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International audience; Venous thromboembolism (VTE) is a potentially lethal clinical condition that is suspected in patients with common clinical complaints, in many and varied, clinical care settings. Once VTE is diagnosed, optimal therapeutic management (thrombolysis, IVC filters, type and duration of anticoagulants) and ideal therapeutic management settings (outpatient, critical care) are also controversial. Clinical prediction tools, including clinical decision rules and D-Dimer, have been developed, and some validated, to assist clinical decision making along the diagnostic and therapeutic management paths for VTE. Despite these developments, practice variation is high and there remain many controversies in the use of the clinical prediction tools. In this narrative review, we highlight challenges and controversies in VTE diagnostic and therapeutic management with a focus on clinical decision rules and D-Dimer.

Background Direct oral anticoagulants (DOACs) are used for treatment of venous thromboembolism (VTE) and stroke prevention in atrial fibrillation (AF). Given the shorter half-life and lack of laboratory monitoring compared to vitamin-K antagonists (VKAs), adequate adherence to DOACs is important. Reported anticoagulation adherence is unclear in clinical practice. Objectives To assess self-reported anticoagulation adherence in a tertiary center anticoagulation clinic. Patients/Methods Cross-sectional study of patients on oral anticoagulants (VKAs, rivaroxaban, dabigatran and apixaban). Anticoagulation adherence was assessed using the 4-item Morisky score. Baseline characteristics were evaluated for association with adherence. Results Five hundred patients completed the survey; 74% were on VKAs and 26% on DOACs: rivaroxaban 102 (79%); dabigatran 26 (19%); apixaban 2 (2%). Main indications for anticoagulation were VTE (72%) and AF (18%). Self-reported anticoagulation adherence using the 4-item Morisky scale was 56.2% for patients on VKAs and 57.1% for patients on DOACs. Predictors of anticoagulation adherence were age (OR = 1.02; 95% CI:1.01-1.03), female gender (OR = 1.58; 95% CI:1.10-2.27), use of additional oral medications (OR = 2.78; 95% CI:1.67-4.63), and retired employment status (OR = 2.31; 95% CI:1.51-3.55). In backward selection multivariate analyses age, female gender and use of other oral medications remained significantly associated with anticoagulation adherence. Conclusions Self-reported anticoagulation adherence was similar between VKAs and DOACs. Until laboratory assays are universally available to evaluate DOAC adherence, physicians should emphasize the importance of anticoagulation adherence at each patient encounter. The Morisky scale provides simple assessment of anticoagulation adherence; however it has not yet been validation for this purpose.

A 35-year-old woman with recurrent severe placenta-mediated pregnancy complications in her 2 pregnancies asks: Will low-molecular-weight heparin help prevent recurrent placenta-mediated pregnancy complications in my next pregnancy? We performed a meta-analysis of randomized controlled trials (RCTs) comparing low-molecular-weight heparin (LMWH) vs no LMWH for the prevention of recurrent placenta-mediated pregnancy complications. We identified six RCTs that included a total of 848 pregnant women with prior placenta-mediated pregnancy complications. The primary outcome was a composite of pre-eclampsia (PE), birth of a small-for-gestational-age (SGA) newborn (20 weeks. Overall, 67 (18.7%) of 358 of women being given prophylactic LMWH had recurrent severe placenta-mediated pregnancy complications compared with 127 (42.9%) of 296 women with no LMWH (relative risk reduction, 0.52; 95% CI, 0.32 to 0.86; P = .01; I2, 69%, indicating moderate heterogeneity). We identified similar relative risk reductions with LMWH for individual outcomes, including any PE, severe PE, SGA

International audience; BACKGROUND: Deep vein thrombosis (DVT) can be safely and reliably excluded in patients with a low clinical probability and a negative D-dimer result but the accuracy and utility of such a strategy is unclear in elderly patients. OBJECTIVES: We sought to compare the performance of the Wells pretest probability (PTP) model and D-dimer testing between patients of different age groups and to examine the utility of the two PTP model classification schemes (low/moderate/high vs. unlikely/likely) in excluding DVT in elderly outpatients. PATIENTS/METHODS: Pooled analysis of databases from three prospective diagnostic studies evaluating consecutive outpatients with suspected DVT. RESULTS: A total of 2696 patients were evaluated. DVT was diagnosed in 400 (15%) patients overall and in 50 out of 325 (15.5%) patients > or = 60 years old. The PTP distribution and the prevalence of DVT in each PTP category were similar among the different age groups. The negative predictive values of a low or unlikely PTP score in combination with a negative D-dimer result were 99% for all groups. A negative D-dimer in combination with a low or unlikely PTP excluded 21.7% and 31% of patients > or = 80 years old, respectively. CONCLUSIONS: The combination of a low or unlikely PTP with a negative D-dimer result can effectively and safely exclude DVT in a significant proportion of elderly outpatients. However, this clinical prediction rule needs to be prospectively validated with different D-dimer assays in this specific population.

International audience; Venous thromboembolism may be the earliest sign of cancer. Currently, there is a great diversity in practices regarding screening for occult cancer in a person who has an unprovoked venous thromboembolism. We sought to assess the efficacy of a screening strategy for occult cancer that included comprehensive computed tomography (CT) of the abdomen and pelvis in patients who had a first unprovoked venous thromboembolism. We conducted a multicenter, open-label, randomized, controlled trial in Canada. Patients were randomly assigned to undergo limited occult-cancer screening (basic blood testing, chest radiography, and screening for breast, cervical, and prostate cancer) or limited occult-cancer screening in combination with CT. The primary outcome measure was confirmed cancer that was missed by the screening strategy and detected by the end of the 1-year follow-up period. Of the 854 patients who underwent randomization, 33 (3.9%) had a new diagnosis of occult cancer between randomization and the 1-year follow-up: 14 of the 431 patients (3.2%) in the limited-screening group and 19 of the 423 patients (4.5%) in the limited-screening-plus-CT group (P=0.28). In the primary outcome analysis, 4 occult cancers (29%) were missed by the limited screening strategy, whereas 5 (26%) were missed by the strategy of limited screening plus CT (P=1.0). There was no significant difference between the two study groups in the mean time to a cancer diagnosis (4.2 months in the limited-screening group and 4.0 months in the limited-screening-plus-CT group, P=0.88) or in cancer-related mortality (1.4% and 0.9%, P=0.75). The prevalence of occult cancer was low among patients with a first unprovoked venous thromboembolism. Routine screening with CT of the abdomen and pelvis did not provide a clinically significant benefit. (Funded by the Heart and Stroke Foundation of Canada; SOME ClinicalTrials.gov number, NCT00773448.).

International audience; BACKGROUND: Thrombophilias are common disorders that increase the risk of pregnancy-associated venous thromboembolism and pregnancy loss and can also increase the risk of placenta-mediated pregnancy complications (severe pre-eclampsia, small-for-gestational-age infants, and placental abruption). We postulated that antepartum dalteparin would reduce these complications in pregnant women with thrombophilia. METHODS: In this open-label randomised trial undertaken in 36 tertiary care centres in five countries, we enrolled consenting pregnant women with thrombophilia at increased risk of venous thromboembolism or with previous placenta-mediated pregnancy complications. Eligible participants were randomly allocated in a 1:1 ratio to either antepartum prophylactic dose dalteparin (5000 international units once daily up to 20 weeks' gestation, and twice daily thereafter until at least 37 weeks' gestation) or to no antepartum dalteparin (control group). Randomisation was done by a web-based randomisation system, and was stratified by country and gestational age at randomisation day with a permuted block design (block sizes 4 and 8). At randomisation, site pharmacists (or delegates) received a randomisation number and treatment allocation (by fax and/or e-mail) from the central web randomisation system and then dispensed study drug to the local coordinator. Patients and study personnel were not masked to treatment assignment, but the outcome adjudicators were masked. The primary composite outcome was independently adjudicated severe or early-onset pre-eclampsia, small-for-gestational-age infant (birthweight

International audience; Many anticoagulant strategies are available for the treatment of acute venous thromboembolism, yet little guidance exists regarding which drug is most effective and safe. To summarize and compare the efficacy and safety outcomes associated with 8 anticoagulation options (unfractionated heparin [UFH], low-molecular-weight heparin [LMWH], or fondaparinux in combination with vitamin K antagonists); LMWH with dabigatran or edoxaban; rivaroxaban; apixaban; and LMWH alone) for treatment of venous thromboembolism. A systematic literature search was conducted using MEDLINE, EMBASE, and the evidence-based medicine reviews from inception through February 28, 2014. Eligible studies were randomized trials reporting rates of recurrent venous thromboembolism and major bleeding in patients with acute venous thromboembolism. Of the 1197 studies identified, 45 trials including 44,989 patients were included in the analyses. Two reviewers independently extracted trial-level data including number of patients, duration of follow-up, and outcomes. The data were pooled using network meta-analysis. The primary clinical and safety outcomes were recurrent venous thromboembolism and major bleeding, respectively. Compared with the LMWH-vitamin K antagonist combination, a treatment strategy using the UFH-vitamin K antagonist combination was associated with an increased risk of recurrent venous thromboembolism (hazard ratio [HR], 1.42; 95% credible interval [CrI], 1.15-1.79). The proportion of patients experiencing recurrent venous thromboembolism during 3 months of treatment were 1.84% (95% CrI, 1.33%-2.51%) for the UFH-vitamin K antagonist combination and 1.30% (95% CrI, 1.02%-1.62%) for the LMWH-vitamin K antagonist combination. Rivaroxaban (HR, 0.55; 95% CrI, 0.35-0.89) and apixaban (HR, 0.31; 95% CrI, 0.15-0.62) were associated with a lower risk of bleeding than was the LMWH-vitamin K antagonist combination, with a lower proportion of patients experiencing a major bleeding event during 3 months of anticoagulation: 0.49% (95% CrI, 0.29%-0.85%) for rivaroxaban, 0.28% (95% CrI, 0.14%-0.50%) for apixaban, and 0.89% (95% CrI, 0.66%-1.16%) for the LMWH-vitamin K antagonist combination. Using meta-analytic pooling, there were no statistically significant differences for efficacy and safety associated with most treatment strategies used to treat acute venous thromboembolism compared with the LMWH-vitamin K antagonist combination. However, findings suggest that the UFH-vitamin K antagonist combination is associated with the least effective strategy and that rivaroxaban and apixaban may be associated with the lowest risk for bleeding.

International audience; : In many countries, new oral anticoagulants are only covered for patients with suboptimal anticoagulation control on vitamin K antagonists (VKAs). The quality of VKA management is often reported using the time in therapeutic range (TTR). We sought to predict a TTR 65% or less using a surrogate measure [number of changes in VKA dose and number of international normalized ratio (INR) tests] that could be easily determined by primary care physicians. This cross-sectional study included consecutive patients whose VKA therapy was managed in a specialized anticoagulation clinic. Patients were dichotomized according to their TTR in the past 6 months (TTR > or ≤65%). The ability of the number of INR tests and VKA dose changes to predict TTR group was assessed using receiver-operating characteristics (ROC) curve analysis. The analyses included 1381 patients with a median age of 63 years. The mean TTR was 81% (interquartile range 70-90) and 17.4% of patients had a TTR 65% or more. Based on the ROC curve, patients were stratified according to whether they had either 3 or more dose changes or 9 or more INR tests within the last 6 months. The sensitivity to identify patients with TTR 65% or less was 87% and the specificity was 63%. The number of dose changes and the number of INR tests might be used as indicators of TTR; they could offer a simple way for clinicians to identify patients who are good candidates for the new oral anticoagulants. However, external validation studies in different clinical settings are needed to confirm these findings.

International audience

International audience; INTRODUCTION: Patients with cancer-associated thrombosis are at a high risk of developing recurrent events despite anticoagulant therapy. Escalation of the dose of low molecular weight heparin (LMWH) has been suggested as a potential treatment option to manage these patients. We sought to confirm the benefit and risk of this management strategy in patients with recurrent cancer-associated thrombosis. MATERIAL AND METHODS: A retrospective cohort study of consecutive cancer outpatients seen for management of a symptomatic recurrent cancer-associated thrombosis while on anticoagulation was undertaken. Objectively confirmed episodes of recurrent thrombosis were treated with either dose escalation of LMWH or initiation of therapeutic dose of LMWH in patients already anticoagulated with LMWH or vitamin K antagonist (VKA) respectively. Included patients were followed for a minimum of 3months after the index recurrent event. RESULTS: Fifty-five cancer patients with a recurrent venous thromboembolism (VTE) despite anticoagulation were included. At the time of the recurrence, 89% of patients were on LMWH. The median time between the initial cancer-associated thrombosis to the index recurrent event was 2.3months (range 0.1 to 30.4months). Four patients (7.3%; 95% CI: 2.0 to 17.6%) had a second recurrent VTE during the 3-month follow-up period. Three patients (5.5%; 95% CI 1.1 to 15.1%) had major bleeding complications after dose escalation of LMWH. There were no recurrent fatal VTE or major bleeding episodes. CONCLUSION: Escalating the dose of LMWH seems effective and safe for managing patients with recurrent cancer-associated thrombosis despite anticoagulant therapy.

International audience; BACKGROUND: The risk of major bleeding in patients who have completed anticoagulation therapy for unprovoked venous thromboembolism (VTE) is unknown. OBJECTIVE: To report the major bleeding and fatal bleeding rates in patients randomized to placebo or observation (i.e. no anticoagulation therapy) for the secondary prevention of recurrent VTE. PATIENTS/METHODS: We performed a systematic review and meta-analysis of the literature to summarize the rates of major bleeding and fatal bleeding in patients randomized to placebo or observation during the secondary prevention of VTE. Unrestricted searches of Medline (1950 to August 31, 2013), Embase (1980 to August 31, 2013), and the Cochrane Register of Controlled Trials using the OVID interface were conducted. Publications from potentially relevant journals were also searched by hand. We used a random-effects model to pool study results and I(2) testing to assess for heterogeneity. RESULTS: The analysis included 11 studies and 3,965 patients who were followed for a median of 24 months. The overall pooled major bleeding rate was 0.45 per 100 patient-years (95% CI: 0.29 to 0.64; I(2) : 0%), and the overall pooled fatal bleeding rate was 0.14 per 100 patient-years (95% CI: 0.057 to 0.26; I(2) : 0%). CONCLUSIONS: Patients not receiving anticoagulant therapy for the secondary prevention of VTE experience major bleeding events and this may impact recommendations for extended treatment in this patient population. This article is protected by copyright. All rights reserved.

Summary Background The clinical impact of a tumor thrombus in renal cell carcinoma (RCC) patients awaiting radical nephrectomy and thrombectomy is unknown. Objective To determine the incidence of venous thromboembolism (VTE) in RCC patients with tumor thrombus prior to nephrectomy. Patients and methods We conducted a retrospective cohort study including all late-stage (stage 3–4 excluding T1–2 N0M0) RCC patients who underwent radical nephrectomy at our institution between 1 January 2005 and 1 July 2012. Tumor thrombus was defined as the presence of an intraluminal filling defect in the renal vein, hepatic vein, portal vein, or inferior vena cava, directly extending from a renal mass detected on computed tomography. Results A total of 176 patients were included in the study. Fifty-three (30.1%) patients had tumor thrombus diagnosed on imaging Three patients with tumor thrombus (5.7%; 95% confidence interval [CI] 1.4–16.8) developed a VTE while awaiting radical nephrectomy, whereas none (0%; 95% CI 0–2.9) of the patients without a tumor thrombus had an event (P = 0.026). All three events were deep vein thrombosis. Times from tumor thrombus diagnosis to VTE were 5, 15 and 21 days. Conclusions Tumor thrombus on imaging is a frequent finding among RCC patients awaiting nephrectomy. The presence of tumor thrombus in these patients increases the incidence of preoperative VTE.

International audience; BACKGROUND: The administration of anticoagulant thromboprophylaxis for all patients with cancer who are hospitalized for acute medical illness is considered standard practice and strongly recommended in clinical guidelines. These recommendations are extrapolated from randomized controlled prophylaxis trials not specifically conducted in cancer cohorts. Because hospitalized patients with cancer constitute a unique population with increased risk of venous thromboembolic events and major hemorrhage, validation of the efficacy and safety of primary thromboprophylaxis in this population is critical. We sought to summarize the rates of venous thromboembolic events and major bleeding episodes among hospitalized patients with cancer who were receiving anticoagulant therapy compared with placebo. METHODS: A systematic literature search strategy was conducted using MEDLINE, EMBASE, and the Cochrane Register of Controlled Trials. Two reviewers independently extracted data onto standardized forms. The primary end points were all venous thromboembolic events. Secondary end points included major bleeding episodes and symptomatic venous thromboembolic events. Pooled analysis with relative risk using a random effect model was used as the primary measurement. RESULTS: A total of 242 citations were identified by the literature search. Of these, 3 placebo-controlled randomized trials included venous thromboembolic events as a primary outcome and were analyzed according to cancer subgroups. The pooled relative risk of venous thromboembolic events was 0.91 (95% confidence interval, 0.21-4.0; I(2): 68%) among hospitalized patients with cancer who were receiving thromboprophylaxis compared with placebo. None of the trials reported the rates of symptomatic venous thromboembolic events or major bleeding episodes according to cancer status. CONCLUSIONS: The risks and benefits of primary thromboprophylaxis with anticoagulant therapy in hospitalized patients with cancer are not known. This is especially relevant because numerous Medicare-type pay-for-performance incentives mandate prophylaxis specifically in patients with cancer.

International audience; BACKGROUND: The bariatric surgical population is a particularly high risk population for VTE. It is unclear if standard (i.e. non-adjusted) thromboprophylaxis doses of low-molecular weight or unfractionated heparin provide adequate protection for obese patients undergoing bariatric surgery, or if higher doses are required. We sought to determine whether a weight based thromboprophylactic dosing regimen is safe and effective in the post-operative period for obese patients undergoing bariatric surgery. METHODS: A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews. Pooled proportions for the different outcomes were calculated. RESULTS: A total of 6 studies (1 RCT, 4 cohort studies and one quasi experimental trial) containing 1,858 patients were include in the systematic review. Post bariatric surgery patients receiving weight-adjusted prophylactic doses of heparin products, had an in hospital rate of VTE of 0.54% (95% CI: 0.2 to 1.0%) compared to 2.0% (95% CI: 0.1 to 6.4%) for those that did not weight adjust doses. Rates of major bleeding were similar for both groups: 1.6% (95% CI: 0.6 to 3.0%) for patients receiving weight-adjusted dosing compared to 2.3% (95% CI: 1.1% to 3.9%) for those receiving standard doses of heparin products. CONCLUSIONS: Adjusting the dose of heparin products for thromboprophylaxis post-bariatric surgery seems to be associated with a lower rate of in hospital VTE compared to a strategy of not adjusting the dose, although this did not reach statistical significance. This practice does not lead to an increase in adverse major bleeding events.

International audience; INTRODUCTION: The true incidence of symptomatic implanted port related venous thromboembolism (VTE) in cancer patients is unclear and there is very limited data on its associated risk factors. MATERIALS AND METHODS: We performed a retrospective cohort study of consecutive cancer outpatients who received an ultrasound guided implanted port insertion for the administration of chemotherapy. The primary outcome measure was symptomatic VTE. Univariable and multivariable logistic regression analyses were used to identify risk factors for symptomatic VTE. RESULTS: A total of 400 cancer patients with a newly inserted implanted port for deliverance of chemotherapy were included in the study. Median age was 58years (range of 21 to 85years) and 120 (30%) were males. Patients were followed for a median of 12months and none received thrombophrophylaxis. Of the 400 patients included in the analysis, 34 patients (8.5%; 95% CI: 6.0 to 11.7%) had symptomatic VTE (16 DVTs, 16 PEs, and 2 with both). In the univariate analyses, metastatic disease, male gender and right sided implanted port insertion were significantly associated with the risk of VTE. In the multiple-variable analysis, male gender (OR 2.17, p=0.04) and presence of metastases (OR 8.22, p

International audience; D-dimer measurement is an important step in diagnostic strategies for venous thromboembolism. It allows the safe ruling out of the diagnosis with no need for imaging tests in approximately 30% of outpatients. However, the usefulness of d-dimer is limited in elderly patients; the likelihood of a negative d-dimer strongly decreases with age, making physicians reluctant to order the test. Several attempts to improve the performance of D-dimer in elderly patients have been pursued. Recently, an age-adjusted cutoff was derived; the optimal cutoff value (in µg/l) appears to be equal to the patient's age (in years) multiplied by ten in patients over 50 years of age with a low pretest clinical risk of venous thromboembolism. This age-adjusted cutoff value has been extensively and externally validated in retrospective studies that included mostly outpatients with suspected deep vein thrombosis or pulmonary embolism and used various quantitative D-dimer assays. All available studies confirmed the increased usefulness and similar safety of the age-adjusted cutoff compared with the conventional cutoff, the most important benefit being obtained in elderly patients. However, before any recommendation for clinical practice can be made, a prospective diagnostic management outcome study is lacking, in which all low clinical risk patients with D-dimer levels below their age-adjusted cutoff would be left untreated with no further diagnostic testing.