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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.

Background: Venous thromboembolism (VTE) can be the first manifestation of cancer. Whether screening for an occult malignancy should be systematically performed in patients with unprovoked VTE is a daily challenge for clinicians. Recently, two randomized trials demonstrated that limited cancer screening in patients with a first unprovoked VTE could be the standard of care. However, the one-year incidence of occult malignancy found in these trials was unexpectedly low (4.5%) raising the hypothesis of an inclusion bias. We aimed at estimating the real-life one-year incidence of cancer following a first unprovoked VTE to inform physicians and policy makers in establishing recommendations for cancer screening in VTE patients. Methods: The EPIGETBO study is an epidemiologic study that aimed to measure the incidence of VTE in the Brest District, France1. All symptomatic VTE cases (deep vein thrombosis of the lower limb and pulmonary embolism) diagnosed between March 1st, 2013 and February 28th, 2014 among the 367,911 inhabitants of the district were recorded and validated by an adjudication committee. A systematic follow-up was planned in order to study patients' outcome. Unprovoked VTE was defined as the absence of surgical procedure, pregnancy, delivery, immobilization, admission to hospital for an acute medical illness in the 3 months preceding VTE or known active cancer. The 1-year cumulative incidence of cancer was estimated using the Kaplan-Meier method. Then, the hazard for occult cancer diagnosis associated with age>60, male sex, and current smoking was assessed by Cox regression. Results: During the study period, 576 symptomatic validated VTE events were diagnosed in 562 inhabitants of the Brest District. Five patients did not undergo follow-up (4 refusals, 1 aged60 and male sex were associated with a non significant increased risk for occult cancer diagnosis (HR 4.92; 95% CI 0.60-40.30 and 1.42; 95% CI 0.25-8.13 respectively). Conversely, current smoking was independently associated with a significant 11.8-fold increased risk for occult cancer diagnosis (HR 11.80; 95% CI 1.19-116.52). No cancer was diagnosed in patients aged≤50 years. Conclusion: In this comprehensive real-life epidemiological study, we confirmed that the one-year incidence of occult malignancy following a first episode of unprovoked VTE is low, especially in non-smokers. Current smoking was associated with a higher risk for occult cancer diagnosis; however, even in this patient subgroup, the absolute frequency was no higher than 8%. 1 Thromb Haemost 2016; Epub ahead of print DOI: 10.1160/TH16-03-0205 Disclosures No relevant conflicts of interest to declare.

Background: Randomized controlled trials demonstrated that low-molecular-weight heparin (LMWH), unfractionated heparin (UFH), or fondaparinux, are efficient for venous thromboembolism (VTE) prevention in acutely ill medical patients. However, asymptomatic VTE, whose clinical relevance is unknown, represented the vast majority of outcome events of these trials. Objectives: Using a case-control design, we aimed to estimate the association between admission to hospital for acute medical illness, prescription of pharmacological thromboprophylaxis during admission and symptomatic VTE. Methods: 750 symptomatic non-surgical, non-cancer, and non-pregnancy-related VTE cases and their 750 age and sex-matched controls were analyzed. Patients hospitalized for an acute medical illness within three months prior to inclusion in the study were identified, and their hospital charts were reviewed. We considered that patients receiving pharmacological thromboprophylaxis were those prescribed either 1) LMWH at an approved preventive dose; 2) low dose UFH (5000 units bid or tid); or 3) fondaparinux 2.5mg once daily, for at least 6 days. Results: Patients' mean age was 67.2 ± 17.1 years, and 664 (44.3%) were men. A total of 145 cases (19.3%) and 91 controls (12.1%) were hospitalized for acute medical illness at least once in the preceding 3 months prior to inclusion in the study (p In patients Conclusion: Our case-control study suggests that VTE prevention in acutely ill medical patients may be less effective in patients ≥75 years as compared with younger patients. This finding will be addressed in a randomized double blind controlled trial comparing enoxaparin 40mg once daily to placebo for the prevention of symptomatic VTE and fatal PE in patients ≥75 years admitted to hospital for an acute medical illness (NCT02379806). Disclosures No relevant conflicts of interest to declare.

Background: Patients with a first episode of unprovoked pulmonary embolism have a high risk of recurrent venous thromboembolism (VTE) after anticoagulation is discontinued. Prolongation of anticoagulant therapy beyond the initial period of 3 to 6 months is associated with a significant reduction of recurrent VTE, but an excess of bleeding events. In addition, most studies assessing prolonged treatment did not follow the patients after treatment had been stopped. Thus, the optimal duration of anticoagulation in patients with a first unprovoked pulmonary embolism remains uncertain. Method: In a multicenter, randomized, double-blind, controlled trial, we compared an additional 18 months of warfarin (target International Normalized Ratio, 2 to 3) with placebo in patients with a first episode of unprovoked pulmonary embolism that had been initially treated with a vitamin K antagonist for 6 uninterrupted months. In both groups, all patients were followed up for an additional median period of 2 years after treatment had been stopped. Primary outcome was the composite of recurrent VTE or major bleeding during the 18-month treatment period. Secondary outcomes included the composite outcome during the entire study period (i.e. 18 months plus a median follow-up of 2 years), deaths not caused by pulmonary embolism or major bleeding and the components of the composite outcome during the treatment period and during the entire study period. All outcomes were centrally adjudicated. Results: A total of 371 patients were included in the study and analyzed on an intention-to-treat basis. During the treatment period, the composite outcome occurred in 6 of 184 patients (3.3%) in the warfarin group and in 25 of 187 patients (13.5%) in the placebo group (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.09-0.55; p=0.0004). Recurrent VTE occurred in 3 (1.7%) patients in the warfarin group and in 25 (13.5%) in the placebo group (HR, 0.11; 95%CI, 0.03-0.37); major bleeding occurred in 4 (2.2%) patients in the warfarin group and in 1 (0.5%) in the placebo group (HR, 4.07; 95%CI, 0.45-36.38). Two deaths not related to the study outcome occurred in each group. During the entire median study period of 41 months, the composite outcome occurred in 33 (20.8%) patients in the warfarin group and in 41 (23.5%) in the placebo group (HR, 0.76; 95%CI, 0.48-1.20; p=0.24) (Figure 1). Recurrent VTE occurred in 28 (17.9%) patients in the warfarin group and in 39 (22.1%) in the placebo group (HR, 0.67; 95%CI, 0.41-1.08); major bleeding occurred in 6 (3.5%) patients in the warfarin group and in 4 (2.5%) in the placebo group (HR, 1.57; 95%CI, 0.44-5.55). Thirteen (11.9%) patients died in the warfarin group, four deaths being related to recurrent VTE and one to major bleeding; six (3.6%) patients died in the placebo group from a cause unrelated to recurrent VTE or bleeding (p=0.08). Of the 67 episodes of recurrent VTE, 52 (77.6%) were pulmonary embolism and 58 (86.6%) were unprovoked. Conclusion: After 6 months of anticoagulation for a first episode of unprovoked pulmonary embolism, extending anticoagulation for an additional 18 months was associated with a major reduction in the risk of recurrent VTE or major bleeding during the treatment period. However, this benefit was not maintained after discontinuation of anticoagulation. (ClinicalTrials.gov number NCT00740883). Figure 1. Cumulative risk of the composite outcome (recurrent VTE or major bleeding) over the entire study period Figure 1. Cumulative risk of the composite outcome (recurrent VTE or major bleeding) over the entire study period Disclosures Couturaud: Astra Zeneka: Co-investigator in clinical trial, Co-investigator in clinical trial Other, Membership on an entity's Board of Directors or advisory committees; Bayer: Co-investigator in clinical trial Other, Membership on an entity's Board of Directors or advisory committees. Sanchez:Bayer: Membership on an entity's Board of Directors or advisory committees. Mismetti:Bayer: Membership on an entity's Board of Directors or advisory committees; pfizer: Membership on an entity's Board of Directors or advisory committees; boerhinger ingelheim: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Jego:Bayer: Membership on an entity's Board of Directors or advisory committees; actelion: Research Funding; GlaxoSmithKline: Research Funding. Parent:Bayer: Membership on an entity's Board of Directors or advisory committees. Lorillon:Astra Zeneka: Membership on an entity's Board of Directors or advisory committees, symposium invitation Other; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Girard:Leo Pharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Lacut:Bayer-Healthcare: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Boehringer Ingelheim: Research Funding. Leroyer:Novartis: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Investigator in COPD clinical trials, Investigator in COPD clinical trials Other, Membership on an entity's Board of Directors or advisory committees; Astra Zeneka: Investigator in asthma clinical trials Other, Membership on an entity's Board of Directors or advisory committees. Decousus:Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Meyer:Sanofi-Aventis: Research Funding; LEO Pharma: Research Funding; Bayer: Research Funding; Boehringer Ingelheim: Research Funding. Mottier:Pfizer: Membership on an entity's Board of Directors or advisory committees; bayer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding.

Abstract 3342 Background: In patients with venous thromboembolism (VTE) provoked by major surgery, the risk of recurrence is low during and after the anticoagulation period. Conversely, cancer patients with VTE have a very high risk of VTE recurrence even under anticoagulant therapy. Some cancer patients develop VTE within three months following surgical treatment of their malignancy. It is unknown whether these patients have a low risk of recurrence of VTE, or if they have the high risk of recurrence associated with cancer. Methods: We analyzed data of a single center cohort study conducted at the Brest University Hospital, France. All consecutive cancer patients with pulmonary embolism and/or deep vein thrombosis of the lower limbs diagnosed between January 2000 and July 2009 in our center were followed-up for VTE recurrence. Patients were classified as “surgical” patients if they had major surgery for cancer in the three months before VTE. Probabilities of recurrence of VTE in surgical patients and in non-surgical patients were estimated according to Kaplan-Meier method and were compared by log-rank test. Hazard Ratios (HR) for VTE recurrence and 95% confidence intervals (CI) were obtained using Cox proportional hazard regression models with adjustments on age, sex, past history of VTE, cancer site, and metastases. Results: We followed 220 cancer patients with symptomatic VTE (mean age 69.9 ± 11.0 years, male sex n=127 (57.7%)). Of these patients, 42 (19.1%) had major surgery for cancer three months before the index VTE and 178 (80.9%) were non-surgical cancer patients. Surgical patients were more often men (30/42 (71.4%) vs. 97/178 (54.5%), p=0.05) and had less metastases at baseline (7/42 (16.7%) vs. 61/178 (34.3%), p=0.03) than non-surgical patients. Mean age was not different between surgical and non-surgical patients (70.1±10.5 vs. 69.8±11.2, p=0.90). Most surgical patients discontinued anticoagulation after six months of treatment, whereas non-surgical patients were receiving long term anticoagulation. At two years, 29 patients had a recurrence of VTE (2/44 surgical patients and 27/180 non-surgical patients). The cumulative probability of recurrence of VTE was lower in surgical patients than in non-surgical patients (2.8% (95% CI −2.5 to 8.1) vs. 11.3% (95% CI 5.8 to 16.8) at 6 months (p=0.14), 3.0% (95% CI −2.3 to 8.3) vs. 16.2% (95% CI 9.3 to 23.1) at 1 year (p=0.06), and 9.3% (95% CI −4.0 to 22.6) vs. 27.5% (95% CI 18. To 36.9) at 2 years (p=0.04)). At two years, the adjusted hazard ratio for recurrence of VTE was 0.20 (95% CI 0.05 to 0.91) in surgical patients compared with non-surgical cancer patients. There was a trend for a lower cumulative probability of death in surgical patients than in non-surgical patients after two years of follow-up (40.2% (95% CI 23.0 to 57.4) vs. 57.7% (95% CI 49.5 to 65.9), p=0.06). Conclusion: In this study, patients with cancer who develop VTE after major cancer surgery had a lower risk of recurrence of VTE than non-surgical cancer patients. Disclosures: No relevant conflicts of interest to declare.

Rationale: LMWHs accumulate in patients with impaired renal function. As this accumulation depends on heparin chain length and subsequent reticulo-endothelial/renal elimination/catabolism LMWHs of different degree of depolymerisation (different distribution and length of heparin chains) should have different pharmacodynamic profile. Do these differences contribute to accumulation of LMWHs in case of renal insufficiency? Patients, methods and material: An open randomized parallel group trial has been conducted. The primary objective was to detect any accumulation effect of two LMWHs, enoxaparin and tinzaparin, after repeated administration of a prophylactic dose over 8 days in elderly patients (age >75 years) with impaired renal function (creatinine clearance between 20 and 50 ml/min)and body weight Results: 55 patients have been included (mean age 87.9 ± 5.5 years). The mean renal creatinine clearance is 34.7± 11.4 ml/min; the mean body weight is 52.3± 8.6 kg. The main pharmacokinetic data are summarized in the table below. Discussion: In this pharmacodynamic study, a statistically significant accumulation effect was observed after 8 days of prophylactic treatment with enoxaparin but not with tinzaparin. These results reflect the impact of different chain lengths of LMWHs on elimination patterns in elderly patients with impaired renal function. Trials based on clinical endpoints should be conducted to evaluate the clinical relevance of these observations Peak level Amax D1 IU/mL (SD) Amax D8IU/mL (SD) Accumulation factor P-value (1): Within treatment comparison of D8 and D1 values by one sample t-test tinzaparin 0.44 (0.16) 0.46 (0.19) 1.05 0.2961 enoxaparin 0.67 (0.23) 0.67 (0.23) 1.22

Background: Preliminary reports suggest that use of antipsychotic drugs is associated with an increased risk of venous thromboembolism (VTE), but others did not confirm these results. Objective: To evaluate the relationship between antipsychotic drugs and VTE. Design: Case-control study (EDITH) designed to investigate genetic and environmental risk factors of VTE. Setting: Brest University Hospital. Participants: 857 patients consecutively hospitalized for a documented venous thromboembolic event were included between May 2000 and May 2004. Controls were matched on age, sex and the main risk factors of venous thromboembolism (cancer, surgery, pregnancy…). Results: The mean age of patients was 67.7 year. No significant difference was found between cases and controls concerning the main characteristics, except for smocking and body mass index. Among cases, 89 (10.4%) were current users of neuroleptics compared to 35 (4.8%) among controls. Current use of neuroleptics was associated with a significant increased risk of venous thromboembolism (OR = 2.32, 95% CI: 1.55–3.48). Excluding neuroleptics used for non psychiatric disorders, and after adjustment on the main confounding factors, this association remained significant (OR = 3.48, 95% CI: 2.00–6.04). No difference was found between the different chemical categories of neuroleptics, but the number of patients in some groups had limited statistical power to demonstrate significant differences. Biological mechanisms of action have been proposed to explain this relation. Analyses are ongoing for anti-phospholipid antibodies and homocysteine. Conclusion: In this case-control study of hospitalized patients, neuroleptics use was associated with a significant increased risk of venous thromboembolism. These results are concordant with previous reports. Nevertheless, further investigations are needed to explain wich mechanisms may be involved in such association and before use of neuroleptics can be definitely considered as risk factor for venous thromboembolism.

Introduction: Factor V Leiden is the most common inherited risk factor for venous thromboembolism (VTE). A four- to sevenfold increased risk of VTE for the heterozygous state has been reported by numerous epidemiological studies but most of them did not include patients over 70 years. Surprisingly, we found in a previous study no association between Factor V Leiden and VTE in patients over 70 years. Methods Therefore we conducted a large hospital-based matched case-control study to test the hypothesis of an interaction between age and the factor V mutation, as well as G20210A prothrombin gene variation. Results: We analysed 392 patients experiencing VTE not related to a major acquired risk factor and their matched controls. Factor V Leiden was not associated with VTE in patients aged 80 years and over: odds ratio 0.8 (95%CI 0.2-3.4). There was a significant interaction between age and the mutation for VTE risk (p=0.03). Conversely, the association between the G20210A variant and VTE was consistent across age-groups: odds ratio 2.8 (95%CI 1.4–5.8). In conclusion, age may modify the relation between factor V Leiden and VTE. The prevalence of the factor V mutation decreased with increasing age among patients with VTE but not among controls.

Background: Previous studies of selected patients have suggested a reduction in the risk of venous thromboembolism (VTE) with the use of statins, and no effect of fibrates. Objective: To evaluate the influence of statin and fibrate use on the risk of venous thromboembolic events. Design: Case-control study (EDITH) designed to investigate genetic and environmental risk factors of VTE. Setting: Brest University Hospital. Participants: 857 patients consecutively hospitalized for a documented venous thromboembolic event were included between May 2000 and May 2004. Controls were matched on age, sex and the main risk factors of VTE (cancer, surgery, pregnancy…). Results: The mean age of patients was 67.7 year. No significant difference was found between cases and controls concerning the main characteristics, except for smocking and body mass index. Controls had more often previous vascular events (coronary heart disease, stroke or arteriopathy of the lower limbs) than cases but the difference was no significant. Statin use was associated with a significant decreased risk of VTE (odds ratio (OR) = 0.58; 95% confidence interval (CI), 0.41–0.82), whereas fibrate use was associated with a significant increased risk of VTE (OR = 1.60; 95% CI, 1.09–2.34). After adjustment on the main confounding factors including aspirin use and cardiovascular disease, these associations remained significant. Among pleiotropic effects of statins, some antithrombotic mechanisms could be proposed to explain their possible protective effect. Concerning the possible negative effect of fibrates, some authors found that the most prescribed fibrates, but not statins, caused hyperhomocysteinemia. In our study, analyses of homocysteinemia are ongoing. Conclusion: In this case-control study of hospitalized patients, statin use was associated with a significant decreased risk of VTE, whereas fibrate use was associated with a significant increased risk. Homocysteinemia may be involved in the difference between the effects of these two categories of lipid-lowering drugs on VTE. Because our study was observational, the protective effect of statins as regards the risk of VTE remains questionable and further prospective studies are needed.