Search

International audience; Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening pulmonary embolism's (PE) complication whose incidence and predictors are not precisely determined.Objective: To determine the frequency and predictors for CTEPH after a first unprovoked PE.Patients/methods: In a randomized trial comparing an additional 18-month warfarin versus placebo in patients after a first unprovoked PE initially treated with vitamin K antagonist for 6 months, we applied recommended CTEPH screening strategies through 8-year follow-up to determine cumulative incidence of CTEPH. CTEPH predictors were estimated using Cox models. Pulmonary vascular obstruction (PVO) and systolic pulmonary arterial pressure (sPAP) at PE diagnosis and 6 months were studied by receiver operating curves analysis. All CTEPH cases and whether they were incident or prevalent were adjudicated.Results: During a median follow-up of 8.7 years, 9 CTEPH cases were diagnosed among 371 patients, with a cumulative incidence of 2.8% (95% confidence interval [CI], 0.95-4.64), and of 1.31% (95%CI, 0.01-2.60) after exclusion of 5 cases adjudicated as prevalent. At PE diagnosis, PVO>45% and sPAP>56mmHg were associated with CTEPH with a hazard ratio (HR) of 33.00 (95%CI 1.64-667.00, p=0.02) and 12.50 (95%CI 2.10-74.80, p65 years, lupus anticoagulant antibodies and non-O blood groups were also predictive of CTEPH. PVO>14% and sPAP>34mmHg at 6-month were associated with CTEPH (HRs 63.90 [95%CI, 3.11-1310.00, p

International audience; Background: The orally available kinase inhibitor R-roscovitine has undergone clinical trials against various cancers and is currently under clinical evaluation against Cushing disease and rheumatoid arthritis. Roscovitine displays biological properties suggesting potential benefits in CF: it partially corrects F508del-CFTR trafficking, stimulates the bactericidal properties of CF alveolar macrophages, and displays anti-inflammatory properties and analgesic effects.Methods: A phase 2 trial study (ROSCO-CF) was launched to evaluate the safety and effects of roscovitine in Pseudomonas aeruginosa infected adult CF patients carrying two CF causing mutations (at least one F508del-CFTR mutation) and harboring a FEV1 ≥40%. ROSCO-CF was a multicenter, double-blind, placebo-controlled, dose-ranging study (200, 400, 800 mg roscovitine, orally administered daily for 4 days/week/4 weeks).Results: Among the 34 volunteers enrolled, randomization assigned 11/8/8/7 to receive the 0 (placebo)/ 200/400/800 mg roscovitine doses, respectively. In these subjects with polypharmacy, roscovitine was relatively safe and well-tolerated, with no significant adverse effects (AEs) other than five serious AEs (SAEs) possibly related to roscovitine. Pharmacokinetics of roscovitine were rather variable among subjects. No significant efficacy, at the levels of inflammation, infection, spirometry, sweat chloride, pain and quality of life, was detected in roscovitine-treated groups compared to the placebo-treated group.Conclusion: Roscovitine was relatively safe and well-tolerated in CF patients especially at the 200 and 400 mg doses. However, there were 5 subject withdrawals due to SAEs in the roscovitine group and none in the placebo group. The lack of evidence for efficacy of roscovitine (despite encouraging cellular and animal results) may be due to high pharmacokinetics variability, short duration of treatment, and/or inappropriate dosing protocol.

Background Venous thromboembolism (VTE) can be the first manifestation of cancer; however, the current incidence of malignancy in unselected patients with first unprovoked VTE needs to be confirmed. Material and methods Between March 1st, 2013 and February 28th, 2015 we included and followed-up all patients living in the Brest district, France, who were seen in hospitals or the community for a first symptomatic unprovoked VTE event. The primary study outcome was the one-year incidence of cancer. Results 526 patients, mean age 66.6 ± 18.1 years, 246 (46.8%) men, were included in the study. In the year following VTE, 26 patients were diagnosed with cancer, corresponding to a one-year cumulative incidence of cancer of 5.06% (95% CI 3.47–7.35). Age ≥60, smoking and pulmonary embolism were significantly associated with cancer diagnosis in multivariate analysis. Fifty percent of cancers were patent at the time of VTE diagnosis, mostly detected on CTPA (Computed Tomographic Pulmonary Angiography) performed for pulmonary embolism assessment. After excluding patients with patent cancer at VTE diagnosis, the one-year incidence of cancer was 2.65% (95% CI: 1.55–4.52); in multivariate analysis, only current smoking was independently associated with a significant 5.4-fold increased risk for cancer diagnosis (HR 5.40; 95% CI 1.31–22.27). No cancer was diagnosed in patients aged 50 years or younger. Conclusion The one-year incidence of cancer after a first unprovoked VTE was 5.06%. Half of the cancers were diagnosed during the diagnosis procedure for pulmonary embolism using CTPA.

Atrial arrhythmias (AA) induce a high rate of thromboses and require vitamin K antagonists (VKA) or direct anticoagulants (DOAC) prescriptions. Essential thrombocythemia (ET) and polycythemia vera (PV) are also pro-thrombotic diseases. The prevention of thromboses is based on the association of cytoreductive drug and low-dose aspirin (LDA). We studied the incidence and complications of AA among patients with ET or PV. We identified 96/713 patients (13.5%) carrying AA. These patients were older (median 72.1 vs. 61.3 years old, p

Direct oral anticoagulants (DOACs) have been approved to treat and prevent thrombotic events. However, they are not yet labeled for use in patients with active cancers. Myeloproliferative neoplasms (MPNs) are clonal chronic disorders with a high incidence of thrombotic events, for which low-dose aspirin (LDA) is the standard drug treatment. We analyzed efficacy and safety of DOACs prescription in patients treated for MPNs. An MPN database, the OBENE registry, was established at our institution. We collected biological and clinical data from diagnosis to last follow-up for every patient included in this study. Thrombotic and hemorrhagic events and hematologic evolutions were categorized as major events in the database. Of the 760 MPN patients in the OBENE registry, 25 (3.3%) were treated with a DOAC. Median follow-up duration was 2.1 years (0.12-4.3 years). The reasons for prescribing DOACs were atrial fibrillation and thrombotic events for 13 and 12 patients, respectively. We only observed one thrombotic event (4%) and three major hemorrhagic events (12%). A case-control study did not detect a significant difference in thrombotic or hemorrhagic events in patients treated with LDA and DOACs. These preliminary results suggest that DOACs may be highly efficient and safe for use in MPN patients.

Background Current guidelines recommend extended anticoagulation in patients with unprovoked venous thromboembolism (VTE). However, a precise description of these patients from the “real-world” is lacking. Methods The EPI-GETBO study is a prospective epidemiologic study of VTE in the geographically well-defined Brest district area. All cases of symptomatic VTE between March 2013 and February 2015 were recorded, adjudicated, and included in the study. Results During the study period, 555 patients with unprovoked symptomatic VTE were included in EPI-GETBO. Patients’ median age was 72.0 years (IQR 57.0;83.0), 45.2% were male, 64.7% had a pulmonary embolism (PE) associated or not with a deep vein thrombosis (DVT) and 29.2% had a previous history of VTE. 5.6% of the patients had atrial fibrillation at the time of VTE diagnosis, 5.9% had a history of coronary artery disease, and 17.3% received antiplatelet medications. A total of 283 (51.0%) patients discontinued anticoagulation during the observation period. In these patients, the median duration of treatment was 183 days (range 0 to 853 days). Patients with PE associated or not with DVT were treated for a longer time than patients with isolated DVT (P = 0.01). A total of 40 recurrences (14.1%) were observed during follow-up (up to 2 years after initial VTE event) after anticoagulation discontinuation. Based on indirect standardization, we expect an annual 50,054 cases of unprovoked VTE in France, including 32,346 PEs. Conclusion The 14,1% recurrence rate of VTE after anticoagulation discontinuation confirms the need for extended duration of treatment in this patient population. Attention should be made for the significant number of patients with concomitant arterial disease who may need aspirin if low-dose DOAC is chosen for extended therapy or who may not be eligible for a low-dose DOAC in case of presence of atrial fibrillation.

Is blood anti-Müllerian hormone (AMH) concentration a strong determinant of unexplained recurrent early miscarriage (REM)?In the first part of the study, AMH concentrations measured using an Immunotech ELISA Kit were compared between 188 unselected (mostly fertile) women consecutively referred for three or more miscarriages in the first trimester of pregnancy and 376 age-matched parous women without pregnancy loss. Cases and controls were previously enrolled in an incident case-control study on thrombophilic mutations. Blood samples were collected2 months after any recognized obstetric event or hormonal treatment. In the second part of the study, a prospective 2-year follow-up of cases was performed.When considering all women irrespective of age, AMH concentration did not significantly differ between cases and controls. However, in the subgroup ≥25 years old (176 cases versus 358 controls of ∼33.5 years), the cases had significantly lower AMH concentrations than the controls (median [interquartile range]: 2.8 [1.4-4.7] versus 3.25 [1.7-5.5], P = 0.046) and the proportion of cases with an AMH concentration1 ng/ml was significantly higher (17.6% versus 10.6%; odds ratio 1.80; 95% confidence interval 1.07-3.00, P = 0.028). With regard to the subsequent pregnancy, AMH concentration was not correlated with either the conception delay or the miscarriage occurrence. However, increased age and number of previous miscarriages were significantly predictive of a subsequent miscarriage (P = 0.046 and 0.03, respectively).An altered ovarian reserve is a possible determinant of unexplained REM. However, AMH blood concentration predicts neither the delay nor the outcome of a subsequent pregnancy.

Background Pulmonary embolism (PE) is associated with increased risk for ischemic stroke, but the underlying mechanism remains unclear. The authors hypothesized that paradoxical embolism through patent foramen ovale (PFO) should be the main mechanism. Objective To determine the frequency of recent ischemic stroke in patients with symptomatic PE according to whether PFO was detected. Design Prospective cohort study with masked assessment of stroke outcomes. (ClinicalTrials.gov: NCT01216423). Setting 4 French hospital centers. Participants 361 consecutive patients with symptomatic acute PE from 13 November 2009 through 21 December 2015. Intervention Systematic contrast transthoracic echocardiography (TTE) and cerebral magnetic resonance imaging (MRI) within 7 days after enrollment. Measurements Recent symptomatic or silent ischemic stroke was diagnosed on the basis of clinical examination and cerebral MRI showing a hypersignal on the trace diffusion-weighted image with reduction or pseudonormalization of apparent diffusion coefficient. Results Contrast TTE was conclusive in 324 of 361 patients and showed PFO in 43 patients (13%). The median age was 66 years (interquartile range, 54 to 77 years). In total, 51% of patients (145/284) had associated deep venous thrombosis, 91% (279/306) had cardiovascular risk factors, and 10% (16/151) presented with arrhythmia (no difference between PFO and non-PFO groups). Cerebral MRI was conclusive in 315 patients. Recent ischemic stroke was more frequent in the PFO group than in the non-PFO group (9 of 42 patients [21.4%] vs. 15 of 273 patients [5.5%]; difference in proportions, 15.9 percentage points [95% CI, 4.7 to 30.7 percentage points]). Limitation Because of inconclusive contrast TTE or MRI, 46 patients were excluded from analysis. Conclusion Frequency of recent ischemic stroke in patients with symptomatic PE was higher in patients with PFO than in those without PFO. This finding supports the hypothesis that paradoxical embolism is an important mechanism of ischemic stroke in patients with PFO. Primary funding source French Ministry of Health.

The optimal duration of anticoagulation after a first episode of unprovoked deep-vein thrombosis is uncertain. We aimed to assess the benefits and risks of an additional 18 months of treatment with warfarin versus placebo, after an initial 6 months of anticoagulation for a first unprovoked proximal deep-vein thrombosis. We conducted a multicenter, randomized, double-blind, controlled trial comparing an additional 18 months of warfarin with placebo in patients with a unprovoked proximal deep-vein thrombosis initially treated for 6 months (treatment period: 18 months; follow up after treatment period: 24 months). The primary outcome was the composite of recurrent venous thromboembolism or major bleeding at 18 months. Secondary outcomes were the composite at 42 months, as well as each component of the composite, and death unrelated to pulmonary embolism or major bleeding, at 18 and 42 months. All outcomes were centrally adjudicated. A total of 104 patients, enrolled between July 2007 and October 2013 were analyzed on an intention-to-treat basis; no patient was lost to follow-up. During the 18-month treatment period, the primary outcome occurred in none of the 50 patients in the warfarin group and in 16 out of 54 patients (cumulative risk, 29.6%) in the placebo group (hazard ratio, 0.03; 95% confidence interval: 0.01 to 0.09; P

International audience

We aimed to identify risk factors for recurrent venous thromboembolism (VTE) after unprovoked pulmonary embolism.Analyses were based on the double-blind randomised PADIS-PE trial, which included 371 patients with a first unprovoked pulmonary embolism initially treated during 6 months who were randomised to receive an additional 18 months of warfarin or placebo and followed up for 2 years after study treatment discontinuation. All patients had ventilation/perfusion lung scan at inclusion (i.e. at 6 months of anticoagulation).During a median follow-up of 41 months, recurrent VTE occurred in 67 out of 371 patients (6.8 events per 100 person-years). In main multivariate analysis, the hazard ratio for recurrence was 3.65 (95% CI 1.33–9.99) for age 50–65 years, 4.70 (95% CI 1.78–12.40) for age >65 years, 2.06 (95% CI 1.14–3.72) for patients with pulmonary vascular obstruction index (PVOI) ≥5% at 6 months and 2.38 (95% CI 1.15–4.89) for patients with antiphospholipid antibodies. When considering that PVOI at 6 months would not be available in practice, PVOI ≥40% at pulmonary embolism diagnosis (present in 40% of patients) was also associated with a 2-fold increased risk of recurrence.After a first unprovoked pulmonary embolism, age, PVOI at pulmonary embolism diagnosis or after 6 months of anticoagulation and antiphospholipid antibodies were found to be independent predictors for recurrence.

We aimed to assess the risk of recurrent venous thromboembolism (VTE) in patients with chronic obstructive pulmonary disease (COPD) following cessation of anticoagulation therapy.In a prospective cohort of 1468 patients with a documented episode of VTE, followed for up to 5 years after cessation of anticoagulation therapy, the diagnosis of COPD was confirmed in 136. The main outcome was recurrent VTE. The secondary outcome was overall mortality. Univariate and multivariate analyses were performed to identify the risk factors of recurrence.Of the 1468 patients included, recurrent VTE was observed in 306 (34 with COPD and 272 without) during a median follow-up period of 36.5 months. The incidence rate of recurrent VTE was 9.1% (95% CI 6.5–12.8) for COPD patients and 7.0% (95% CI 6.2–7.9) for non-COPD patients. COPD was not associated with an increased risk of VTE recurrence on univariate or multivariate analyses (hazard ratio: 1.0 (95% CI 0.7–1.4)). The risk of death, adjusted for demographic and clinical characteristics, showed no increase in COPD patients, as compared to non-COPD patients.In patients with COPD who had an acute episode of VTE, the risk of recurrent VTE was not any higher than that in non-COPD patients.

International audience; When counseling first-degree relatives of patients with venous thromboembolism (VTE), it is important to know whether factors other than thrombophilia influence their risk for thrombosis. We assessed the risk for VTE in 915 first-degree relatives of patients with provoked VTE, compared this with the risk in 1752 first-degree relatives of patients with unprovoked VTE, and then combined data from the 2 groups of relatives to identify predictors of thrombosis. There had been 123 VTEs in 2617 first-degree relatives (0.12 per 100 person-years). The risk for VTE in first-degree relatives was higher if the index cases had an unprovoked compared with a provoked VTE (odds ratio [OR], 2.38; 95% confidence interval [CI], 1.43-3.85), if the index case was younger (OR, 0.97 per year older; 95% CI, 0.96-0.99), and if an additional family member had VTE (OR, 2.71; 95% CI, 2.22-3.31). Among first-degree relatives of an index case with factor V Leiden or the prothrombin 20210A gene variant, the presence of these abnormalities also predicted thrombosis (OR, 4.42; 95% CI, 1.35-14.38). We conclude that thrombosis at a young age and unprovoked VTE predict VTE in first-degree relatives, and that the influence of these 2 factors is additive.

RésuméL’athérothrombose et la maladie veineuse thromboembolique sont traditionnellement considérées comme deux entités distinctes, étant donné leurs différences en termes de mécanismes physiopathologiques, de facteurs de risque et de thérapeutiques. Cependant, depuis quelques années, et la publication de plusieurs études épidémiologiques, une association entre maladie veineuse thromboembolique et athérothrombose est fortement suggérée. Cet article résume les principales données épidémiologiques soutenant les liens entre les deux entités, présente le rôle potentiel des facteurs de risque communs, et passe en revue les données disponibles concernant les effets potentiels des médicaments hypolipémiants et antiagrégants plaquettaires, pierre angulaire de la prévention artérielle, dans la prise en charge de la maladie veineuse thromboembolique. Les conséquences pour la pratique médicale sont également discutées.SummaryAtherothrombosis and venous thromboembolism have traditionally been viewed as two distinct conditions, with differences in pathophysiological mechanisms, risk factors and treatment. However, in recent years and with the publication of several epidemiological studies, a possible association between venous and arterial thrombotic disorders has been suggested. This article summarizes the main epidemiological data supporting the links between both entities, presents the potential role of shared risk factors, and reviews available data addressing the possible effects of lipid-lowering drugs and antiplatelet agents, which are the cornerstone of arterial prevention, in the management of venous thromboembolism. Consequences for medical practice are also discussed.

The risk of recurrent venous thromboembolism (VTE) in young women after a first oestrogen contraception associated VTE episode is unknown. This uncertainty has an impact on the decision whether to stop anticoagulant treatment. Our objective was to assess the risk of recurrent VTE in women after a first VTE episode on oestrogen contraception. This was a prospective cohort study in which we consecutively enrolled between 1992 and 2011 all women under 50years with a first objectively confirmed VTE. The incidence of recurrent VTE during follow-up after stopping anticoagulation was compared between women users and non-users of combined oral contraception (COC) at the time of index VTE. Of the 241 women aged 50 or younger seen for a first VTE and followed-up after stopping anticoagulation there were 180 COC-users and 61 non-users. Median duration of follow-up off-anticoagulants was 66 months (interquartile range: 33-103). There were 14 recurrences in COC-users and 5 cases in non-users. No significant association was found between exposure to COC and the incidence of recurrent VTE after adjustment for age or after restricting the analysis to major unprovoked VTE: incidence rate of recurrence 17.9/1000/year (95% CI: 9.6-33.2) in women with COC as compared with 17.6/1000/year (95% CI: 6.6-47) with an incidence ratio of 0.7 (95% CI: 0.2-2.4 p=0.59). The risk of recurrent VTE is low in young women after a first VTE. However this risk is not significantly lower in women after a first VTE while exposed to combined oral contraception. Copyright (c) 2013 Elsevier Ltd. All rights reserved.

BACKGROUND: Surgical resection is the best treatment for stage I and II non-small cell lung cancer. Despite an improvement in the perioperative management of cancer patients and specialization of surgical teams, morbidity and mortality remains significant. Non-invasive ventilation (NIV) is an effective therapeutic option in hypercapnic respiratory failure. It also improves functional and gasometric parameters when undertaken before surgery. The objective of the preOVNI study is to demonstrate that preoperative non-invasive ventilation for 7 days, at home, reduces the postoperative respiratory and cardiovascular complications of lung resection surgery, in a high-risk population. METHODS: A prospective, randomized, controlled open-labelled multicentric French study, under the supervision of the Groupe Francais de Pneumocancerologie (GFPC), comparing 7 days of preoperative non-invasive ventilation with standard treatment. Inclusion criteria are: patients suitable for lobectomy or segmentectomy for primary bronchial carcinoma and presenting with obstructive or restrictive lung disease, obesity or chronic cardiac insufficiency. The primary criterion is a composite one, including all respiratory and cardiac complications. The number of patients is 150 in each treatment arm, 300 in total. EXPECTED RESULTS: We think that preoperative NIV will be able to reduce the rate of postoperative complications. If this objective is achieved, the management of these patients could be changed.

SummaryIn 1998 we estimated the incidence of venous thromboembolism (VTE) to be 1.8/1,000 per year. The aim of this study was to compare current VTE incidence to that observed in 1998. We prospectively recorded all cases of symptomatic pulmonary embolism (PE) and deep vein thrombosis (DVT) of the lower limbs diagnosed between March 1, 2013 and February 28, 2014 in hospitals and in the community, using the same method and geographic area than in 1998. The 2013 incidence rates of VTE were computed and compared with those of 1998 using age- and sex-specific standardised incidence ratios (SIRs). In 2013, we recorded 576 VTE cases (279 isolated DVT and 297 PE ± DVT). Among 367,911 inhabitants, the overall incidence of VTE was 1.57/1,000 (95 % CI 1.44–1.69). The overall VTE incidence was significantly lower in 2013 as compared with 1998: SIR 0.72 (95 % CI 0.67–0.79) as well as the incidence of isolated DVT: SIR 0.53 (95 % CI 0.47–0.60); conversely, the overall incidence of PE was unchanged: SIR 1.10 (95 % CI, 0.98–1.23) despite an increase in the incidence of isolated PE: SIR 1.29 (95 % CI, 1.10–1.52). In 1998, 4.4 % of PE cases were diagnosed using CTPA as compared with 73.7 % in 2013 (p < 0.001). In conclusion, between 1998 and 2013, the incidence of symptomatic DVT decreased. Conversely, we found no similar reduction in the incidence of symptomatic PE; whether this is due to changes in diagnostic tests and algorithms in the management of suspected PE requires further investigations.Supplementary Material to this paper is available online at www.thrombosis-online.com.

Lipid parameters disorders are clearly associated with cardiovascular diseases and are one of the most important targets for primary and secondary prevention. The association between lipid parameters and venous thromboembolism (VTE) has been evaluated in several clinical studies. In this review, we present the results from available literature on lipid parameters (lipids, lipoproteins and apoproteins) and VTE, and comment on the studies’ limitations. We also describe the possible pathophysiological links between dyslipidemia and hemostasis. Then, we discuss the potential role of lipid-lowering drugs, statins and fibrates on VTE risk and the potential underlying mechanisms.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • CYP2C9 and VKORC1 genetic variants contribute to differences in patients' responses to anticoagulant coumarin derivatives. Patients carrying the VKORC1 1173TT genotype have a decreased time to the first INR within the therapeutic range and to the first INR >4, and also require lower warfarin maintenance doses. Patients carrying the *2 or *3 CYP2C9 allele have lower maintenance warfarin requirements than those carrying the wild-type allele. The role of CYP2C9 and VKORC1 genetic variants in fluindione response is unknown. WHAT THIS STUDY ADDS • Our results showed that VKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P 4 (P= 0.0002) and on the average daily dose of fluindione during the first period of stability (19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT, P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to fluindione. This report provides new information on the respective role of common genetic polymorphisms on anticoagulation induced by another class of anticoagulant drugs rather than coumarin derivatives. AIM Genetic variants of the enzyme that metabolizes warfarin, cytochrome P-450 2C9 (CYP2C9) and of a key pharmacologic target of vitamin K antagonists, vitamin K epoxide reductase (VKORC1), contribute to differences in patients' responses to coumarin derivatives. The role of these variants in fluindione response is unknown. Our aim was to assess whether genetic factors contribute to the variability in the response to fluindione. METHODS Four hundred sixty-five patients with a venous thromboembolic event treated by fluindione for at least 3 months with a target international normalized ratio (INR) of 2.0 to 3.0 were studied. VKORC1, CYP2C9, CYP4F2 and EPHX1 genotypes were assessed. INR checks, fluindione doses and bleeding events were collected. RESULTSVKORC1 genotype had a significant impact on early anticoagulation (INR value ≥2 after the first two intakes) (P 4 (P= 0.0002). The average daily dose of fluindione during the first period of stability was significantly associated with the VKORC1 genotype: 19.8 mg (±5.5) for VKORC1 CC, 14.7 mg (±6.2) for VKORC1 CT and 8.2 mg (±2.5) for VKORC1 TT (P < 0.0001). CYP2C9, CYP4F2 and EPHX1 genotypes did not significantly influence the response to fluindione. CONCLUSIONSVKORC1 genotype strongly affected anticoagulation induced by fluindione whereas CYP2C9, CYP4F2 and EPHX1 genotypes seemed less determining.

Resume Introduction La maladie veineuse thromboembolique (MVTE) est une pathologie frequente dont l’incidence augmente avec l’âge. Chez les sujets âges de plus de 75 ans, son incidence atteint un cas pour 100 personnes par an. Etat des connaissances En dehors des circonstances a risque majeures (chirurgie, traumatismes, affections medicales aigues), quatre facteurs de risque modifient la prise en charge de la MVTE quel que soit le contexte, et sont particulierement importants a considerer : âge, cancer, antecedent de MVTE, grossesse. Biologiquement, hormis le syndrome des antiphospholipides et certains deficits en antithrombine, les « thrombophilies » n’ont pas d’interet clinique majeur demontre dans la prise en charge de la MVTE. Perspectives Les « thrombophilies » sont de formidables outils de comprehension de la MVTE, et la recherche de nouvelles anomalies biologiques et l’etude de leur impact doivent se poursuivre. La mise en evidence recente des liens entre MVTE et pathologie arterielle, en particulier atherothrombotique, font emerger le concept de maladie et de prevention vasculaire globale. Conclusions La MVTE est un probleme majeur de sante publique. Il apparait necessaire d’en connaitre les facteurs de risque et d’identifier les patients a haut risque afin de limiter son incidence et sa mortalite.

Absence of CALR mutation among a cohort of 394 unselected patients with a first episode of unprovoked venous thromboembolism

Introduction La maladie veineuse thromboembolique (MVTE) est une cause majeure de mortalite maternelle en post-partum et peut etre prevenue par l’utilisation d’heparines de bas poids moleculaire (HBPM). Cependant, plusieurs etudes ont revele des echecs de la prophylaxie par HBPM en particulier chez les femmes a haut risque (dose insuffisante chez les femmes obeses ?). Une mauvaise observance du traitement pourrait etre une cause d’echec, mais il existe peu de donnees dans la litterature. L’objectif de ce travail etait de decrire le vecu et l’adhesion au traitement de femmes traitees par HBPM en post-partum. Patients et methodes Nous avons mene une etude prospective concernant toutes les femmes accouchant dans deux maternites. Lorsqu’une prophylaxie par HBPM etait prescrite apres l’accouchement, les patientes recevaient un carnet de suivi pour noter la date et l’heure de chaque injection ainsi que les evenements survenant lors des injections (douleur, hematome, oublis…). La duree de traitement realisee etait comparee a la prescription medicale sur l’ordonnance de sortie de la maternite. Resultats Entre le 1 juin 2015 et le 31 mai 2016, 3308 femmes ont participe a l’etude, dont 563 ont recu une prophylaxie par HBPM. Nous avons recu par courrier pretimbre 157 carnets de suivi completes par les patientes. L’âge moyen de ces patientes etait de 32 ans (21–45) et 140 femmes avaient accouche par cesarienne. La duree totale de traitement par HBPM etait de 2674 jours (2 a 50 jours par patiente). Les femmes rapportaient les evenements suivants : 507 episodes d’hematome au site d’injection chez 80 femmes, 339 episodes de douleur a l’injection chez 58 femmes et 16 oublis d’injections. Un retard d’au moins 2 heures etait releve au moins une fois chez 73 femmes. En comparaison de l’ordonnance de sortie, le traitement etait interrompu precocement chez 16 % des femmes (1 a 41 jours). Discussion L’adhesion des patients a la prophylaxie par HBPM en obstetrique est mal connue. Dans une etude utilisant un carnet de suivi et des dosages sanguins, l’adhesion au traitement excellente pendant la grossesse, etait reduite a 93 % en post-partum. Dans une etude recente reposant sur un entretien telephonique, 83 % des femmes avaient suivi completement un traitement de 7 jours. Nos resultats confirment une bonne adhesion au traitement, en particulier pour les traitements courts, mais il existe des effets indesirables frequents et des erreurs de traitement pouvant compromettre l’efficacite de la prophylaxie surtout quand elle est prolongee. De plus, il est probable que seules les femmes les plus adherentes au traitement ont complete et renvoye leur carnet. Conclusion Les effets indesirables des injections d’HBPM en post-partum sont frequents en particulier les hematomes et les douleurs lors des injections, ainsi que les erreurs dans les horaires d’injection. Ces problemes doivent etre pris en compte, en particulier lorsque la prophylaxie doit etre prolongee plusieurs semaines, pour permettre une bonne adhesion des patientes a la prophylaxie.

Resume Propos Malgre un traitement approprie, 10 a 100 % des patients atteints de thrombose veineuse profonde (TVP) des membres inferieurs presenteront une maladie veineuse post-thrombotique (MPT). L’objectif de ce travail etait d’evaluer l’incidence de la MPT au sein des patients de la cohorte EDITH et d’estimer l’association entre les caracteristiques initiales de la maladie thrombotique et le risque ulterieur de survenue d’une MPT. Methodes Cent quatre-vingts patients de la cohorte EDITH âges de moins de 70 ans inclus a l’occasion d’un premier episode de TVP des membres inferieurs sans signes cliniques d’insuffisance veineuse chronique au moment de l’inclusion ont ete convoques quatre ans apres leur episode initial thromboembolique. La presence de MPT a ete evaluee a l’aide du score de Villalta. Resultats Quatre-vingt-quinze patients (45 hommes, âge moyen 50,7 ± 16,9 ans) ont repondu a la convocation. Parmi eux, 28,4 % (IC 95 % 19,3–37,5) ont developpe une MPT, aucun n’a developpe de MPT severe. Les signes cutanes les plus frequemment retrouves chez les patients porteurs d’une MPT etaient les varices (59 %), une corona phlebectatica (48 %), un œdeme de jambe (30 %) et une dermite ocre (26 %). Aucun facteur de risque teste pour la MPT (âge, sexe, IMC, localisation, recidive et aspect symptomatique de thrombose initiale, thrombophilie, etiologie, antecedents familiaux de TVP) n’a pu etre mis en evidence. Conclusion La MPT est une pathologie frequente mais le manque d’uniformite des criteres diagnostiques entre les etudes ne permet pas d’etablir clairement ses facteurs de risque.

IntroductionLa maladie thromboembolique veineuse (MTEV) acquise à l’hôpital représente une part importante de morbi-mortalité évitable chez les patients hospitalisés en secteur médical. D’un autre côté, la thromboprophylaxie anticoagulante expose les patients à un risque hémorragique et majore les dépenses de santé. L’identification des patients hospitalisés à risque de MTEV est en cela cruciale. L’objectif de cette étude est d’évaluer de manière externe, les performances de 3modèles de risque (score de Padua, Carpini et Improve) et de les comparer aux performances de l’âge pris isolément.Patients et méthodesIl s’agit d’une étude rétrospective sur une base de patients inclus prospectivement dans une étude randomisée en cluster sans intervention directe sur le patient. Les patients de plus de 40ans, hospitalisé depuis les urgences en secteur médical plus de 48h ont consécutivement été inclus et suivi à 3mois. Les patients chez qui un diagnostic de MTEV avait été porté dans les 48premières heures d’hospitalisation, ou ayant reçu un traitement anticoagulant pour une raison autre que la MTEV, ou encore ayant subi une chirurgie sous anesthésie générale ont été exclus. Les modèles de risques ont été calculés à posteriori. La réduction de mobilité a été déduite de la durée d’hospitalisation moins un jour. Le critère de jugement principal était la survenue d’un épisode thrombotique veineux symptomatique ou le décès brutal inexpliqué adjudiqué à 3mois.RésultatsParmi les 14910patient éligibles, 14659 (98,3) étaient évaluables. 263 (1,8%) ont présenté une MTEV symptomatique ou un décès brutal inexpliqué. Les aires sous la courbe ROC étaient respectivement 0,60 [0,57–0,63], 0,62 [0,58–0,64] et 0,62 [0,59–0,65] pour les scores Caprini, Improve et Padua. Aucun de ces modèles n’a montré de performances supérieures à l’âge pris isolément (AUC 0,61 [0,58–0,64]). Ces résultats étaient similaires ne considérant que les évènements symptomatiques non fatals: (0,62 [0,58–0,66], 0,62 [0,58–0,66], 0,63 [0,59–0,67] et 0,58 [0,54–0,62]); ou dans le sous-groupe de patients ne recevant pas de thromboprophylaxie anticoagulante: 0,62 [0,58–0,67], 0,64 [0,60–0,68], 0,64 [0,59–0,68] et 0,66 [0,62–0,70] pour le score Caprini, Improve, Padua et l’âge, respectivement.ConclusionLes scores de Padua, Caprini et Improve ont des capacités de discrimination faible vis-à-vis de la MTEV acquise à l’hôpital, similaire à une évaluation se basant uniquement sur l’âge. Les meilleurs modèles de risque sont nécessaires.

Resume Le but de notre etude etait d’evaluer la concordance d’interpretation d’images « pseudoplanaires » resultantes de sommes angulaires de donnees tomoscintigraphiques pulmonaires comparativement aux images resultantes d’acquisitions planaires pour le diagnostic d’embolie pulmonaire. Dans le cadre d’une etude prospective, 110 patients suspects d’embolie pulmonaire ont beneficie d’une scintigraphie pulmonaire avec acquisitions planaire et tomographique. Des images pseudoplanaires ont ete extraites des donnees tomographiques selon une technique de somme angulaire. Les deux modalites ont ete interpretees selon les criteres revises de Pioped par deux medecins nucleaires et comparees. Les concordances intermodalites et interobservateurs ont ete evaluees par un test kappa pondere. Le degre de concordance entre les deux modalites etait bon (κ = 0,696). Le degre d’accord interobservateurs etait similaire en planaire (κ = 0,919) et en somme angulaire (κ = 0,903). Ces resultats suggerent que la somme angulaire de donnees tomoscintigraphiques pulmonaires de ventilation-perfusion permet d’obtenir des images planaires interpretables et concordantes aux images resultantes d’acquisitions planaires.

Patients with suspected deep vein thrombosis (DVT) are often managed on an outpatient basis by primary care physicians. International guidelines recommend anticoagulant treatment for patients with suspected DVT when diagnostic testing is delayed or when clinical probability is high. Our goal was to build a clinical prediction rule specifically for easy use in primary care to help decide about starting anticoagulant therapy while awaiting ultrasound examination. Between January and December 2006, 276 patients with clinically suspected DVT were included in this study by 189 general practitioners from Brittany, France. All patients underwent a standardized clinical assessment and were then referred for ultrasonography. The diagnosis of DVT was confirmed in 103 (37%) patients. The final clinical prediction rule comprises four risk factors for DVT (personal history of venous thromboembolism +1, immobilization in previous month +1, estrogen contraceptive +2, active malignancy +3), one clinical sign (swelling of the calf +1), and the presence of an alternative diagnosis more likely than that of DVT (-3). The proportion of confirmed DVT was 26% in patients classified as at low risk, with a score less than 2 points, and 63% in patients classified at high risk, that is, with a score of 2 points or more. This clinical prediction rule is based on simple history and clinical factors that are routinely collected by GPs from patients with suspected DVT. It could help to decide about the immediate prescription of anticoagulation pending ultrasound. This rule should be externally validated before its use in clinical practice can be recommended.

Among the many factors likely to favour the occurrence of venous thromboembolism (VTE), exposure to certain drugs has to be taken into account. Although hormone treatments, oral contraception and hormone replacement therapy (HRT) for menopause have been studied, these are not the only drugs associated with an increased risk of VTE. The antipsychotics have also been incriminated in the occurrence of venous thromboembolism. The association of thalidomide and dexamethasone, used in the treatment of multiple myeloma, is responsible for a major increase in the risk of VTE. The physiopathological mechanisms accounting for the possible prothrombotic effect of most of these drugs is still not fully understood. Further observational and interventional clinical studies should provide a better understanding of VTE, potentially associated with drugs. However, certain drugs may be associated with a reduced risk of VTE. Although several studies indicate that aspirin and statins may favourably influence the risk of VTE, it is still not possible to draw up any practical recommendations.

BACKGROUND: After stopping a 3 to 6 months course of oral anticoagulation for a first episode of idiopathic venous thromboembolism (VTE), the risk of recurrent VTE is high (10% per year). In this setting, international guidelines recommend at least 6 months treatment. However, this recommendation is not satisfactory for the following reasons: (1) no randomized trial has compared 6 months to extended duration (2 years) anticoagulation; and (2), even though the frequency of recurrent VTE is similar after pulmonary embolism (PE) and deep vein thrombosis (DVT), the fatality rate of recurrent VTE after PE is higher than that after DVT. METHODS: A French multicentre double blind randomized trial. The main objective is to demonstrate, after a first episode of symptomatic idiopathic PE treated for 6 months using a vitamin K antagonist, that extended anticoagulation for 18 months (INR between 2 and 3) is associated with an increased benefit / risk ratio (recurrent VTE and severe anticoagulant-related bleeding) compared to placebo. The double blind evaluation is ensured using by active warfarin and placebo, and blinded INR. The protocol was approved by the ethics board of the Brest Hospital on the 7th of March 2006. For an alpha risk of 5% and a beta risk of 20%, the estimated sample size is 374 patients. EXPECTED RESULTS: This study has the potential to: (1) demonstrate that the benefit / risk ratio of extended anticoagulation for 18 months is higher than that observed with placebo in patients with a first episode of idiopathic PE initially treated for 6 months, during and after the treatment period; and (2) to validate or invalidate the contribution of isotope lung scans, lower limb Doppler ultrasound and D-Dimer at 6 months of treatment as predictors of recurrent VTE (medico-economic analysis included).

Karine Lacut, Grégoire Le Gal, Dominique MottierGETBO EA 3878, CHU de Brest, Department of Internal Medicine and Chest Diseases, Hôpital Cavale Blanche, Brest, FranceAbstract: Primary prophylaxis with the use of an effective and safe intervention appears the best approach of venous thromboembolism (VTE) management in medical elderly patients, the most affected by VTE. With increasing life expectancy, prevention of VTE, particularly in elderly patients, will arise as a major public health problem. Few well designed clinical trials evaluating thromboprophylaxis in medical settings were conducted in the specific population of geriatric patients. However, among the several pharmacological treatments evaluated, low molecular weight heparins enoxaparin 40 mg daily or dalteparin 5000 IU daily appeared effective and safe in the prevention of VTE in elderly patients. Despite available data, and recommendations for VTE prevention in medical patients, thromboprophylaxis is underused or misused in practice. Heterogeneity of clinical studies, selected populations, concern about bleeding, and lack of a clear clinical benefit are some of the reasons that could explain the gap between theory and practice. In this review, after a brief report of epidemiologic data and specificities of VTE in elderly patients, the authors discuss the available results of VTE primary prevention trials for elderly medical patients, the limitations of these data, and the challenges to improve the practice and to reduce the incidence of this frequent but preventable disease.Keywords: venous thromboembolism, prophylaxis, elderly patients, medical settings, review

International audience; BACKGROUND: Multislice CT (MSCT) combined with D-dimer measurement can safely exclude pulmonary embolism in patients with a low or intermediate clinical probability of this disease. We compared this combination with a strategy in which both a negative venous ultrasonography of the leg and MSCT were needed to exclude pulmonary embolism. METHODS: We included 1819 consecutive outpatients with clinically suspected pulmonary embolism in a multicentre non-inferiority randomised controlled trial comparing two strategies: clinical probability assessment and either D-dimer measurement and MSCT (DD-CT strategy [n=903]) or D-dimer measurement, venous compression ultrasonography of the leg, and MSCT (DD-US-CT strategy [n=916]). Randomisation was by computer-generated blocks with stratification according to centre. Patients with a high clinical probability according to the revised Geneva score and a negative work-up for pulmonary embolism were further investigated in both groups. The primary outcome was the 3-month thromboembolic risk in patients who were left untreated on the basis of the exclusion of pulmonary embolism by diagnostic strategy. Clinicians assessing outcome were blinded to group assignment. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00117169. FINDINGS: The prevalence of pulmonary embolism was 20.6% in both groups (189 cases in DD-US-CT group and 186 in DD-CT group). We analysed 855 patients in the DD-US-CT group and 838 in the DD-CT group per protocol. The 3-month thromboembolic risk was 0.3% (95% CI 0.1-1.1) in the DD-US-CT group and 0.3% (0.1-1.2) in the DD-CT group (difference 0.0% [-0.9 to 0.8]). In the DD-US-CT group, ultrasonography showed a deep-venous thrombosis in 53 (9% [7-12]) of 574 patients, and thus MSCT was not undertaken. INTERPRETATION: The strategy combining D-dimer and MSCT is as safe as the strategy using D-dimer followed by venous compression ultrasonography of the leg and MSCT for exclusion of pulmonary embolism. An ultrasound could be of use in patients with a contraindication to CT.

Objectives This trial sought to assess the influence of omeprazole on clopidogrel efficacy. Background Clopidogrel has proved its benefit in the treatment of atherothrombotic diseases. In a previous observational study, we found clopidogrel activity on platelets, tested by vasodilator-stimulated phosphoprotein (VASP) phosphorylation, to be diminished in patients receiving proton pump inhibitor (PPI) treatment. Methods In this double-blind placebo-controlled trial, all consecutive patients undergoing coronary artery stent implantation received aspirin (75 mg/day) and clopidogrel (loading dose, followed by 75 mg/day) and were randomized to receive either associated omeprazole (20 mg/day) or placebo for 7 days. Clopidogrel effect was tested on days 1 and 7 in both groups by measuring platelet phosphorylated-VASP expressed as a platelet reactivity index (PRI). Our main end point compared PRI value at the 7-day treatment period in the 2 groups. Results Data for 124 patients were analyzed. On day 1, mean PRI was 83.2% (standard deviation [SD] 5.6) and 83.9% (SD 4.6), respectively, in the placebo and omeprazole groups (p = NS), and on day 7, 39.8% (SD 15.4) and 51.4% (SD 16.4), respectively (p Results Omeprazole significantly decreased clopidogrel inhibitory effect on platelet P2Y12 as assessed by VASP phosphorylation test. Aspirin-clopidogrel antiplatelet dual therapy is widely prescribed worldwide, with PPIs frequently associated to prevent gastrointestinal bleeding. The clinical impact of these results remains uncertain but merits further investigation. (OCLA: Influence of Omeprazole on the Antiplatelet Action of Clopidogrel Associated to Aspirin; http://www.clinicaltrials.gov/ct2/show/NCT00349661; NCT00349661)

International audience; INTRODUCTION: There are very few data assessing a family history of venous thromboembolism (VTE) as a risk factor for VTE. This question is nonetheless of interest as inherited risk factors are involved but at least partly unknown. METHODS: The E.D.I.TH. study is a prospective hospital-based case-control study. The family history was assessed by using a standard questionnaire, considering the total number of the first-degree relatives and the number of these relatives who had suffered from VTE. We analysed 698 first VTE cases and their matched controls, 507 pairs without and 191 pairs with a major acquired risk factor (active malignancy, surgery or plaster cast in the past three months, pregnancy or delivery in the past three months). RESULTS: A family history of VTE was associated with VTE occurrence, irrespective of carrying or not factor V Leiden mutation or G20210A prothrombin gene mutation and irrespective of the presence or absence of major acquired risk factors; adjusted conditional odds ratio: 2.7 (95%CI, 1.8-3.8). CONCLUSION: A family history might well be considered when estimating type and duration of prophylaxis for VTE specifically in patients with active cancer or who experienced surgery. Family history of VTE could be added to a prior VTE history to define a concept of clinical thrombophilia which is not necessarily related to carrying a known inherited risk factor.

International audience; BACKGROUND: Previous studies reported that statin use was associated with a decreased risk of venous thromboembolism (VTE), whereas no association was found between fibrate use and VTE. This report aims to test the hypothesis that part of these contrasting associations is related to total homocysteine level (tHcy). MATERIALS AND METHODS: This report from a case-control study included 677 cases hospitalised with confirmed VTE and no major acquired risk factor of VTE and their 677 controls. Statin and fibrate exposure was defined as a current use of drugs at admission. Fasting serum tHcy was measured in all patients. RESULTS: The estimated odds ratio for VTE related to statin use was 0.53 (CI 95% 0.37-0.78), whereas it was 1.88 (CI 95% 1.29-2.74) for fibrate use. No difference was found for tHcy levels between patients who were current users of statin compared to non users (17.7 micromol/L+/-7.3 in users vs 18.4 micromol/L+/-8.4 in non users, p=0.50). In contrast, fibrate users had a significant higher mean level of tHcy than non users (23.2 micromol/L+/-8.7 in users vs 18.4 micromol/L+/-8.4 in non users, p

Clinical signs of pulmonary embolism are neither sensitive nor specific enough to rule in or out the diagnosis in suspected patients. As an example, a chest pain that is reproducible at palpation in suspected patients was recently shown not to be associated with a lower proportion of confirmed cases of pulmonary embolism. However, clinical evaluation of patients with suspected pulmonary embolism is important, because it allows the physician to assess the clinical probability of pulmonary embolism, a mandatory step in diagnostic strategies for this disease. In elderly patients, the diagnosis of pulmonary embolism is particularly challenging. Indeed, the diagnostic value of symptoms and clinical signs of pulmonary embolism is reduced, the evaluation of the clinical probability is more difficult, and performances of some diagnostic tests are diminished with increasing age. The diminution of the proportion of confirmed cases among suspected patients is a new challenge for physicians, and raises the question of what is a clinical suspicion of pulmonary embolism.