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The postthrombotic syndrome (PTS) is chronic venous insufficiency secondary to a prior deep vein thrombosis (DVT). It is the most common complication of venous thromboembolism (VTE) and, while not fatal, it can lead to chronic, unremitting symptoms as well as societal and economic consequences. The cornerstone of PTS treatment lies in its prevention after DVT. Specific PTS preventative measures include the use of elastic compression stockings and pharmacomechanical catheter-directed thrombolysis. However, the efficacy of these treatments has been questioned by large randomized controlled trials (RCTs). So far, anticoagulation, primarily prescribed to prevent DVT extension and recurrence, appears to be the only unquestionably effective treatment for the prevention of PTS. In this literature review we present pathophysiological, biological, radiological, and clinical data supporting the efficacy of anticoagulants to prevent PTS and the possible differential efficacy among available classes of anticoagulants (vitamin K antagonists [VKAs], low molecular weight heparins [LMWHs] and direct oral anticoagulants [DOACs]). Data suggest that LMWHs and DOACs are superior to VKAs, but no head-to-head comparison is available between DOACs and LMWHs. Owing to their potentially greater anti-inflammatory properties, LMWHs could be superior to DOACs. This finding may be of interest particularly in patients with extensive DVT at high risk of moderate to severe PTS, but needs to be confirmed by a dedicated RCT.

Contains fulltext : 232751.pdf (Publisher’s version ) (Closed access) Clinical research in venous thromboembolism (VTE) is hindered by variability in the collection and reporting of data and outcomes. A consistent data language facilitates efficiencies, leads to higher quality data, and permits between-study comparisons and evidence synthesis. The International Society on Thrombosis and Haemostasis (ISTH) launched an international task force of more than 50 researchers to develop common data elements for clinical research in venous thromboembolism. The project was organized in seven working groups, each focusing on a topic area: General Core Data Elements; Anticoagulation and Other Therapies; Chronic VTE and Functional Outcomes; Diagnosis of VTE; Malignancy; Perioperative; and Predictors of VTE. The groups met via teleconference to collaboratively identify key data elements and develop definitions and data standards that were structured in a project-specific taxonomy. A Steering Committee met by teleconference and in-person to determine the overall scope of the project and resolve questions arising from the working groups. ISTH held an open public comment period to enable broader stakeholder involvement and feedback. The common data elements were then refined by the working groups to create a set of 512 unique data elements that are publicly available at http://isth.breakthrough.healthcare. The ISTH VTE Common Data Elements are intended to be a living project with ongoing curation, future expansion, and adaptation to meet the needs of the thrombosis and hemostasis research community.

Background International guidelines recommend using the Villalta score (VS) to diagnose the postthrombotic syndrome (PTS). However, a high proportion of PTS detected with VS could just reflect the presence of preexisting primary venous insufficiency (PVI). Furthermore, it is unclear whether the contralateral VS (cl-VS) can be used to assess for preexisting PVI. Objectives To estimate whether cl-VS can be used to assess for preexisting PVI, and to assess the proportion of PTS that could be attributable to preexisting PVI. Methods Subanalysis of the SOX multicenter randomized trial focusing on patients with a first unilateral proximal deep vein thrombosis (DVT) followed for up to 2 years. PVI was defined as a baseline cl-VS > 4, and PTS as VS > 4 in the leg ipsilateral to DVT starting 6 months after DVT. Results Among 680 patients, mean cl-VS remained stable over time: 1.23 (standard deviation [SD] ±2.49) at baseline and 1.17 (±2.20), 1.59 (±2.81), 1.54 (±2.50), 1.65 (±2.82), and 1.55 (±2.63) at the 1-, 6-, 12-, 18-, and 24-month visits, respectively. Baseline cl-VS and ipsilateral VS measured during follow-up were mildly correlated (Pearson correlation = 0.13-0.25). This association disappeared after subtracting the cl-VS measured at the same visit from the ipsilateral VS. Overall, 48.8% of patients developed PTS of whom 12.8% had baseline cl-VS > 4. Conclusion In our study of patients with a first unilateral proximal DVT, the proportion of patients with PTS who had a cl-VS > 4 is modest. However, cl-VS appears to be stable over time. Its assessment could constitute a simple way of documenting preexisting PVI and help to classify patients as having PTS.

Postthrombotic syndrome (PTS) is a burdensome and costly complication of deep vein thrombosis (DVT) that develops in 20%‐40% of patients within 2 years after proximal DVT. In the absence of effective curative treatment, management of PTS relies on its prevention after DVT. The effectiveness of elastic compression stockings (ECS) to prevent PTS is uncertain. We present an overview of published studies assessing the efficacy of ECS to prevent PTS and present the protocol for the CELEST clinical trial. While previous open‐label randomized trials have reported a 50% risk reduction in PTS in patients treated with >30 mm Hg ankle pressure ECS, a large double‐blind trial reported no effect of ECS. We discuss the main potential limitations of these trials, including a placebo effect and suboptimal compliance to ECS. We present the protocol of the CELEST double‐blind randomized trial comparing 2 years of high strength (ankle pressure 35 mm Hg) versus lower strength (ankle pressure 25 mm Hg) ECS in the prevention of PTS after a first acute symptomatic, unilateral, proximal DVT. The use of lower‐strength ECS than that used in previous studies should favor compliance. CELEST may provide important evidence about the efficacy of ECS in the prevention of PTS after DVT. The results will be interpreted in the light of results from recent clinical trials assessing ECS for PTS prevention that reported that the duration of ECS use should be tailored to the individual, if ECS are efficacious in the prevention of PTS.

Introduction Elastic compression stockings (ECSs) are used to treat symptoms of venous insufficiency. However, lack of patient compliance can limit their effectiveness. In a secondary analysis of the SOX Trial, a randomized trial of active vs. placebo ECSs worn for 2 years to prevent postthrombotic syndrome after deep vein thrombosis, we aimed to describe patient‐reported reasons for nondaily use of ECS and to identify predictors of noncompliance during follow‐up. Methods At each follow‐up visit of the SOX Trial, patients were asked how many days per week they wore study stockings, and if not worn daily, to specify the reason(s). Reasons for nondaily use of ECSs were tabulated. Multiple logistic regression modeling was used to identify predictors of stocking noncompliance during follow‐up (defined as use

IntroductionAfter deep vein thrombosis, up to 50% of patients develop post-thrombotic syndrome (PTS). PTS is a chronic condition that reduces quality of life (QOL). Cornerstones of PTS treatment include the use of elastic compression stockings but this treatment is usually incompletely effective and is burdensome. Venoactive drugs have been reported to be effective to treat chronic venous insufficiency (CVI). However, the level of evidence supporting their use in CVI in general and in PTS in particular is low.Methods and analysisThe MUFFIN-PTS trial is an academic, publically funded, multicentre randomised placebo-controlled trial assessing the efficacy of micronised purified flavonoid fraction (MPFF, Venixxa), a venoactive drug, to treat PTS. Eighty-six patients with PTS (Villalta score (VS) ≥5) and experiencing at least two of the following PTS manifestations among daily leg heaviness, cramps, pain or oedema will be randomised to receive 1000 mg of oral MPFF or a similar appearing placebo for 6 months, in addition to their usual PTS treatment. Total study follow-up will be 9 months, with visits at inclusion/baseline, 3, 6 and 9 months. Primary outcome is the proportion of patients with improvement in VS in each group, where improvement is defined as a decrease of at least 30% in VS or a VS Ethics and disseminationPrimary ethics approval was received from Centre intégré universitaire de santé et de services sociaux (CIUSSS) West-Central Montreal Research Ethics Board. Results of the study will be disseminated via peer-reviewed publications and presentations at scientific conferences.Trial registration numberClinicalTrials.gov Registry (NCT03833024); Pre-results.

Purpose of review Management of isolated distal deep vein thrombosis (IDDVT) remains controversial. We summarize recent studies regarding the natural history of IDDVT as well as pertinent therapeutic trials. We also provide our management approach. Recent findings IDDVT is more commonly associated with transient risk factors and less often associated with permanent, unmodifiable risk factors than proximal DVT. IDDVT has a significantly lower risk of proximal extension and recurrence than proximal DVT. Cancer-associated IDDVT has a similar natural history to cancer-associated proximal DVT, with substantially less favourable outcomes than noncancer-associated IDDVT. Anticoagulant treatment reduces the risk of proximal extension and recurrence in IDDVT at the cost of increased bleeding risk. Intermediate dosing of anticoagulation may be effective for treating noncancer-associated IDDVT in patients without prior DVT. Summary IDDVT with a transient risk factor can be treated for 6 weeks in patients without a prior DVT. Unprovoked IDDVT in patients without malignancy can be treated for 3 months. Outpatients without malignancy or a prior DVT can be left untreated and undergo surveillance compression ultrasound in one week to detect proximal extension, but few patients opt for this in practice. Cancer-associated IDDVT should be treated analogously to cancer-associated proximal DVT.

Resume Introduction La maladie veineuse thromboembolique (thrombose veineuse profonde et embolie pulmonaire) est une pathologie frequente, grave mais aussi chronique. Lors de precedentes etudes, la plupart des medecins traitants et des medecins vasculaires declaraient participer a l’education therapeutique de leurs patients. Objectif Evaluer, du point de vue du patient, le role et l’implication des medecins traitants et des medecins vasculaires dans l’information delivree au patient lors de la prise en charge d’une thrombose veineuse profonde. Methode Enquete telephonique realisee aupres des patients francais inclus dans l’essai therapeutique CACTUS sur le traitement des thromboses veineuses profondes distales des membres inferieurs. Resultats Cent trois patients ont ete interroges. Quatre-vingt-douze pour cent (n = 95) se declaraient satisfaits de l’information recue, jugee necessaire dans 96 % (n = 99) des cas et 85 % (n = 88) des patients n’ont pas eprouve le besoin de consulter d’autres sources d’information. Les medecins vasculaires auraient consacre plus de temps a l’information des patients et auraient delivre un message plus exhaustif et plus comprehensible. Plus de 75 % des patients ont declare qu’aucun medecin n’avait aborde les problematiques des precautions a prendre sous anticoagulants, des complications a long terme et de la prevention de la recidive de la maladie veineuse thromboembolique. Conclusion Dans l’etude CACTUS, les medecins vasculaires auraient consacre davantage de temps a l’information medicale qui est jugee satisfaisante d’apres les patients. Des themes importants n’auraient pas ete abordes suggerant la necessite d’une protocolisation de l’information au patient.

Introduction Postthrombotic syndrome (PTS) is a form of secondary chronic venous insufficiency (CVI) that occurs after deep vein thrombosis (DVT). Effective treatments for PTS are lacking. Micronized purified flavonoid fraction (MPFF) is a venoactive drug used in the treatment of CVI. Objective To determine whether MPFF is a good candidate to explore as a therapeutic agent for PTS. Methods We performed a narrative review in which we identified 14 systematic reviews, 33 randomized controlled trials, and 19 observational studies that discussed the use of MPFF in CVI, as well as studies that reported on the mechanistic action of MPFF in relation to the pathophysiology of PTS. Results MPFF targets a number of pathophysiologic components of PTS. Based on animal models and human studies investigating objective vascular and lymphatic measures, MPFF promotes venous recanalization after DVT, decreases venous remodeling and reflux, inhibits inflammatory processes, improves venous tone and stasis, improves lymphatic circulation, improves capillary hyperpermeability, and decreases tissue hypoxia. Furthermore, MPFF shows promise in improving clinical manifestations, quality of life, and objective venous parameters of CVI. Studies suggest good patient acceptability and tolerability with the use of MPFF in CVI. Conclusion MPFF is a good candidate to explore as a potential therapy for PTS. Confirmatory high‐quality studies are still needed to reinforce the evidence supporting the use of MPFF in CVI. Double‐blind randomized controlled trials with clinical endpoints are needed to assess the clinical efficacy of MPFF in the treatment of PTS.

Background Direct oral anticoagulants (DOACs) are prescribed for over 80% of patients who start anticoagulant therapy for a new diagnosis of atrial fibrillation (AF). Inappropriate DOAC prescriptions are associated with increased mortality. However, limited data exist as to what proportion of primary care physicians (PCPs) initiate anticoagulation in patients with new AF and the extent of their DOAC knowledge. Material and methods We conducted a telephone survey of randomly selected PCPs in Ontario, Canada. Our primary objective was to determine the percentage of PCPs who initiate anticoagulation in new AF patients and the proportion of patients they initiate on DOACs. Our secondary objectives were to assess PCPs' knowledge about DOACs and to identify educational opportunities to address any knowledge gaps. Results Our survey included 50 respondents. After making a new AF diagnosis, 66% of PCPs stated that they usually initiate anticoagulation themselves and 84% prescribed a DOAC at least 75% of the time. Potential DOAC knowledge gaps included: administration considerations, off-label dosing, concomitant use of acetylsalicylic acid (ASA) in stable coronary artery disease (CAD) and use in valvular AF. Conclusion Most PCPs initiate anticoagulants for AF and prescribe DOACs for the vast majority of new patients. PCPs were well versed in certain aspects of DOAC prescribing, however, a number of knowledge gaps were identified. PCPs may benefit from targeted education in these areas to improve patient outcomes in AF.

Isolated distal deep-vein thrombosis (DVT, infra-popliteal DVT without pulmonary embolism) is a common presentation of venous thromboembolism (VTE), but was an exclusion criterion from the pivotal trials that validated the use of direct oral anticoagulants (DOACs) for VTE management. Using data from the international RIETE registry, we analyzed and compared trends in DOACs prescription between January 2011 and June 2019 in patients with distal vs. proximal DVT. We also assessed DOACs' prescriptions and compared the outcomes (VTE recurrence, bleeding and death) of distal DVT patients treated with DOACs vs. those on vitamin K antagonists (VKAs). 2308 patients with distal DVT and 11,364 patients with proximal DVT were included in the current analysis. DOACs were more frequently prescribed in patients with distal than proximal DVT (25% vs. 16%, p < 0.001). DOACs use increased sharply during the observation period (P < 0.001 for trend). In 2018, 56% of patients with distal DVT received DOACs. Distal DVT patients treated with rivaroxaban or edoxaban received the dose recommended for VTE management in most (> 85%) cases. Patients treated with apixaban were older, more likely to have underlying conditions than patients treated with rivaroxaban and, in most cases (> 75%), did not receive the recommended 1-week loading dose for acute VTE management. Outcomes between distal DVT patients treated with VKAs or DOACs appeared to be similar. In patients with distal DVT, DOACs have become the most common anticoagulant regimen. Specific trials are needed to determine the optimal DOACs dose regimen for treatment of distal DVT.

Background: Isolated distal deep vein thrombosis (IDDVT) is a common form of venous thromboembolism (VTE). Limited data exist about the clinical characteristics, initial treatment, and short-term outcomes of these patients. Methods: Using the data from the RIETE registry (05/2001-02/2019), we identified patients with IDDVT without pulmonary embolism (PE). We determined the clinical presentation, initial treatment, and 30-day and 90-day outcomes. We compared the findings with patients with proximal DVT without PE. Results: We identified 5,359 patients with IDDVT (mean age 61±17 years, 50% women). The most prevalent comorbidities were hypertension (39%), anemia (28%), prior VTE (14%), active cancer (12%), heart failure (6.7%), and diabetes (6.6%). Recent surgery was reported in 16%. Most participants received anticoagulation (99%), most commonly with low-molecular-weight heparin (88%). No patient received thrombolytics and use of vena cava filters was rare (0.4%). At 30 days, 59 patients (1.1% [99% CI, 0.8%-1.5%]) died, including only 3 from PE (0.1% [99% CI, 0.01%-0.2%]), 44 (0.8% [99% CI, 0.5%-1.2%]) had nonfatal VTE recurrence, and 31 (0.6% [99% CI, 0.4%-0.9%]) had major bleeding. At 90 days, 2.9% (99% CI, 2.4%-3.6%) died (no additional death from PE), 1.5% (99% CI, 1.1%-2.0%) had nonfatal VTE recurrence, and 0.9% (99% CI, 0.6%-1.3%) had major bleeding. When compared with 25,420 individuals with proximal DVT without PE, those with IDDVT had lower co-morbidity burden including diabetes, heart failure, and cancer, but were more likely to have had recent surgery (P Conclusions: In a large multinational study, IDDVT occurred in patients with low comorbidity burden. Most patients with IDDVT received anticoagulation. Fatal PE was rare, and patients had a more benign prognosis compared with those with proximal DVT.

Summary Objectives To assess: (1) lower limb primary lymphedema or post-thrombotic syndrome patient's pathway in terms of health care professional use and (2) if aetiology of edema has an impact on this pathway. Methods Ancillary survey of the transversal prospective CHROEDEM pilot study. Forty patients with either lower limb primary lymphedema or post-thrombotic syndrome were invited to participate. Results Seventy-five percent of primary lymphedema patients and 50% of post-thrombotic patients benefited from a multidisciplinary management (P = 0.10) including the general practitioner, the vascular medicine physician and either a physiotherapist (particularly in case of primary lymphedema), a registered nurse (particularly in case of post-thrombotic syndrome). Main ambulatory health care professionals’ correspondent of hospital-based vascular medicine physicians were general practitioners (80%) in post-thrombotic patients, and general practitioners (60%) and physiotherapists (45%) in primary lymphedema patients. Pharmacists were also involved in patient education. Conclusion Management of primary lymphedema and post-thrombotic related chronic edema is usually multidisciplinary. General practitioners and vascular medicine physicians are the cornerstones of this management, that also involves the physiotherapist in case of primary lymphedema and in a lesser extent the registered nurse and the pharmacist. This suggests that these five healthcare professional should play a key role in case of development of standardized patient pathways for primary lymphedema and post-thrombotic syndrome.

International audience; The post-thrombotic syndrome (PTS) is a form of chronic venous insufficiency secondary to prior deep vein thrombosis (DVT). It affects up to 50% of patients after proximal DVT. There is no effective treatment of established PTS and its management lies in its prevention after DVT. Optimal anticoagulation is key for PTS prevention. Among anticoagulants, low-molecular-weight heparins have anti-inflammatory properties, and have a particularly attractive profile. Elastic compression stockings (ECS) may be helpful for treating acute DVT symptoms but their benefits for PTS prevention are debated. Catheter-directed techniques reduce acute DVT symptoms and might reduce the risk of moderate–severe PTS in the long term in patients with ilio-femoral DVT at low risk of bleeding. Statins may decrease the risk of PTS, but current evidence is lacking. Treatment of PTS is based on the use of ECS and lifestyle measures such as leg elevation, weight loss and exercise. Venoactive medications may be helpful and research is ongoing. Interventional techniques to treat PTS should be reserved for highly selected patients with chronic iliac obstruction or greater saphenous vein reflux, but have not yet been assessed by robust clinical trials.

International audience; After a proximal lower limb deep vein thrombosis (DVT; involving popliteal veins or above), up to 40% of patients develop postthrombotic syndrome (PTS) as assessed by the Villalta scale (VS). Poor initial anticoagulant treatment is a known risk factor for PTS. The risk of developing PTS after isolated distal DVT (infra-popliteal DVT without pulmonary embolism), and the impact of anticoagulant treatment on this risk, are uncertain.Methods: Long-term follow-up of CACTUS double-blind trial comparing 6 weeks of s.c. nadroparin (171 IU/kg/d) versus s.c. placebo for a first symptomatic isolated distal DVT. At least 1 year after randomization, patients had a PTS assessment in clinic or by phone using the VS.Results: After a median follow-up of 6 years, PTS was present in 30% (n = 54) of the 178 patients who had a PTS assessment. PTS was moderate or severe in 24% (n = 13) of cases. There was no statistically significant difference in prevalence of PTS in the nadroparin versus placebo groups (29% versus 32%, P = .6), except in patients without evidence of primary chronic venous insufficiency (9% versus 24%, P = .04). Rates of venous thromboembolism recurrence during follow-up in the nadroparin and placebo groups were, respectively, 8% (n = 7) and 14% (n = 13; P = .2).Conclusion: After a first isolated distal DVT, the risk of PTS is substantial but much lower than that reported after proximal DVT. Anticoagulation with nadroparin doesn't provide any clear benefit to prevent PTS, except in patients without preexisting chronic venous insufficiency. Anticoagulation might be associated with a lower risk of venous thromboembolism recurrence.

International audience; Background: Distal deep vein thrombosis (infrapopliteal DVT without proximal DVT or pulmonary embolism [PE]) generally shares the same triggering risks factors as proximal DVT. In women of childbearing age, a frequent triggering risk factor is the use of combined oral contraceptive (COC) pills. However, data on the epidemiology and long-term outcomes of COC-associated distal DVT are lacking.Objectives: To assess the epidemiology and long-term outcomes of COC-associated distal DVT.Methods: Using data from the OPTIMEV (Optimisation de l'Interrogatoire dans l'évaluation du risque thrombo-Embolique Veineux [Optimization of Interrogation in the Assessment of Thromboembolic Venous Risk]) multicenter cohort study of patients with objectively confirmed venous thromboembolism (VTE) enrolled between 2004 and 2006, we assessed in nonpregnant or postpartum women aged ≤ 50 years without cancer or history of VTE (i) proportion of COC-associated distal DVTs among women with distal DVTs and among women with COC-associated VTEs (distal DVT, proximal DVT, or PE) and (ii) 3-year incidence of death, bleeding, and VTE recurrence.Results: COC-associated distal DVTs (n = 54) represented 43.9% of all distal DVTs and 51.9% of COC-associated VTEs. All but one woman with a COC-associated distal DVT received therapeutic anticoagulation for a median of 3 months. At 3-year follow-up, all women with COC-associated distal DVTs were alive, and none had bled during anticoagulant treatment or had experienced a DVT or PE recurrence after stopping anticoagulants. Similar results were found in patients with COC-associated proximal DVT and PE: The VTE recurrence rate was 1.7% per patient-year (PY) and 0% PY, respectively, and there were no deaths or major bleeds in either group.Conclusions: Distal DVT was the most frequent clinical presentation of COC-associated VTE and had similarly favorable long-term outcomes as other COC-associated VTE.

Introduction: Elastic compression stockings (ECS) are commonly used for the prevention of post-thrombotic syndrome (PTS) after deep venous thrombosis (DVT). However, their efficacy is controversial. While two open-label studies reported a 50% risk reduction of PTS in the ECS vs. no-ECS groups, a large double-blind study didn't find any benefit of ECS vs. placebo-ECS to prevent PTS. These opposite results could be explained either by a placebo effect in the open-label studies or to a lack of compliance to study ECS in the double-blind study. Additional data on the impact of compliance on ECS efficacy, obtained in a double-blind way, are therefore needed. Methods: We analyzed data from the French, CELEST, multicentre double-blind trial comparing 25mmHg ECS vs. 35mmHg ECS to prevent PTS at 2 years after a first symptomatic ipsilateral proximal DVT (NCT01578122). All CELEST patients who had complete data for primary outcome (i.e. PTS, defined as a Villalta score ≥5 on the DVT affected leg at the one- or 2-year follow up visit) were included. The objectives of this predefined analysis were to: i) compare the incidences of PTS at 2 years according to compliance to ECS (irrespective of allocated treatment group) during the first 3 months of treatment and during the 2-year follow-up; ii) assess independent predictors of PTS using a stepwise multivariable model including all of the following variables (baseline patients' and DVT characteristics, anticoagulant treatment and compliance to ECS) if they achieved a p value of 0.2 or less in univariate analysis as well as ECS strength allocation group; iii) build an induction tree algorithm to measure the impact in terms of incidence of PTS of each of the independent predictor of PTS. Compliance to ECS was defined as reasonable and optimal if the patient had worn the study ECS more than 50% and more than 80% of the time respectively and had a modified GIRERD score of 0-2. Results: 249 patients were eligible for this analysis. Mean baseline age was 57 years, 70% (n=174) were men, 20% (n=50) were obese, 21% (n=52) had previous VTE event, 7% (n=18) had a baseline Villalta score ≥5 and the most proximal extent of DVT was the iliac vein in 15% (n=37) of cases. In 80% (n=179) of cases patients were treated with anticoagulation for more than 6 months after DVT and a direct oral anticoagulant (DOAC) was used in 69% (n=164) of cases. 32 % (n=80) of patients developed PTS at 2 years. When patients wore study ECS>80% of the time (i.e optimal compliance), incidence of PTS over 2 years was 26.1% (n=31). Incidence of PTS was 25.0% (n=10) and 40.5% (n=34) in those patients who wore ECS 50-80% and Conclusions: In our double bling study assessing 25mmHg vs. 35mmHg ECS to prevent PTS, compliance to ECS was a significant independent predictor of PTS in our multivariable model. Impact of ECS use became apparent when patient used ECS at least 50% of the time without any strong benefit beyond. Wearing study ECS>50% of the time was associated with 2-fold decreased risk of developing PTS, which is consistent with the results from previous 'positive' open-label studies. It suggests that use of ECS influences the risk of developing PTS. Our induction tree algorithm evidences that being compliant with ECS seems particularly beneficial in - non-obese - patients with extensive DVT. Figure 1 Figure 1. Disclosures Verriere: Laboratoires Innothera: Current Employment.

Essentials Clinical significance of cancer-related isolated distal deep vein thrombosis (iDDVT) is unknown. We studied patients with iDDVT, with and without cancer, and proximal DVT with cancer. Cancer-related iDDVT patients have a much poorer prognosis than iDDVT patients without cancer. Cancer-related iDDVT patients have a similar prognosis to cancer-related proximal DVT patients. SummaryBackground Isolated distal deep vein thrombosis (iDDVT) (infra-popliteal DVT without pulmonary embolism [PE]) is a frequent event and, in the absence of cancer, is usually considered to be a minor form of venous thromboembolism (VTE). However, the clinical significance of cancer-related iDDVT is unknown. Methods Using data from the observational, prospective multicenter OPTIMEV cohort, we compared, at 3 years, the incidences of death, VTE recurrence and major bleeding in patients with cancer-related iDDVT with those in cancer patients with isolated proximal DVT (matched 1:1 on age and sex) and patients with iDDVT without cancer (matched 1:2 on age and sex). Results As compared with patients with cancer-related isolated proximal DVT (n = 92), those with cancer-related iDDVT (n = 92) had a similar risk of death (40.8% per patient-year (PY) vs. 38.3% per PY; aHR = 1.0, 95% CI[0.7–1.4]) and of major bleeding (3.8% per PY vs. 3.6% per PY, aCHR = 0.9 [0.3–3.2]) and a higher risk of VTE recurrence (5.4% per PY vs. 11.5% per PY; aCHR = 1.8 [0.7–4.5]). As compared with patients with iDDVT without cancer (n = 184), those with cancer-related iDDVT had a nine times higher risk of death (3.5% per PY vs. 38.3% per PY; aHR = 9.3 [5.5–15.9]), a higher risk of major bleeding (1.8% per PY vs. 3.6% per PY; aCHR = 2.0 [0.6–6.1]) and a higher risk of VTE recurrence (5.0% per PY vs. 11.5% per PY; aCHR = 2.0 [1.0–3.7]). The results remained similar in the subgroup of patients without history of VTE. Conclusion Patients with cancer-related iDDVT seem to have a prognosis that is similar to that of patients with cancer-related isolated proximal DVT and a dramatically poorer prognosis than patients with iDDVT without cancer. This underlines the high clinical significance of cancer-related iDDVT and the need for additional studies.

Background In routine clinical practice, in most countries, patients with pulmonary embolism (PE) are hospitalized for clinical surveillance and to start anticoagulant treatment. Clinical trials and guidelines suggest that patients with stable PE can be safely treated as outpatients. This shift in management may increase general practitioners' (GP) role in PE early management. However, GP opinion regarding PE home treatment has never been assessed. Methods Survey conducted in France among a random sample of 360 GP (564 contacted to reach targeted sample size) working in regions representative of national access to French healthcare system. Main objectives were to assess i) GP’ acceptability to PE home treatment ii) GP’ preferred outpatient pathway. Results 87% of GP were favorable to home treatment of stable PE if the medical report is immediately available when the patient is discharged from ER (100%), in the absence of social and medical facility isolation of the patient (99%) and if the patient (99%) and GP (76%) consented. Outpatient pathways should be collaborative, between GP and a thrombosis specialist, and should include specialized follow-up visits at one week (80%), 3–6 months (80%) and when anticoagulant treatment is stopped (97%). 61% of GP felt that direct oral anticoagulants (DOAC) should facilitate PE home treatment, which should improve patient's quality of life. Conclusion The vast majority of interviewed GP are favorable to home treatment of stable PE if a formal outpatient pathway is established. DOAC are perceived as another key for the success of the development of PE home treatment.

International audience; In its promotion and scientific program, the French Society for Vascular Medicine (SFMV) has addressed a consensus statement regarding the “Unresolved questions on venous thromboembolic disease”.Indeed, several international guidelines were already proposed regarding management of venous thromboembolic disease, but many questions remain without clear established recommendations.In this context, a task force, mandated by the French society, has addressed issues regarding: Diagnosis of lower-limb deep vein thrombosis recurrence; Therapeutic management of superficial vein thrombosis; Therapeutic management of distal vein thrombosis; Therapeutic management of post thrombotic syndrome.The purpose of the consensus process was to provide expert guidance to answer to these specific cases that are not currently entirely resolved.For each of the identified questions, a systematic review of the available literature through Medline (1980–2017) and the Cochrane Central Register of Controlled Trials analysis was performed. References in included studies and previous systematic reviews were also reviewed for additional potential studies.A multidisciplinary expert consensus group from 19 participants with expertise in the areas of vascular medicine, haematology, internal medicine, methodology, identified important clinical challenges for each issue. A steering committee of 5 to 6 participants was designed for each issue and developed the initial statements, associated with summaries of the evidence graded according to level of evidence

Essentials Management of patients with calf deep vein thrombosis remains controversial. We conducted a post-hoc analysis of a placebo controlled LMWH randomized clinical trial. Pain was assessed using visual analogue scale at inclusion, one and six weeks. There was no difference in pain control between the two arms. SUMMARY: Background The optimal management of distal deep vein thrombosis (DVT) is highly debated. The only available placebo-controlled trial suggested the absence of clear benefit of anticoagulation. Many physicians feel that, beyond preventing thromboembolic complications, anticoagulation with low-molecular-weight heparin (LMWH) has the potential to improve pain control. Objectives To analyze whether LMWHs decrease pain in patients with distal deep vein thrombosis. Patients and methods Two-hundred and fifty-two patients included in a multicenter, placebo-controlled, randomized clinical trial of LMWH in patients with acute distal DVT and who were asked to rate their pain at inclusion and at each medical visit, using a visual analogue pain scale (VAS). Results One hundred and thirty patients were randomized in the therapeutic nadroparin arm and 122 patients were randomized in the placebo arm. Mean VAS values were 4.6 (standard deviation [SD] 2.5) at inclusion, 2.1 (SD 2.0) at 1 week and 0.4 (SD 1.2) at 6 weeks. We calculated the individual variation in VAS between inclusion and 1 week in patients in whom VAS was available at the two study time-points. There was no difference in the mean VAS reduction between patients treated with therapeutic nadroparin (n = 106) and with placebo (n = 109): -2.6 (SD 2.4) vs. -2.3 (SD 2.0) after 1 week and -4.4 (SD 2.8) vs. -4.0 (SD 2.4) after 6 weeks, respectively. The use of compression stockings was associated with a reduction in pain. Conclusion These data suggests that LMWH use does not improve pain control as compared with placebo in patients with acute distal DVT.

Background There is a lack of knowledge with regards to contemporary presentation, management, and outcomes of patients with venous thromboembolism (VTE). Many clinically important subgroups (including the elderly, those with recent bleeding, and pregnant patients) have been under-represented in clinical trials. Further, design of clinical trials is challenging in some scenarios, such as in those with hemodynamically-unstable pulmonary embolism (PE). Objectives RIETE (Registro Informatizado Enfermedad TromboEmbolica) is a large prospective multinational ongoing registry, designed to address these unmet needs using representative data from multiple centers. Methods Initiated in Spain in 2001, RIETE currently includes 206 centers in 28 countries and has enrolled over 87,000 patients with VTE. The overarching goal is to improve the management of VTE through better understanding of prevention, as well as demographics, co-morbidities, treatment patterns, and outcomes of patients with VTE. Results RIETE has helped characterize the pattern of presentation and outcomes of VTE, including in the aforementioned understudied subgroups, in over 150 research articles. RIETE has recently expanded to collect long-term outcomes data, and has broadened its inclusion criteria to enroll other forms of venous thrombosis (such as cerebral vein thrombosis and splanchnic vein thrombosis). The RIETE platform is also being used to conduct pragmatic comparative effectiveness studies, including randomized trials. Future steps would focus on collaboration with additional centers across the world, and efforts to ensure the quality and expansion of the registry. It is expected that RIETE will continue to provide clinical evidence for understudied subgroups with VTE, and will have more prominent role for facilitation of multicenter (and multinational studies) that could be used for assessment of variations and disparities in care, quality improvement, and conducting comparative effectiveness research. Conclusions RIETE is a large ongoing registry of patients with VTE and other thrombotic conditions. Its results could be helpful for improving our understanding of the epidemiology, patterns of care and outcomes of patients with thrombotic disease.

In patients with deep-vein thrombosis (DVT) in the lower limbs, venous ulcer is the most debilitating and end-stage clinical expression of the post-thrombotic syndrome (PTS). To date, risk factors for PTS-related ulcer in DVT patients have not been identified.We used the international observational RIETE registry to assess the evolution of PTS signs and symptoms during a 3-year follow-up period and to identify independent predictors of PTS ulcer at 1 year in patients with acute DVT.Among 1,866 eligible patients, cumulative rates of PTS ulcer at 1, 2 and 3 years were 2.7% (n = 50), 4.3% (n = 54) and 7.1% (n = 60), respectively. The proportion of patients with PTS symptoms at 1, 2 or 3 years remained stable (≈40%), while the proportion of patients with PTS signs increased slightly over time (from 49 to 53%). Prior history of venous thromboembolism (VTE) (odds ratio [OR] = 5.5 [2.8–10.9]), diabetes (OR = 2.3 [1.1–4.7]), pre-existing leg varicosities (OR = 3.2 [1.7–6.1]) and male sex (OR = 2.5 [1.3–5.1]) independently increased the risk of PTS ulcer at 1 year. Obesity also increased the risk but failed to reach statistical significance (OR = 1.8 [0.9–3.3]). DVT treatment characteristics (duration or drug) did not influence the risk.Our results evidence that after acute DVT, pre-existing leg varicosities, prior venous thromboembolism, diabetes and male gender independently increased the risk for PTS ulcer. This suggests that clinicians should consider strategies aimed to prevent ulcers in high-risk DVT patients, such as preventing VTE recurrence, use of stockings in those with pre-existing venous insufficiency, careful monitoring of diabetic patients and encouraging weight loss in obese patients.

International audience; BACKGROUND: Cancer patients who develop a deep-vein thrombosis (DVT) or a pulmonary embolism (PE) are at higher risk of death than similar cancer patients who do not develop DVT or PE. The impact of isolated superficial venous thrombosis (SVT) (i.e. without DVT or PE) on the prognosis of cancer patients is unknown. METHODS: Data from the OPTIMEV, multicentre, observational study, to compare at 3 years the incidences of death, DVT-PE recurrence and bleeding of cancer patients with objectively confirmed SVT vs. cancer patients with DVT (matched 1:2 on age, sex, cancer stage) and vs. patients with SVT without cancer (matched 1:3 on age and sex). RESULTS: Cancer patients with SVT (n = 34) had a high risk of death (23.2%patient-year(PY)), that was similar to that of cancer patients with DVT (aHR = 1.0[0.6-1.9]) and higher to that of SVT patients without cancer (aHR = 9.0[3.5-23.1]). Cancer patients with SVT received anticoagulants for a median duration of 45 days and had a high risk of DVT-PE recurrence (6.0%PY), similar to that of cancer patients with DVT (adjusted cause-specific HR (aCHR) = 1.5[0.4-5.8]) and higher to that of SVT patients without cancer (aCHR = 2.9[0.7-11.9]). In our population, venous thrombosis on varicose veins was associated with a lower risk of death (aHR = 0.6[0.3-1.0]) and DVT-PE recurrence (aCHR = 0.6[0.2-1.7]). CONCLUSION: Our results suggest that cancer patients with SVT have a poor prognosis, similar to that of patients with cancer-related DVT. The high rate of DVT-PE recurrence suggests that such patients may need longer duration of anticoagulant treatment.

International audience; INTRODUCTION:Distal deep-vein thromboses (iDDVT) are infra-popliteal DVTs. They are as frequent but less serious than proximal DVT. Their management is debated.METHODS:Clinical practice survey among a random selection of 111 general practitioners (GP) and 56 vascular medicine physicians (VMP) working in Languedoc-Roussillon (France) to assess and compare iDDVTs management by GP and VMP.RESULTS:In case of DVT, GP manage their patients alone in 35% of cases. In case of collaborative management, VMP initiate and stop anticoagulants (>74% of cases) whereas GP monitor anticoagulation (>76% of cases). With iDDVT, there was no difference between GP and VMP in terms of use (94% vs. 92%) and intensity of anticoagulation (full dose: 99%vs.100%). Duration of anticoagulation differed: GP modulated less frequently duration of anticoagulation in presence of a transient risk factor (58% vs. 90%, p

International audience

SummaryAcute deep venous thrombosis (DVT) causes leg pain. Elastic compression stockings (ECS) have potential to relieve DVT-related leg pain by diminishing the diameter of distended veins and increasing venous blood flow. It was our objective to determine whether ECS reduce leg pain in patients with acute DVT. We performed a secondary analysis of the SOX Trial, a multicentre randomised placebo controlled trial of active ECS versus placebo ECS to prevent the post-thrombotic syndrome.The study was performed in 24 hospital centres in Canada and the U.S. and included 803 patients with a first episode of acute proximal DVT. Patients were randomised to receive active ECS (knee length, 30–40 mm Hg graduated pressure) or placebo ECS (manufactured to look identical to active ECS, but lacking therapeutic compression). Study outcome was leg pain severity assessed on an 11-point numerical pain rating scale (0, no pain; 10, worst possible pain) at baseline, 14, 30 and 60 days after randomisation. Mean age was 55 years and 60% were male. In active ECS patients (n=409), mean (SD) pain severity at baseline and at 60 days were 5.18 (3.29) and 1.39 (2.19), respectively, and in placebo ECS patients (n=394) were 5.38 (3.29) and 1.13 (1.86), respectively. There were no significant differences in pain scores between groups at any assessment point, and no evidence for subgroup interaction by age, sex or anatomical extent of DVT. Results were similar in an analysis restricted to patients who reported wearing stockings every day. In conclusion, ECS do not reduce leg pain in patients with acute proximal DVT.

International audience; BACKGROUND:The efficacy and safety of anticoagulant treatment is not established for patients with acute symptomatic deep vein thrombosis (DVT) of the calf. We aimed to assess whether therapeutic anticoagulation is superior to placebo in patients with symptomatic calf DVT.METHODS:In this randomised, double-blind, placebo-controlled trial, we enrolled low-risk outpatients (without active cancer or previous venous thromboembolic disease) with a first acute symptomatic DVT in the calf from 23 university medical centres or community medical clinics in Canada, France, and Switzerland. We randomly assigned (1:1) patients to receive either the low-molecular-weight heparin nadroparin (171 UI/kg, subcutaneously, once a day) or placebo (saline 0·9%, subcutaneously, once a day) for 6 weeks (42 days). Central randomisation was done using a computer-generated randomisation list, stratified by study centre. Random allocation sequences of variable block size were centrally determined by an independent research clinical centre. Study staff, patients, and outcome assessors (central adjudication committee) were masked to group assignment. Numbered boxes of active drug or placebo were provided to pharmacies in identical packaging. All patients were prescribed compression stockings and followed up for 90 days. The primary efficacy outcome was a composite measure of extension of calf DVT to proximal veins, contralateral proximal DVT, and symptomatic pulmonary embolism at day 42 in the modified intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding at day 42. The trial was registered with ClinicalTrials.gov, number NCT00421538.FINDINGS:Between Feb 1, 2008, and Nov 30, 2014, we screened 746 patients, enrolling 259 patients (50% of the prespecified sample size), before the trial steering committee terminated the trial because of expiry of study drug and slow recruitment. The intention-to-treat analysis population comprised 122 patients in the nadroparin group and 130 in the placebo group. There was no significant difference between the groups in the composite primary outcome, which occurred in four patients (3%) in the nadroparin group and in seven (5%) in the placebo group (risk difference -2·1%, 95% CI -7·8 to 3·5; p=0·54). Bleeding occurred in five patients (4%) in the nadroparin group and no patients in the placebo group (risk difference 4·1, 95% CI 0·4 to 9·2; p=0·0255). In the nadroparin group one patient died from metastatic pancreatic cancer and one patient was diagnosed with heparin-induced thrombocytopenia type 2.INTERPRETATION:Nadroparin was not superior to placebo in reducing the risk of proximal extension or venous thromboembolic events in low-risk outpatients with symptomatic calf DVT, but did increase the risk of bleeding. Avoidance of systematic anticoagulation for calf DVT could have a substantial impact on individual patients and from a public health perspective.FUNDING:Swiss National Science Foundation, the Programme Hospitalier de Recherche Clinique in France, and the Canadian Institutes of Health Research.

International audience; The post-thrombotic syndrome (PTS), which refers to chronic clinical manifestations of venous insufficiency after a deep vein thrombosis (DVT), is a frequent occurrence. Because treatment options for PTS are limited, its management mainly relies on the prevention of its occurrence after DVT. Among identified predictors of PTS, extensive proximal location of DVT directly modifies the treatment of DVT because of the possibility of performance of complementary endovascular techniques. The association between poor international normalized ratio control and subsequent PTS should encourage physicians to perform frequent and regular international normalized ratio monitoring of patients receiving vitamin K antagonists. Other identified PTS risk factors are ipsilateral DVT recurrence, older age, pre-existing primary venous insufficiency, obesity, and residual venous obstruction, but these are less amenable to therapy. Because of their potential therapeutic implications, identification of biomarkers that are predictive of PTS such as markers of inflammation is crucial and such research is ongoing.

International guidelines recommend extended duration secondary prophylaxis in cancer patients who develop primary venous thromboembolism (VTE). Agent selection is guided in part by one large randomized trial (i.e., CLOT; Lee et al., N Engl J Med 349:146–53, 2003) which demonstrated that dalteparin reduced the relative risk of recurrence by 52% compared with oral vitamin K antagonists (VKA; HR = 0.48, 95% CI, 0.30 to 0.77). In a subgroup analysis from that same trial, patients with renal impairment also derived benefit with dalteparin (VTE rates = 3% vs. 17%; p = 0.011). To measure the economic value of secondary VTE prophylaxis with dalteparin, a patient-level pharmacoeconomic analysis was conducted from the Austrian and French healthcare system perspectives. Chapter 1 Healthcare resource use collected during the CLOT trial was extracted and converted into direct cost estimates. Incremental cost differences between the dalteparin and VKA groups were then combined with health state utilities to measure the cost per quality-adjusted life year (QALY) gained. The dalteparin group had significantly higher costs than the VKA group in both countries (Austria: dalteparin = €2687 vs. VKA = €2012; France: dalteparin = €2053 vs. VKA = €1352: p

Essentials Long-term risk of recurrence of isolated superficial vein thrombosis (SVT) is under-studied. We analyzed data from a cohort of first SVT and proximal deep vein thrombosis (DVT) without cancer. The risk of recurrence as DVT or pulmonary embolism is twice lower in SVT patients. However, overall risk of recurrence is similar between SVT and proximal DVT patients. Click to hear Dr Decousus' perspective on superficial vein thrombosis SUMMARY: Background Isolated superficial vein thrombosis (iSVT) (without concomitant deep vein thrombosis [DVT] or pulmonary embolism [PE]) is a frequent event, but available data on long-term outcomes are scarce and retrospective. Therefore, we aimed to determine prospectively the risk and type of venous thromboembolism (VTE) recurrence after iSVT and compare them with those of proximal DVT. Methods Using data from the prospective, multicenter, observational, OPTIMEV study, we assessed, at 3 years and after anticoagulants were stopped, the incidence and the type of VTE recurrence (iSVT/DVT/PE) of patients with a first objectively confirmed iSVT without cancer (n = 285), and compared these with those of patients with a first proximal DVT without cancer (n = 262). Results As compared with proximal DVT patients, iSVT patients had a similar overall incidence of VTE recurrence (5.4% per patient-year [PY] versus 6.5% per PY, adjusted hazard ratio [aHR] 0.9, 95% confidence interval [CI] 0.5-1.6), but iSVT recurred six times more often as iSVT (2.7% versus 0.6%, aHR 5.9, 95% CI 1.3-27.1) and 2.5 times less often as deep-VTE events (2.5% versus 5.9%, aHR 0.4, 95% CI 0.2-0.9). Varicose vein status did not influence the risk or the type of VTE recurrence. Saphenian junction involvement by iSVT was not associated with a higher risk of recurrence (5.2% per PY versus 5.4% per PY), but was associated with recurrence exclusively as deep-VTE events. Conclusion In patients with a first iSVT without cancer, after stopping anticoagulants, the incidence of deep-VTE recurrence is half that of DVT patients, but the overall risk of recurrence is similar. Ssaphenian junction involvement seems to influence the risk of deep-VTE recurrence, whereas varicose vein status has no impact or a low impact on VTE recurrence.

International audience; The post-thrombotic syndrome (PTS) is a frequent, potentially disabling complication of deep vein thrombosis (DVT) that reduces quality of life and is costly. Clinical manifestations include symptoms and signs such as leg pain and heaviness, edema, redness, telangiectasia, new varicose veins, hyperpigmentation, skin thickening and in severe cases, leg ulcers. The best way to prevent PTS is to prevent DVT with pharmacologic or mechanical thromboprophylaxis used in high risk patients and settings. In patients whose DVT is treated with a vitamin K antagonist, subtherapeutic INRs should be avoided. We do not suggest routine use of elastic compression stockings (ECS) after DVT to prevent PTS, but in patients with acute DVT-related leg swelling that is bothersome, a trial of ECS is reasonable. We suggest that selecting patients for catheter-directed thrombolytic techniques be done on a case-by-case basis, with a focus on patients with extensive thrombosis, recent symptoms onset, and low bleeding risk, who are seen at experienced hospital centers. For patients with established PTS, we suggest prescribing 20-30 mm Hg knee-length ECS to be worn daily. If ineffective, a stronger pressure stocking can be tried. We suggest that intermittent compression devices or pneumatic compression sleeve units be tried in patients with moderate-to-severe PTS whose symptoms are inadequately controlled with ECS alone. We suggest that a supervised exercise training program for 6 months or more is reasonable for PTS patients who can tolerate it. We suggest that management of post-thrombotic ulcers should involve a multidisciplinary approach. We briefly discuss upper extremity PTS and PTS in children.

Isolated distal deep-vein thrombosis (iDDVT) is a distal deep-vein thrombosis (DVT) without proximal DVT or pulmonary embolism. Although its clinical significance is uncertain, its prevalence is increasing with the use of whole leg compression ultrasonography. Epidemiological data giving reported rates of venous thromboembolism (VTE) are scarce, and there is potential conflict regarding the need to treat with anticoagulant drugs. Therefore, iDDVT management varies widely from one country/physician to another.Data are available from two large multicenter observational studies of iDDVT and proximal DVT without pulmonary embolism (iPDVT), comparing risk factor profiles and early prognosis, and also from clinical trials on iDDVT.iDDVT and iPDVT differ in terms of risk factor profile, iPDVT being more associated with chronic risk factors and iDDVT with transient ones. In the short term, case fatality rates associated with iDDVT suggest that it is a clinically relevant entity and should at least be diagnosed. From a therapeutic point of view, differences in population profile and outcomes between iPDVT and iDDVT, and results from recent clinical trials in favor of a modest VTE potential of iDDVT indicate that specific randomized double-blind trials are necessary to determine an appropriate and accepted mode of care for iDDVT.

The Sapporo criteria-related definition commonly used for diagnosis of the antiphospholipid syndrome (APS) associates the occurrence of thrombotic and/or obstetrical events with persistently positive antiphospholipid antibodies (aPL-Ab), including lupus anticoagulant (LAC), anticardiolipin IgG (aCL-G) or IgM, and/or anti-b2-glycoprotein I IgG or IgM antibodies. Criteria used to define the purely obstetrical clinical subtype of the APS syndrome include the aPLs listed above plus a fetal loss later than 10-weeks gestation, 3 or more unexplained consecutive embryonic losses before the 10th week gestation, or eclampsia or features of placental insufficiency requiring the preterm birth before 34 weeks of a morphologically normal child. Some investigators have questioned the serological criteria associated with this form of APS and have suggested that the aCL-G, anticardiolipin IgM, and anti-b2-glycoprotein I IgM measurements should be excluded. To determine the effects of the various aPL-Ab subtypes on pregnancy outcome, the investigators prospectively monitored women who had had an unexplained embryonic loss during their first pregnancy and were undergoing their untreated second pregnancy. They selected women who did not have APS; any hormonal abnormalities; or inflammatory, infectious, or malignant diseases; and who had normal parental karyotypes; the pregnancy outcomes of 142 women who tested positive for at least 1 of the 5 classical aPL-Abs were compared with those of 142 control women who were confirmed to be aPL-Abs negative. Compared with the women without aPL-Abs, the aPL-Ab-positive women experienced more clinical complications during their second pregnancy, including pregnancy loss (of which the majority were embryonic losses), preeclampsia, placental abruption, and intrauterine fetal growth restriction. The presence of LAC alone (type IIa aPL-Ab positivity) was associated with the highest risk of recurrent embryonic loss and intrauterine growth restriction. Positive tests for combinations of aPL-Ab (type I aPL-Ab positivity) were associated with the highest risk of late complications, placental abruption, and preeclampsia. A finding of anti-b2-glycoprotein I IgM positivity had no apparent diagnostic clinical relevance. These findings demonstrate that among women with a first unexplained pregnancy loss before the 10th week of gestation, those who are aPL-Abs positive have a higher risk of complications in their next pregnancy, including embryonic loss, preeclampsia, placental abruption, and intrauterine growth restriction, than women who are aPL-Abs negative. These findings suggest that the aPL-Ab LAC, aCL-G or IgM, and anti-b2-glycoprotein I IgG are helpful in identifying patients at increased risk of an adverse outcome, whereas anti-b2-glycoprotein I IgM has questionable diagnostic value.

Summary. Background: The clinical significance of symptomatic isolated distal deep vein thrombosis (DVT) is uncertain. Consequently, this leads to important disparities in its management. Objective: To examine the clinical history of isolated distal DVT and to compare it with that of proximal DVT. Methods: Using data from the international, prospective, RIETE registry on patients with confirmed symptomatic venous thromboembolism (VTE), we compared the risk factors and 3-month outcome in patients with isolated distal DVT vs. proximal DVT. Results: Eleven thousand and eighty-six patients with symptomatic DVT, but without pulmonary embolism, were included between 2001 and 2008; 1921 (17.3%) exhibited isolated distal DVT. Anticoagulant treatment was received by 89.1% (1680/1885) of isolated distal DVT and 91.8% (7911/8613) of proximal DVT patients for the entire follow-up period. Isolated distal DVTs were more associated with transient risk factors (i.e. recent travel, hospitalization, recent surgery), whereas proximal DVTs were more associated with chronic states (i.e. ≥75 years or with active cancer). At 3 months, major bleeding rate was lower in patients with isolated distal DVT (1.0% vs. 2.2%, P

Objective We studied the relation between Parkinson disease (PD) and professional exposure to pesticides in a community-based case-control study conducted in a population characterized by a high prevalence of exposure. Our objective was to investigate the role of specific pesticide families and to perform dose-effect analyses. Methods PD cases (n = 224) from the Mutualite Sociale Agricole (France) were matched to 557 controls free of PD affiliated with the same health insurance. Pesticide exposure was assessed using a 2-phase procedure, including a case-by-case expert evaluation. Analyses of the relation between PD and professional exposure to pesticides were first performed overall and by broad category (insecticides, fungicides, herbicides). Analyses of 29 pesticide families defined based on a chemical classification were restricted to men. Multiple imputation was used to impute missing values of pesticide families. Data were analyzed using conditional logistic regression, both using a complete-case and an imputed dataset. Results We found a positive association between PD and overall professional pesticide use (odds ratio [OR] = 1.8, 95% confidence interval [CI] = 1.1–3.1), with a dose-effect relation for the number of years of use (p = 0.01). In men, insecticides were associated with PD (OR = 2.2, 95% CI = 1.1–4.3), in particular organochlorine insecticides (OR = 2.4, 95% CI = 1.2–5.0). These associations were stronger in men with older onset PD than in those with younger onset PD, and were characterized by a dose-effect relation in the former group. Interpretation Our results support an association between PD and professional pesticide exposure, and show that some pesticides (ie, organochlorine insecticides) may be more particularly involved. Ann Neurol 2009;66:494–504

Objective: To analyse the determinants of anti-haemophilic drug costs in hospitalised patients with haemophilia and to estimate the impact of recombinant activated factor VII (rFVIIa) therapy on this expenditure. Perspective: The perspective of the study was from the viewpoint of the hospital. Design and setting: A prospective study was carried out. All patients with haemophilia who were hospitalised in 1999 in Bicetre public hospital, Paris, France were included in the cohort. Main outcome measures and results: For each of the 96 patients (154 hospital stays), we estimated the costs of anti-haemophilic drugs (coagulation concentrates) used. Costs were then stratified by different variables (severity of the disease, presence of a circulating inhibitor to coagulation factors, etc.) and a multivariate model was developed to determine the relationship between these variables and total anti-haemophilic drug costs, while controlling for potential confounders. Our study revealed: (i) the independent role of the five following variables in contributing to high anti-haemophilic drug expenditure: presence of a circulating inhibitor to coagulation factors, odds ratio (OR) = 16.9 (95% CI: 4.3–66); severity of the disease (factor VIII or factor IX≤0.01 IU/mL), OR = 3.7 (95% CI: 1.6–8.6); length of hospital stay >4 days, OR = 8 (95% CI: 2.2–29.4); age >18 years old, OR = 6.2 (95% CI: 1.6–24.5); and surgical reasons for hospitalisation (whether surgery was haemophilia related [OR = 35.7 (95% CI: 7.3–175)] or not [OR = 5.4 (95% CI: 1.3–22.5)]); (ii) the large share that rFVIIa represented in this expenditure on medicines: rFVIIa was used in 20.1% of hospital stays and accounted for 56.2% of the total anti-haemophilic drug costs, which were estimated at €4 384 732 (2000 values). Conclusions: Our data underline the heavy cost of the treatment of haemophilic patients with an inhibitor to coagulation factors. But, to the question of whether the high expenditure linked to rFVIIa utilisation will be balanced out by later benefits, it is not yet possible to reply with any certainty; further cost-benefit evaluation should be carried out.

Purpose of review Postthrombotic syndrome (PTS) is the most frequent complication of deep vein thrombosis. Its pathophysiology is incompletely understood and therapeutic options are limited. This review aims to present and discuss recently published studies that have improved our knowledge related to PTS. Recent findings From a prognostic point of view, some polymorphisms of plasminogen activator inhibitor-1 and platelet endothelial cell adhesion molecule 1 influence the degree of thrombus resolution after deep vein thrombosis and the subsequent rate of PTS, and could help in predicting the risk of PTS. From a therapeutic point of view, the results of a large multicenter placebo-controlled trial suggest an absence of effectiveness of elastic compression stockings to prevent PTS. In addition, although the Cavent trial of catheter-directed thrombolysis to treat ilio-femoral deep vein thrombosis showed significant reduction in the incidence of PTS that was cost-effective, secondary analyses did not show dramatic improvements in quality of life associated with use of catheter-directed thrombolysis. Summary Choice of anticoagulant to treat deep vein thrombosis may represent a new cornerstone of PTS therapeutic management. Studies are needed to assess the impact of new oral anticoagulants and the benefit of extended courses of low molecular weight heparins on the risk of PTS.

www.thelancet.com Vol 384 July 12, 2014 129 left to the discretion of the observer with no quantitative measurement or use of CEAP (Clinical, Etiological, Anatomical, and Pathophysiological) classification. The results were not reported at 2 years as planned, but rather were a cumulative incidence of post-thrombotic syndrome from 6 to 24 months. There was no diff erence for both endpoints, with 2-year data for the primary outcome available in only 45·5% of patients, and for the secondary endpoint in 27% of patients. This study contradicts previous fi ndings. The design and execution of this trial, including the timing of application of elastic compression stockings, the application itself, and defi nition and evaluation of compliance, seem inappropriate. Patients were randomised at a mean of 4·7 days from the time of deep venous thrombosis, and elastic compression stockings were applied within the first 2 weeks of diagnosis. What was the mean time from diagnosis to elastic compression stockings application? Optimum management in this acute phase is crucial for early symptom relief, recurrence, and late outcome. This has clearly been shown for adequate anticoagulation treatment, but also for compression and immediate mobilisation. Compression and walking exercises reduce pain and swelling immediately, and symptoms diminish after 1 week. The aim of continuing wearing elastic compression stockings is to maintain this effect—this could be crucial because the patient might recognise the immediate benefit from using elastic compression stockings and therefore overall compliance would be improved. Sizing was based on leg measurements and elastic compression stockings were sent to patients without provision of proper training. Most patients are unable to apply stockings without specific instruments or training, especially post-thrombotic syndrome: heparin, a drug discovered a century ago by Jay McLean (in 1916), which revolutionised deep-vein thrombosis prognosis. Moreover, a well-conducted anticoagulation treatment has also been associated with a decreased rate of post-thrombotic syndrome. Therefore, the results of the SOX trial should not be “leaving doctors empty handed”, but should rather reinforce their role in off ering a high-quality anticoagulant treatment to their patients. An ongoing international placebocontrolled trial should assess more precisely the eff ect of heparin on the natural history of post-thrombotic syndrome after a distal deep-vein thrombosis (NCT00539058). The eff ect of new oral anticoagulants on the prevention of post-thrombotic syndrome is another important issue.

Post-thrombotic syndrome (PTS) refers to chronic manifestations of venous insufficiency following a deep-vein thrombosis (DVT). It is a frequent, chronic, burdensome and costly disease for which therapeutic options are limited. Above all, the optimal management of PTS consists of preventing its occurrence: first, by preventing DVT, and second, by preventing development of PTS after a DVT. Prevention of DVT is challenging, particularly in the case of nonsurgical hospital inpatients, where physician’s adherence to recommended thromboprophylaxis is often low. In our opinion, this adherence should be improved by generalizing the use of multi-component approaches, including that of automatic reminders. For prevention of PTS after an acute DVT, our recommendations are as follows. After a proximal (popliteal and above) DVT we recommend early ambulation with daily use of 30–40 mmHg graduated elastic compression stockings (ECS) for two years, in addition to careful monitoring of anticoagulant therapy. Below-knee ECS are preferred to thigh-length ECS, as they have similar efficacy in preventing PTS and are better tolerated. To improve compliance with ECS, patient education is important, and use of lighter strengths of compression in patients not tolerating traditional strengths should be considered. Catheter-directed thrombolysis of acute DVT was recently shown to be effective in preventing PTS, but we believe that confirmatory studies are needed before recommending its general use. The cornerstone of management of established PTS relies on patient education and use of compression therapy. We encourage ambulation, use of ECS to manage symptoms, and participation in an exercise training program, which has the potential to improve patients’ quality of life (QOL) and PTS scores. In the absence of symptom relief, ECS that provide a higher strength (40–50 mmHg) should be tried. In case of moderate to severe PTS, intermittent compressive devices can be used to improve PTS symptoms. Surgery and endovascular procedures, including balloon angioplasty, stent placement, endovenectomy or valve reconstruction should be considered only in specialized centers, and only for patients with severe PTS for whom previous conservative treatment has failed. These techniques are still under evaluation and the level of evidence supporting their use is low.

International audience; BACKGROUND: Post-thrombotic syndrome (PTS) is the most frequent complication of deep vein thrombosis (DVT). Its diagnosis is based on clinical characteristics. However, symptoms and signs of PTS are non-specific, and could result from concomitant primary venous insufficiency (PVI) rather than DVT. This could bias evaluation of PTS. METHODS: Using data from the REVERSE multicenter study, we assessed risk factors for PTS in patients with a first unprovoked unilateral proximal DVT 5-7 months earlier who were free of clinically significant PVI (defined as absence of moderate or severe venous ectasia in the contralateral leg). RESULTS: Among the 328 patients considered, the prevalence of PTS was 27.1%. Obesity (odds ratio [OR] 2.6 [95% confidence interval (CI) 1.5-4.7]), mild contralateral venous ectasia (OR 2.2 [95% CI 1.1-4.3]), poor International Normalized Ratio (INR) control (OR per additional 1% of time with INR < 2 during anticoagulant treatment of 1.018 [95% CI 1.003-1.034]) and the presence of residual venous obstruction on ultrasound (OR 2.1 [95% CI 1.1-3.7]) significantly increased the risk for PTS in multivariable analyses. When we restricted our analysis to patients without any signs, even mild, of contralateral venous insufficiency (n = 244), the prevalence of PTS decreased slightly to 24.6%. Only obesity remained an independent predictor of PTS (OR 2.6 [95% CI 1.3-5.0]). Poor INR control and residual venous obstruction also increased the risk, but the results were no longer statistically significant (OR 1.017 [95% CI 0.999-1.035] and OR 1.7 [95% CI 0.9-3.3], respectively). CONCLUSIONS: After a first unprovoked proximal DVT, obese patients and patients with even mild PVI constitute a group at increased risk of developing PTS for whom particular attention should be paid with respect to PTS prevention. Careful monitoring of anticoagulant treatment may prevent PTS.

Gris, Jean-Christophe Bouvier, Sylvie Molinari, Nicolas Galanaud, Jean-Philippe Cochery-Nouvellon, Eva Mercier, Erik Fabbro-Peray, Pascale Balducchi, Jean-Pierre Mares, Pierre Quere, Isabelle Dauzat, Michel; The incidence of thrombosis in the purely obstetric form of antiphospholipid syndrome is uncertain. We performed a 10-year observational study of 1592 nonthrombotic women who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal death at or beyond the 10th week of gestation. We compared the frequencies of thrombotic events among women positive for antiphospholipid Abs (n = 517), women carrying the F5 6025 or F2 rs1799963 polymorphism (n = 279), and women with negative thrombophilia screening results (n = 796). The annual rates of deep vein thrombosis (1.46%; range, 1.15%-1.82%), pulmonary embolism (0.43%; range, 0.26%-0.66%), superficial vein thrombosis (0.44%; range, 0.28%0.68%), and cerebrovascular events (0.32%; range, 0.18%-0.53%) were significantly higher in aPLAbs women than in the other groups despite low-dose aspirin primary prophylaxis. Women carrying 1 of the 2 polymorphisms did not experience more thrombotic events than women who screened negative for thrombophilia. Lupus anticoagulant was a risk factor for unprovoked proximal and distal deep and superficial vein thrombosis and women in the upper quartile of lupus anticoagulant activity had the highest risk. Despite data suggesting that aPLAbs may induce pregnancy loss through nonthrombotic mechanisms, women with purely obstetric antiphospholipid syndrome are at risk for thrombotic complications

SummarySuperficial venous thrombosis (SVT) prognosis is debated and its management is highly variable. It was the objective of this study to assess predictive risk factors for concurrent deep-vein thrombosis (DVT) at presentation and for three-month adverse outcome. Using data from the prospective multicentre OPTIMEV study, we analysed SVT predictive factors associated with concurrent DVT and three-month adverse outcome. Out of 788 SVT included, 227 (28.8%) exhibited a concurrent DVT at presentation. Age >75years (odds ratio [OR]=2.9 [1.5–5.9]), active cancer (OR=2.6 [1.3–5.2]), inpatient status (OR=2.3 [1.2–4.4]) and SVT on non-varicose veins (OR=1.8 [1.1–2.7]) were significantly and independently associated with an increased risk of concurrent DVT. 39.4% of SVT on non-varicose veins presented a concurrent DVT. However, varicose vein status did not influence the three-month prognosis as rates of death, symptomatic venous thromboembolic (VTE) recurrence and major bleeding were equivalent in both non-varicose and varicose SVTs (1.4% vs. 1.1%; 3.4% vs. 2.8%; 0.7% vs. 0.3%). Only male gender (OR=3.5 [1.1–11.3]) and inpatient status (OR=4.5 [1.3–15.3]) were independent predictive factors for symptomatic VTE recurrence but the number of events was low (n=15, 3.0%). Three-month numbers of deaths (n=6, 1.2%) and of major bleedings (n=2, 0.4%) were even lower, precluding any relevant interpretation. In conclusion, SVT on non-varicose veins and some classical risk factors for DVT were predictive factors for concurrent DVT at presentation. As SVT remains mostly a clinical diagnosis, these data may help selecting patients deserving an ultrasound examination or needing anticoagulation while waiting for diagnostic tests. Larger studies are needed to evaluate predictive factors for adverse outcome.