: Most QCT parameters had a statistically different distribution in patients with diverging mortality risk according to both clinical prediction models (P < 0.01). The cut-offs of QCT parameters were calculated by receiver operating characteristic curve analysis, and most of them could discriminate patients with different mortality risk according to clinical prediction models., Conclusion: QCT assessment of SSc-ILD can discriminate between well-defined different mortality risk categories, supporting its prognostic value. These findings, together with the operator independence, strengthen the validity and clinical usefulness of QCT for assessment of SSc-ILD., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Recently, the European Medicines Agency (EMA) authorized the introduction and marketing of Thorinane® and Inhixa®, biosimilars of the Low Molecular Weight Heparin (LMWH) enoxaparin. The authorization path is considerably different from the guidelines published by the EMA in 2009, as well as from the recommendations from the International Society on Thrombosis and Haemostasis published in 2013. Indeed, both of them recommended that LMWHs biosimilars therapeutic equivalence should be demonstrated in at least one adequately designed clinical trial. Shortly after enoxaparin biosimilars approval, EMA published a revised version of its guideline, no longer requiring the execution of a clinical study in patients at risk of venous thromboembolism. Also the assessment of safety shows some relevant flaws, as it relies only on a 20 healthy volunteers study, clearly underpowered to draw any conclusions about the safety profile of the drug. In our opinion, the approach taken by EMA for approval of enoxaparin biosimilars raises serious concerns about their actual, clinical "similarity". On these grounds, with the endorsement of the Italian Society for Haemostasis and Thrombosis (SISET) and the Italian Society for Angiology and Vascular Medicine (SIAPAV), we elaborated the present document aimed at reviewing and reappraising some critical points regarding the introduction of biosimilars of LMWH in Europe. Moreover, we would strongly advise the Italian National Health Authorities not to entrust safety assessment to the post-marketing surveillance only, but to promote well designed and powered studies aimed at establish the actual efficacy and safety of LMWH biosimilars.

Background and Purposes: This study was designed to derive and validate a score to predict early ischemic events and major bleedings after an acute ischemic stroke in patients with atrial fibrillation., Methods: The derivation cohort consisted of 854 patients with acute ischemic stroke and atrial fibrillation included in prospective series between January 2012 and March 2014. Older age (hazard ratio 1.06 for each additional year; 95% confidence interval, 1.00-1.11) and severe atrial enlargement (hazard ratio, 2.05; 95% confidence interval, 1.08-2.87) were predictors for ischemic outcome events (stroke, transient ischemic attack, and systemic embolism) at 90 days from acute stroke. Small lesions (≤1.5 cm) were inversely correlated with both major bleeding (hazard ratio, 0.39; P =0.03) and ischemic outcome events (hazard ratio, 0.55; 95% confidence interval, 0.30-1.00). We assigned to age ≥80 years 2 points and between 70 and 79 years 1 point; ischemic index lesion >1.5 cm, 1 point; severe atrial enlargement, 1 point (ALESSA score). A logistic regression with the receiver-operating characteristic graph procedure (C statistic) showed an area under the curve of 0.697 (0.632-0.763; P =0.0001) for ischemic outcome events and 0.585 (0.493-0.678; P =0.10) for major bleedings., Results: The validation cohort consisted of 994 patients included in prospective series between April 2014 and June 2016. Logistic regression with the receiver-operating characteristic graph procedure showed an area under the curve of 0.646 (0.529-0.763; P =0.009) for ischemic outcome events and 0.407 (0.275-0.540; P =0.14) for hemorrhagic outcome events., Conclusions: In acute stroke patients with atrial fibrillation, high ALESSA scores were associated with a high risk of ischemic events but not of major bleedings., (© 2017 American Heart Association, Inc.)

Introduction: Atrial fibrillation is an independent risk factor of thromboembolism. Women with atrial fibrillation are at a higher overall risk for stroke compared to men with atrial fibrillation. The aim of this study was to evaluate for sex differences in patients with acute stroke and atrial fibrillation, regarding risk factors, treatments received and outcomes., Methods: Data were analyzed from the "Recurrence and Cerebral Bleeding in Patients with Acute Ischemic Stroke and Atrial Fibrillation" (RAF-study), a prospective, multicenter, international study including only patients with acute stroke and atrial fibrillation. Patients were followed up for 90 days. Disability was measured by the modified Rankin Scale (0-2 favorable outcome, 3-6 unfavorable outcome)., Results: Of the 1029 patients enrolled, 561 were women (54.5%) ( p  < 0.001) and younger ( p  < 0.001) compared to men. In patients with known atrial fibrillation, women were less likely to receive oral anticoagulants before index stroke ( p  = 0.026) and were less likely to receive anticoagulants after stroke (71.3% versus 78.4%, p  = 0.01). There was no observed sex difference regarding the time of starting anticoagulant therapy between the two groups (6.4 ± 11.7 days for men versus 6.5 ± 12.4 days for women, p  = 0.902). Men presented with more severe strokes at onset (mean NIHSS 9.2 ± 6.9 versus 8.1 ± 7.5, p  < 0.001). Within 90 days, 46 (8.2%) recurrent ischemic events (stroke/TIA/systemic embolism) and 19 (3.4%) symptomatic cerebral bleedings were found in women compared to 30 (6.4%) and 18 (3.8%) in men ( p  = 0.28 and p  = 0.74). At 90 days, 57.7% of women were disabled or deceased, compared to 41.1% of the men ( p  < 0.001). Multivariate analysis did not confirm this significance., Conclusions: Women with atrial fibrillation were less likely to receive oral anticoagulants prior to and after stroke compared to men with atrial fibrillation, and when stroke occurred, regardless of the fact that in our study women were younger and with less severe stroke, outcomes did not differ between the sexes.

Background and Purpose: The best time for administering anticoagulation therapy in acute cardioembolic stroke remains unclear. This prospective cohort study of patients with acute stroke and atrial fibrillation, evaluated (1) the risk of recurrent ischemic event and severe bleeding; (2) the risk factors for recurrence and bleeding; and (3) the risks of recurrence and bleeding associated with anticoagulant therapy and its starting time after the acute stroke., Methods: The primary outcome of this multicenter study was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding within 90 days from acute stroke., Results: Of the 1029 patients enrolled, 123 had 128 events (12.6%): 77 (7.6%) ischemic stroke or transient ischemic attack or systemic embolism, 37 (3.6%) symptomatic cerebral bleeding, and 14 (1.4%) major extracranial bleeding. At 90 days, 50% of the patients were either deceased or disabled (modified Rankin score ≥3), and 10.9% were deceased. High CHA2DS2-VASc score, high National Institutes of Health Stroke Scale, large ischemic lesion and type of anticoagulant were predictive factors for primary study outcome. At adjusted Cox regression analysis, initiating anticoagulants 4 to 14 days from stroke onset was associated with a significant reduction in primary study outcome, compared with initiating treatment before 4 or after 14 days: hazard ratio 0.53 (95% confidence interval 0.30-0.93). About 7% of the patients treated with oral anticoagulants alone had an outcome event compared with 16.8% and 12.3% of the patients treated with low molecular weight heparins alone or followed by oral anticoagulants, respectively (P=0.003)., Conclusions: Acute stroke in atrial fibrillation patients is associated with high rates of ischemic recurrence and major bleeding at 90 days. This study has observed that high CHA2DS2-VASc score, high National Institutes of Health Stroke Scale, large ischemic lesions, and type of anticoagulant administered each independently led to a greater risk of recurrence and bleedings. Also, data showed that the best time for initiating anticoagulation treatment for secondary stroke prevention is 4 to 14 days from stroke onset. Moreover, patients treated with oral anticoagulants alone had better outcomes compared with patients treated with low molecular weight heparins alone or before oral anticoagulants., (© 2015 American Heart Association, Inc.)

Pharmacological prophylaxis for preventing venous thromboembolism (VTE) is a worldwide established procedure in hip and knee replacement surgery, as well as in the treatment of femoral neck fractures, but few data exist in other fields of orthopaedics and traumatology. Thus, no guidelines or recommendations are available in the literature except for a limited number of weak statements about knee arthroscopy and lower limb fractures. In any case, none of them are a multidisciplinary effort as the one here presented. The Italian Society for Studies on Haemostasis and Thrombosis (SISET), the Italian Society of Orthopaedics and Traumatology (SIOT), the Association of Orthopaedic Traumatology of Italian Hospitals (OTODI), together with the Italian Society of Anesthesia, Analgesia, Resuscitation and Intensive Care (SIAARTI) and the Italian Society of General Medicine (SIMG) have set down easy and quick suggestions for VTE prophylaxis in a number of surgical conditions for which only scarce evidence is available. This inter-society consensus statement aims at simplifying the approach to VTE prophylaxis in the single patient with the goal to improve its clinical application.

Background: Optimal doses and duration of low-molecular-weight heparin (LMWH) for the treatment of superficial vein thrombosis (SVT) are still uncertain., Objectives: To compare the efficacy and safety of different doses and durations of LMWH parnaparin for symptomatic lower limb SVT., Patients and Methods: Outpatients with at least a 4-cm-long SVT of long or short saphenous veins or their collaterals were randomized to receive parnaparin either 8500 UI once daily ( o.d.) for 10 days followed by placebo for 20 days (group A) or 8500 UI o.d. for 10 days followed by 6400 UI once daily (o.d.) for 20 days (group B) or 4250 UI o.d. for 30 days (group C) in a double-blind fashion in 16 clinics. Primary outcome was the composite of symptomatic and asymptomatic deep vein thrombosis (DVT), symptomatic pulmonary embolism (PE) and relapse and/or symptomatic or asymptomatic SVT recurrence in the first 33 days with 60 days follow-up., Results: Among 664 patients, primary outcome occurred in 33/212 (15.6%), 4/219 (1.8%) and 16/217 (7.3%) subjects in groups A, B and C, respectively (B vs. A: absolute risk reduction [ARR]: 13.7%, 95% confidence intervals [CI]: 8-18.9 P<0.001; B vs. C: ARR: 5.5%; 95% CI: 1.6-9.4 P= 0.011; C vs. A: ARR: 8.2%, 95% CI: 2-14 P=0.012). During days 0-93, the event rate was higher in group A (22.6%) than either in group B (8.7%; P=0.001) or C (14.3%, P=0.034). No major hemorrhages occurred., Conclusions: An intermediate dose of parnaparin for 30 days is superior to either a 30-day prophylactic dose or a 10-day intermediate dose for lower limb SVT treatment., (© 2012 International Society on Thrombosis and Haemostasis.)

Background: The management of acute aortic aneurysm rupture or dissection (AARD) requires specific medical expertise, diagnostic techniques, and therapeutic options, not always available in all hospitals through the entire week. The aim of our study was to evaluate whether an association exists between weekday (WD) or weekend (WE) admission and mortality for patients with ARRD., Methods: Based on the database of routinely collected hospital admissions of the region of Emilia Romagna (RER) of Italy, we examined the discharge sheets of all patients with AARD (January 1999 to December 2009). The risk of in-hospital death was calculated for admissions on the WE compared with the admissions during a WD., Results: The analysis considered 4559 events in 4461 patients. AARD admissions were most frequent on Monday (14.7%) and Friday (14.8%) and less frequent on Saturday (12.6%). The percentage of events admitted on Sunday/holiday was 15.0%, whereas the distribution of death rate with respect to day of admission was significantly different (χ(2) = 23.472; P < .001) with the highest frequency peak on Sunday/holiday (17.4%) and the lowest on Tuesday (12.9%). WE admissions were associated with significantly higher in-hospital mortality (43.4%) than WD admissions (36.9%, P < .001). Multivariate regression analysis showed that WE admission was an independent risk factor for increased in-hospital mortality odds ratio 1.318; 95% confidence interval, 1.144-1.517; P < .001)., Conclusions: Our findings show that hospitalization for AARD on WE is associated with a significantly higher mortality rate than hospitalization on WD. Further studies are needed to investigate whether ensuring optimal diagnostic and therapeutic approaches during the entire week might improve the overall survival of patients with ARRD., (Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Intracranial haemorrhage is a serious and potentially fatal complication of oral anticoagulant therapy. Prothrombin complex concentrates can substantially shorten the time needed to reverse the effects of oral anticoagulants. The aim of this study was to determine the efficacy and safety of a prothrombin complex concentrate for rapid reversal of oral anticoagulant therapy in patients with intracranial haemorrhage., Methods: Patients receiving oral anticoagulant therapy and suffering from acute intracranial haemorrhage were eligible for this prospective cohort study if their International Normalised Ratio (INR) was higher than or equal to 2.0. The prothrombin complex concentrate was infused at doses of 35-50 IU/kg, stratified according to the initial INR., Results: Forty-six patients (25 males; mean age: 75 years; range 38-92 years) were enrolled. The median INR at presentation was 3.5 (range, 2-9). At 30 minutes after administration of the prothrombin complex concentrate, the median INR was 1.3 (range, 0.9-3), and the INR then declined to less than or equal to 1.5 in 75% of patients. The benefit of the prothrombin complex concentrate was maintained for a long time, since the median INR remained lower than or equal to 1.5 (median, 1.16; range, 0.9-2.2) at 96% of all post-infusion time-points up to 96 hours. No thrombotic complications or significant adverse events were observed during hospitalisation; six patients (13%) died, but none of these deaths was judged to be related to administration of the prothrombin complex concentrate., Conclusions: Prothrombin complex concentrates are an effective, rapid and safe treatment for the urgent reversal of oral anticoagulation in patients with intracranial haemorrhage. Broader use of prothrombin complex concentrates in this clinical setting appears to be appropriate.

Anticoagulant prophylaxis for preventing venous thromboembolism (VTE) is a worldwide established procedure in hip and knee replacement surgery, as well as in the treatment of femoral neck fractures (FNF). Different guidelines are available in the literature, with quite different recommendations. None of them is a multidisciplinary effort as the one presented. The Italian Society for Studies on Haemostasis and Thrombosis (SISET), the Italian Society of Orthopaedics and Traumatology (SIOT), the association of Orthopaedists and Traumatologists of Italian Hospitals (OTODI), together with the Italian Society of Anesthesia, Analgesia, Resuscitation, and Intensive Care (SIAARTI) have set down easy and quick suggestions for VTE prophylaxis in hip and knee surgery as well as in FNF treatment. This inter-society consensus statement aims at simplifying the grading system reported in the literature, and its goal is to benefit its clinical application. Special focus is given to fragile patients, those with high bleeding risk, and those receiving chronic antiplatelet (APT) and vitamin K antagonists treatment. A special chapter is dedicated to regional anaesthesia and VTE prophylaxis.

Background: Clinical characteristics and management of acute deep vein thrombosis and pulmonary embolism (PE) have been reported to be different in patients with and without cancer. The aim of this paper was to provide information on clinical characteristics and management of acute venous thromboembolism in patients with cancer by means of a large prospective registry., Design and Methods: MASTER is a multicenter registry of consecutively recruited patients with symptomatic, objectively confirmed, acute venous thromboembolism. Information about clinical characteristics and management was collected by an electronic data network at the time of the index event., Results: A total of 2119 patients were enrolled, of whom 424 (20%) had cancer. The incidence of bilateral lower limb deep vein thrombosis was significantly higher in patients with cancer than in patients without cancer (8.5% versus 4.6%; p<0.01), as were the rates of iliocaval thrombosis (22.6% versus 14%; p<0.001), and upper limb deep vein thrombosis (9.9% versus 4.8%; p<0.001). Major bleeding (3.3% versus 1.1%; p=0.001), in-hospital treatment (73.3% versus 66.6%; p=0.02) and inferior vena cava filter implantation (7.3% versus 4.1%; p=0.005) were significantly more frequent in patients with cancer, in whom oral anticoagulants were less often used (64.2% versus 82%; p<0.0001)., Conclusions: The clinical presentation of acute venous thromboembolism is different and often more extensive in cancer patients than in patients free from malignancy. Moreover, the management of the acute phase of venous thromboembolism is more problematic in cancer patients, especially because of a higher rate of major bleeding and the need for implantation of inferior vena cava filters.

Background: Out of hospital management of patients with suspected deep vein thrombosis (DVT) can be problematic. The accuracy of clinical prediction rules in the primary care setting may be inadequate, D-dimer testing may not be available, and the cost-effectiveness of urgent ultrasonographic evaluation is uncertain., Objective: The purpose of this study was to determine the efficacy and safety of an empiric single therapeutic dose of low-molecular weight heparin (LMWH) in the time interval preceding ultrasound investigation in patients presenting to primary care physicians (PCPs) for suspicion of DVT., Methods: Consecutive patients with suspected DVT who presented to the office of a PCP outside regular thrombosis center working hours were enrolled. All eligible patients received a single therapeutic dose of LMWH (100 anti-Xa IU kg(-1) weight) and were scheduled to undergo clinical and instrumental evaluation at the thrombosis center the morning after. Clinical events were documented after a 3-month follow-up., Results: A total of 534 consecutive patients with suspected DVT were included in this study; of these 102 patients had subsequent diagnosis of DVT. We detected no episodes of pulmonary embolism, major bleeding, or death during the 18-h window between the administration of LMWH and objective evaluation. Of the 432 patients in whom diagnosis of DVT was subsequently excluded, only three (0.7%; CI: 0.2-2.0%) developed venous thromboembolic events during the 3-month follow-up period., Conclusions: Empiric treatment with a single therapeutic dose of LMWH is effective and safe for outpatients with suspected DVT initially managed in a primary care setting. This strategy has the potential to reduce the need for urgent diagnostic imaging.

Background: Retrievable inferior vena cava (IVC) filters offer the attractive possibility to be definitive or to be removed when they become unnecessary., Objective: The purpose of this study was to evaluate the efficacy and the likelihood to remove the retrievable IVC filter ALN., Methods: A total of 30 patients (13 males and 17 females, mean age 57 +/- 15 years) underwent placement of ALN filters. Indications for implantation were acute venous thromboembolism (VTE) with a contraindication to anticoagulation in 26 cases (86%), primary prophylaxis after major trauma in two cases (7%) or before surgery in two patients with very high thromboembolic risk (7%)., Results: The filter was successfully placed in all patients. After a median follow-up of 18.2 months, there were three cases (10%) of trapped emboli within the filter, one case (3%) of asymptomatic migration of the filter toward the heart and two patients (7%) had deep vein thrombosis (DVT) recurrences. ALN retrieval was attempted through transjugular approach in 18 patients (60%) and the maneuver was successful in 14 of them (78%); when the decision of removal was taken more than 3 months after the implantation, the retrieval was possible only in four of eight patients (50%). The median implantation period was 123 days (range: 30-345)., Conclusions: The present study shows the efficacy of ALN filter; it also demonstrates the feasibility and safety of retrieval after a medium-term period of placement. Removal after 3 months after implantation can be unsuccessful and maximum implantation time requires further studies.

Aims: To evaluate the incidence of cardiovascular events in the long-term clinical course of patients with a first episode of symptomatic, objectively confirmed pulmonary embolism., Methods and Results: Three hundred and sixty patients with a first episode of pulmonary embolism were included in a prospective study: 209 with idiopathic pulmonary embolism and 151 with pulmonary embolism associated with transient risk factors. The study outcomes were cardiovascular events (recurrent venous thrombo-embolism, acute myocardial infarction, stroke, sudden otherwise unexplained death), cardiovascular death, and death due to any cause. The median follow-up was 38 months. Sixty-four patients had at least one cardiovascular event (5.5% patient-year). Recurrent venous thrombo-embolism occurred in 45 patients (3.9% patient-year), acute myocardial infarction in 12 patients (1.0% patient-year), stroke in six patients (0.5% patient-year), and sudden otherwise unexplained death in four patients (0.3% patient-year). A cardiovascular event occurred in 47 patients with idiopathic pulmonary embolism (7.5% patient-year) and in 17 patients with pulmonary embolism associated with transient risk factors (3.1% patient-year) (RR 2.0; 95% CI 1.20-3.34; P=0.006). Twenty patients with idiopathic pulmonary embolism (3.2% patient-year) and two patients with pulmonary embolism associated with transient risk factors (0.4% patient-year) presented an arterial cardiovascular event (RR 7.2; 95% CI 1.71-30.45; P=0.001). Thirty-three patients died (9.2%). Cardiovascular mortality and cancer mortality accounted for 42.4 and 21.2% of overall mortality, respectively. Idiopathic pulmonary embolism was an independent predictor of cardiovascular events after adjusting for age., Conclusions: Cardiovascular events are more common in patients with idiopathic pulmonary embolism than in patients with pulmonary embolism associated with transient risk factors. Cardiovascular events are the major cause of death in patients with idiopathic pulmonary embolism.