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BACKGROUND: Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of morbidity and mortality worldwide. METHODS: GARFIELD-VTE is a prospective, non-interventional observational study of real-world treatment practices. We aimed to capture the 36-month clinical outcomes of 10,679 patients with objectively confirmed VTE enrolled between May 2014 and January 2017 from 415 sites in 28 countries. FINDINGS: A total of 6582 (61.6 %) patients had DVT alone, 4097 (38.4 %) had PE ± DVT. At baseline, 98.1 % of patients received anticoagulation (AC) with or without other modalities of therapy. The proportion of patients on AC therapy decreased over time: 87.6 % at 3 months, 73.0 % at 6 months, 54.2 % at 12 months and 42.0 % at 36 months. At 12-months follow-up, the incidences (95 % confidence interval [CI]) of all-cause mortality, recurrent VTE and major bleeding were 6.5 (7.0-8.1), 5.4 (4.9-5.9) and 2.7 (2.4-3.0) per 100 person-years, respectively. At 36-months, these decreased to 4.4 (4.2-4.7), 3.5 (3.2-2.7) and 1.4 (1.3-1.6) per 100 person-years, respectively. Over 36-months, the rate of all-cause mortality and major bleeds were highest in patients treated with parenteral therapy (PAR) versus oral anti-coagulants (OAC) and no OAC, and the rate of recurrent VTE was highest in patients on no OAC versus those on PAR and OAC. The most frequent cause of death after 36-month follow-up was cancer (n = 565, 48.6 %), followed by cardiac (n = 94, 8.1 %), and VTE (n = 38, 3.2 %). Most recurrent VTE events were DVT alone (n = 564, 63.3 %), with the remainder PE, (n = 236, 27.3 %), or PE in combination with DVT (n = 63, 7.3 %). INTERPRETATION: GARFIELD-VTE provides a global perspective of anticoagulation patterns and highlights the accumulation of events within the first 12 months after diagnosis. These findings may help identify treatment gaps for subsequent interventions to improve patient outcomes in this patient population. ispartof: THROMBOSIS RESEARCH vol:222 pages:31-39 ispartof: location:United States status: published

Patients with cancer-associated thrombosis (CAT) are treated with full-dose anticoagulation for at least 3 months, but optimal dosing thereafter is unknown.We explored the feasibility of extended prophylactic-dose low molecular weight heparin (LMWH) treatment following a minimum of 3 months of full-dose LMWH.We conducted a multicenter prospective pilot study of patients with CAT who completed at least 3 months of therapeutic-dose LMWH. Patients received 6 months of prophylactic-dose subcutaneous enoxaparin (40 mg once daily). The primary outcome was recurrence of deep vein thrombosis (DVT) or pulmonary embolism (PE), and secondary outcomes included major, clinically relevant non-major (CRNM), and minor bleeding.From August 2016 to May 2019, 52 patients with a mean age of 64.1 years were included. The study was stopped early because of poor recruitment. Breast (23.1%) and colorectal (19.2%) were the most common cancers, and 61.0% had stage IV malignancy. Index CAT consisted of DVT alone in 57.7% of patients and pulmonary embolism (PE) with or without DVT in 42.3%. Patients received a mean of 7.6 months of weight-adjusted LMWH before enrollment. During a mean follow-up of 5.6 months, one patient was diagnosed with recurrent incidental PE (0.0035 events/subject-month). There were no major bleeding events, one CRNM, and one minor bleeding event. Eight (15.4%) patients died; six from cancer and two from respiratory disease unrelated to PE.These results, in part, provide support for trials of extended reduced-dose anticoagulation for the secondary prevention of CAT. (ClinicalTrials.gov: NCT02752607).

No clinical prediction model has been specifically developed or validated to identify patients with unprovoked venous thromboembolism (VTE) who are at high risk of major bleeding during extended anticoagulation. In a prospective multinational cohort study of patients with unprovoked VTE receiving extended anticoagulation after completing ≥3 months of initial treatment, we derived a new clinical prediction model using a multivariable Cox regression model based on 22 prespecified candidate predictors for the primary outcome of major bleeding. This model was then compared with modified versions of 5 existing clinical scores. A total of 118 major bleeding events occurred in 2516 patients (annual risk, 1.7%; 95% confidence interval [CI], 1.4-2.1). The incidences of major bleeding events per 100 person-years in high-risk and non–high-risk patients, respectively, were 3.9 (95% CI, 3.0-5.1) and 1.1 (0.8-1.4) using the newly derived creatinine, hemoglobin, age, and use of antiplatelet agent (CHAP) model; 3.3 (2.6-4.1) and 1.0 (0.7-1.3) using modified ACCP score, 5.3 (0.6-19.2) and 1.7 (1.4-2.0) using modified RIETE score, 3.1 (2.3-3.9) and 1.1 (0.9-1.5) using modified VTE-BLEED score, 5.2 (3.3-7.8) and 1.5 (1.2-1.8) using modified HAS-BLED score, and 4.8 (1.3-12.4) and 1.7 (1.4-2.0) using modified outpatient bleeding index score. Modified versions of the ACCP, VTE-BLEED, and HAS-BLED scores help identify patients with unprovoked VTE who are at high risk of major bleeding and should be considered for discontinuation of anticoagulation after 3 to 6 months of initial treatment. The CHAP model may further improve estimation of bleeding risk by using continuous predictor variables, but external validation is required before its implementation in clinical practice.

Objective To determine the efficacy and safety of dalteparin postoperative bridging treatment versus placebo for patients with atrial fibrillation or mechanical heart valves when warfarin is temporarily interrupted for a planned procedure. Design Prospective, double blind, randomised controlled trial. Setting 10 thrombosis research sites in Canada and India between February 2007 and March 2016. Participants 1471 patients aged 18 years or older with atrial fibrillation or mechanical heart valves who required temporary interruption of warfarin for a procedure. Intervention Random assignment to dalteparin (n=821; one patient withdrew consent immediately after randomisation) or placebo (n=650) after the procedure. Main outcome measures Major thromboembolism (stroke, transient ischaemic attack, proximal deep vein thrombosis, pulmonary embolism, myocardial infarction, peripheral embolism, or vascular death) and major bleeding according to the International Society on Thrombosis and Haemostasis criteria within 90 days of the procedure. Results The rate of major thromboembolism within 90 days was 1.2% (eight events in 650 patients) for placebo and 1.0% (eight events in 820 patients) for dalteparin (P=0.64, risk difference −0.3%, 95% confidence interval −1.3 to 0.8). The rate of major bleeding was 2.0% (13 events in 650 patients) for placebo and 1.3% (11 events in 820 patients) for dalteparin (P=0.32, risk difference −0.7, 95% confidence interval −2.0 to 0.7). The results were consistent for the atrial fibrillation and mechanical heart valves groups. Conclusions In patients with atrial fibrillation or mechanical heart valves who had warfarin interrupted for a procedure, no significant benefit was found for postoperative dalteparin bridging to prevent major thromboembolism. Trial registration Clinicaltrials.gov NCT00432796 .

Introduction The risk of recurrent venous thromboembolism (VTE) after combined oral contraceptive (COC) use is variably reported. We assessed the long-term risk of recurrent VTE in women on COC at the time of a first VTE, in comparison to women without COC use. Our secondary aim assessed the impact of COC use on the recurrent VTE risk in high-risk and low-risk hyperpigmentation, edema, or redness in either leg; D-dimer level ≥250 μg/L; obesity with body mass index ≥30; or older age, ≥65 years (HERDOO2) subgroups. Methods The REVERSE cohort study derived the HERDOO2 clinical decision rule to predict recurrent VTE in patients who discontinued anticoagulation after 5-7 months for a first unprovoked VTE. Incidence rates of recurrent VTE among women with and without COC exposure were calculated as the number of recurrent VTE over the number of person-years of follow-up, and Cox proportional hazards model was used to compare risks between groups. Results The risk of recurrent VTE among COC users was 1.1% (95% confidence interval [CI] 0.3-2.9) per patient-year as compared with 3.2% per patient-year (95% CI 2.4-4.3) among nonusers (hazard ratio 0.37; 95% CI 0.1-1.0). Women who were COC users and high risk by HERDOO2 score had a recurrence rate of 3.5% (95% CI 0.4-12.5) compared with 6.1% (95% CI 4.3-8.5) among women who were non-COC users and at high risk by HERDOO2 score (HR 0.6, 95% CI 0.1-2.5). Conclusions Women who were COC users at the time of an otherwise unprovoked VTE event had a lower VTE recurrence rate during long-term follow-up, compared with nonusers. The use of HERDOO2 rule may help identify higher risk women with COC use.

Essentials Exercise Limitation 1 year after an acute pulmonary embolism is common.Serial imaging after acute pulmonary embolism is not well described and how it affects exercise limitation remains unknown.1 year after an acute pulmonary embolism chronic changes are common, more so on perfusion lung scanning than CT pulmonary angiography, but imaging findings did not predict exercise limitation. Introduction Risk factors for exercise limitation after acute pulmonary embolism (PE) are unknown. As a planned sub‐study of the prospective, multicenter ELOPE (Evaluation of Long‐term Outcomes after PE) Study, we aimed to describe the results of serial imaging by computed tomography pulmonary angiography (CTPA) and perfusion scan during 1 year after a first episode of acute pulmonary embolism, and to assess the association between imaging parameters and exercise limitation at 1 year. Methods In a prospective cohort study, 100 patients were recruited between June 2010 and February 2013 at five Canadian university–affiliated hospitals. CT pulmonary angiography was performed at baseline and 12 months, perfusion scan at 6 and 12 months, and cardio‐pulmonary exercise testing at 1 and 12 months. Imaging parameters included: on CT pulmonary angiography, CT obstruction index (CTO) (% clot burden in the pulmonary vasculature), and on perfusion scan, pulmonary vascular obstruction (PVO) (% perfusion defect). Abnormal cardio‐pulmonary exercise test (primary outcome) was defined as percent of predicted peak oxygen uptake (VO2) 80% on 1‐year cardio‐pulmonary exercise testing (1.4% [0%; 5.7%] vs 1.0% [0%; 2.4%]; P = .70). Mean (SD) pulmonary vascular obstruction at 6 and at 12 months was similar in patients with percent‐predicted VO2 peak 80% (6 months: 5.9% [0%; 10.4%] vs 6.2% [4.5%; 9.0%]; P = .91; 12 months: 5.1% [0%; 10.2%] vs 6.0% [0%; 9.7%]; P = .71). Conclusions Imaging findings after pulmonary embolism did not predict exercise limitation. Residual thrombus does not appear to explain long‐term functional limitation after pulmonary embolism.

Background We aimed to determine the frequency and predictors of exercise limitation after pulmonary embolism (PE) and to assess its association with health-related quality of life (HRQoL) and dyspnea. Methods One hundred patients with acute PE were recruited at five Canadian hospitals from 2010 to 2013. Cardiopulmonary exercise testing (CPET) was performed at 1 and 12 months. Quality of life (QoL), dyspnea, 6-min walk distance (6MWD), residual clot burden (perfusion scan, CT pulmonary angiography), cardiac function (echocardiography), and pulmonary function tests (PFTs) were measured during follow-up. The prespecified primary outcome was percent predicted peak oxygen uptake (Vo2 peak) Results At 1 year, 40 of 86 patients (46.5%) had percent predicted Vo2 peak Conclusions Almost half of patients with PE have exercise limitation at 1 year that adversely influences HRQoL, dyspnea, and walking distance. CPET or 6MWD testing at 1 month may help to identify patients with a higher risk of exercise limitation at 1 year after PE. Based on our results, we believe that the deconditioning that occurs after acute PE could underlie this exercise limitation, but we cannot exclude the fact that this may have been present before PE. Trial Registry ClinicalTrials.gov; No.: NCT01174628; URL: www.clinicaltrials.gov.

Importance Unprovoked venous thromboembolism (VTE) can be the first manifestation of cancer. It is unclear if extensive screening for occult cancer including a comprehensive computed tomography (CT) scan of the abdomen/pelvis is cost-effective in this patient population. Objective To assess the health care related costs, number of missed cancer cases and health related utility values of a limited screening strategy with and without the addition of a comprehensive CT scan of the abdomen/pelvis and to identify to what extent testing should be done in these circumstances to allow early detection of occult cancers. Participants and setting Cost effectiveness analysis using data that was collected alongside the SOME randomized controlled trial which compared an extensive occult cancer screening including a CT of the abdomen/pelvis to a more limited screening strategy in patients with a first unprovoked VTE, was used for the current analyses. Main outcomes and measures Analyses were conducted with a one-year time horizon from a Canadian health care perspective. Primary analysis was based on complete cases, with sensitivity analysis using appropriate multiple imputation methods to account for missing data. Results Data from a total of 854 patients with a first unprovoked VTE were included in these analyses. The addition of a comprehensive CT scan was associated with higher costs ($551 CDN) with no improvement in utility values or number of missed cancers. Results were consistent when adopting multiple imputation methods. Conclusions and relevance The addition of a comprehensive CT scan of the abdomen/pelvis for the screening of occult cancer in patients with unprovoked VTE is not cost effective, as it is both more costly and not more effective in detecting occult cancer.

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; Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. These patients are at a high risk of VTE recurrence and bleeding during anticoagulant therapy. The International Initiative on Thrombosis and Cancer is an independent academic working group aimed at establishing a global consensus for the treatment and prophylaxis of VTE in patients with cancer. The International Initiative on Thrombosis and Cancer last updated its evidence-based clinical practice guidelines in 2016 with a free, web-based mobile phone application, which was subsequently endorsed by the International Society on Thrombosis and Haemostasis. The 2019 International Initiative on Thrombosis and Cancer clinical practice guidelines, which are based on a systematic review of the literature published up to December, 2018, are presented along with a Grading of Recommendations Assessment Development and Evaluation scale methods, with the support of the French National Cancer Institute. These guidelines were reviewed by an expanded international advisory committee and endorsed by the International Society on Thrombosis and Haemostasis. Results from head-to-head clinical trials that compared direct oral anticoagulant with low-molecular-weight heparin are also summarised, along with new evidence for the treatment and prophylaxis of VTE in patients with cancer.

Importance: Patients with atrial fibrillation (AF) who use a direct oral anticoagulant (DOAC) and request elective surgery or procedure present a common clinical situation yet perioperative management is uncertain. Objective: To investigate the safety of a standardized perioperative DOAC management strategy. Design, Setting, and Participants: The Perioperative Anticoagulation Use for Surgery Evaluation (PAUSE) cohort study conducted at 23 clinical centers in Canada, the United States, and Europe enrolled and screened patients from August 1, 2014, through July 31, 2018. Participants (n = 3007) had AF; were 18 years of age or older; were long-term users of apixaban, dabigatran etexilate, or rivaroxaban; were scheduled for an elective surgery or procedure; and could adhere to the DOAC therapy interruption protocol. Interventions: A simple standardized perioperative DOAC therapy interruption and resumption strategy based on DOAC pharmacokinetic properties, procedure-associated bleeding risk, and creatinine clearance levels. The DOAC regimens were omitted for 1 day before a low-bleeding-risk procedure and 2 days before a high-bleeding-risk procedure. The DOAC regimens were resumed 1 day after a low-bleeding-risk procedure and 2 to 3 days after a high-bleeding-risk procedure. Follow-up of patients occurred for 30 days after the operation. Main Outcomes and Measures: Major bleeding and arterial thromboembolism (ischemic stroke, systemic embolism, and transient ischemic attack) and the proportion of patients with an undetectable or minimal residual anticoagulant level (

Background Parenteral anticoagulants and vitamin K antagonists (VKAs) have constituted the cornerstone of venous thromboembolism (VTE) treatment. Meanwhile, direct oral anticoagulants (DOACs) provide physicians with an alternative. The Global Anticoagulant Registry in the FIELD (GARFIELD)-VTE observes real-world treatment practices. Objectives Describe initial anticoagulation (AC) treatment patterns in VTE patients who received parenteral AC, VKAs, and/or DOACs within ±30 days of diagnosis. Methods VTE patients were categorized into parenteral AC only, parenteral AC with transition to VKA, VKA only, parenteral AC with transition to DOAC, and DOAC only. Results A total of 9647 patients were initiated on AC treatment alone. 4781 (49.6%) patients received DOACs ± parenteral ACs; 3187 (33.0%), VKA ± parenteral ACs; and 1679 (17.4%) parenteral ACs alone. Rivaroxaban was the most frequently used DOAC (79.4%). DOACs were more frequently used in North America/Australia (58.1%), Europe (52.2%), and Asia (47.6%) than in Latin America (29.7%) and the Middle East/South Africa (32.5%). In patients with suspected VTE, most received parenteral AC monotherapy (67.7%). Patients with deep vein thrombosis were more likely to receive DOACs alone than those with pulmonary embolism with or without deep vein thrombosis (36.2% vs 25.9%). Active cancer patients received parenteral AC alone (58.9%), with 25.5% receiving DOAC ± parenteral AC and 12.8% parenteral AC and VKA. A total of 46.5% of pregnant patients received parenteral AC monotherapy, 34.0% were treated with VKA ± parenteral AC, and 19.5% received a DOAC (± parenteral AC). Conclusion AC treatment patterns vary by patient population, geographic region and site of VTE. Guidelines for AC therapy are not always adhered to.

Summary Background Post-thrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT). Objective In the BioSOX study, we investigated whether inflammation markers predict the risk of PTS after DVT. Methods We measured C-reactive protein (CRP), ICAM-1, interleukin (IL)-6, and IL-10, at baseline, and 1 month and 6 months after a first proximal DVT, among 803 participants in the SOX trial. Participants were prospectively followed for 24 months for development of PTS. Results Median CRP levels at 1 month, ICAM-1 levels at baseline, 1 month and 6 months, IL-6 levels at 1 month and 6 months and IL-10 levels at 6 months were higher in patients who developed PTS than in those who did not. Multivariable regression with the median as a cutoff showed risk ratios (RRs) for PTS of 1.23 (95% confidence interval [CI] 1.05–1.45) and 1.25 (95% CI 1.05–1.48) for ICAM-1 at 1 month and 6 months, respectively, and 1.27 (95% CI 1.07–1.51) for IL-10 at 6 months. Quartile-based analysis demonstrated a dose–response association between ICAM-1 and PTS. ICAM-1 and IL-10 were also associated with PTS severity. Analysis of biomarker trajectories after DVT demonstrated an association between the highest-trajectory group of ICAM-1 and PTS. Conclusions In this prospective study, ICAM-1 over time was most consistently associated with the risk of PTS. Further study is required to confirm these findings and assess their potential clinical relevance.

Background Little has been published about the association of venous thromboembolism (VTE) and sarcoma. In this study, we sought to identify clinical features of patients with sarcoma presenting at least one VTE episode. Methods Our study was a retrospective case–control study of a single-institution database with univariate and multivariate analysis using chi-square and Student's t test. A p value less than .05 was considered significant. Results The overall incidence of VTE in patients with sarcoma was 7.9%. Predictive factors identified by multivariate analysis were metastatic disease and administration of chemotherapy. It was not statistically possible to correlate the risk of VTE with specific sarcoma subtypes, but observations suggested malignant peripheral nerve sheath tumor, osteosarcoma, and liposarcoma as having the highest propension. Conclusion VTE is not infrequent in patients with sarcoma. Adoption of common guidelines for cancer-associated thrombosis is recommended.

Background The optimal duration of oral anticoagulant therapy after a first, unprovoked venous thromboembolism is controversial due to tightly balanced risks and benefits of indefinite anticoagulation. Risk stratification tools may assist in decision making. Objectives We sought to determine the relationship between residual pulmonary embolism assessed by baseline ventilation-perfusion scan after completion of 5–7 months of oral anticoagulant therapy and the risk of recurrent venous thromboembolism in patients with the first episode of unprovoked pulmonary embolism. Methods We conducted a multicentre prospective cohort study of participants with a first, unprovoked venous thromboembolism enrolled after the completion of 5–7 months of oral anticoagulation therapy. The participants completed a mean 18-month follow-up. Participants with pulmonary embolism had baseline ventilation-perfusion scan before discontinuation of oral anticoagulant therapy and the percentage of vascular obstruction on baseline ventilation-perfusion scan was determined. During follow-up after discontinuation of oral anticoagulant therapy, all episodes of suspected recurrent venous thromboembolism were independently adjudicated with reference to baseline imaging. Measurements and main results During follow-up, 24 of 239 (10.0%) participants with an index event of isolated pulmonary embolism or pulmonary embolism associated with deep vein thrombosis and central assessment of percentage of vascular obstruction on baseline ventilation-perfusion scan had confirmed recurrent venous thromboembolism. As compared to participants with no residual pulmonary embolism on baseline ventilation-perfusion scan, the hazard ratio for recurrent venous thromboembolism was 2.0 (95% CI 0.5–7.3) for participants with percentage of vascular obstruction of 0.1%–4.9%, 2.1 (95% CI 0.5–7.8) for participants with percentage vascular obstruction of 5.0%–9.9% and 5.3 (95% CI 1.8–15.4) for participants with percentage vascular obstruction greater than or equal to 10%. Conclusions Residual pulmonary embolism assessed by pulmonary vascular obstruction on baseline ventilation-perfusion performed after 5–7 months of oral anticoagulant therapy for the first episode of unprovoked pulmonary embolism was associated with a statistically significant higher risk of subsequent recurrent venous thromboembolism. Percentage of pulmonary vascular obstruction assessment by ventilation-perfusion scans maybe a useful tool to help guide the duration of oral anticoagulant therapy after a first unprovoked pulmonary embolism. Trial registration Registered at www.clinicaltrials.gov identifier: NCT00261014 .

Background The perioperative management of patients who take a direct oral anticoagulant (DOAC) for atrial fibrillation and require treatment interruption for an elective surgery/procedure is a common clinical scenario for which best practices are uncertain. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study is designed to address this unmet clinical need. We discuss the rationale for the PAUSE design and analysis plan as well as the rationale supporting the perioperative DOAC protocol. Methods PAUSE is a prospective study with three parallel cohorts, one for each DOAC, to assess a standardized but patient-specific perioperative management protocol for DOAC-treated patients with atrial fibrillation. The perioperative protocol accounts for DOAC type, patient's renal function and surgery/procedure-related bleeding risk. The primary study aim is to demonstrate the safety of the PAUSE protocol for the perioperative management of each DOAC. The secondary aim is to determine the effect of the pre-procedure interruption on residual anticoagulation when measured by the dilute thrombin time for dabigatran and anti-factor Xa levels for rivaroxaban and apixaban. The study hypothesis is that the perioperative management protocol for each DOAC is safe for patient care, defined by expected risks for major bleeding of 1% (80% power to exclude 2%), and for arterial thromboembolism of 0.5% (80% power to exclude 1.5%) in each DOAC group. Conclusion The PAUSE study has the potential to establish a standard-of-care approach for the perioperative management of DOAC-treated patients. The PAUSE management protocol is designed to be easily applied in clinical practice, as it is standardized and also patient specific.

Summary Background Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis (DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to prevent PTS were small, single-centre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for the prevention of PTS. Methods We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The primary outcome was PTS diagnosed at 6 months or later using Ginsberg's criteria (leg pain and swelling of ≥1 month duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials.gov, number NCT00143598, and Current Controlled Trials, number ISRCTN71334751. Findings From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre 1·13, 95% CI 0·73–1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported frequent use of stockings. Interpretation ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing of ECS after DVT. Funding Canadian Institutes of Health Research.

In this issue of Blood, Amin et al provide data showing early compression therapy post–venous thromboembolism (VTE) to be effective in reducing the incidence of postthrombotic syndrome (PTS) by achieving reduced residual vein obstruction (RVO) on follow-up ultrasound.1

In the Original Article by Douketis et al. "The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study for Patients on a Direct Oral Anticoagulant who Need an Elective Surgery or Procedure: Design and Rationale (Thromb Haemost 2017;117:2415-2424; DOI: 10.1160/TH17-08-0553), the authors have identified two errors that they wish to correct: First, on page 2419, second paragraph, Clinical Outcomes subheading, the authors state that, "The primary clinical outcomes are arterial thromboembolism, comprising stroke (ischemic or haemorrhagic), systemic embolism or transient ischemic attack and major bleeding. The inclusion of "haemorrhagic stroke is incorrect as only ischemic strokes are included in their definition of an arterial thromboembolism outcome. The definitions of study outcomes are correctly indicated in Appendix A (pg. 2424) of the paper, where the authors state: "The second primary outcome is arterial thromboembolism, comprising (1) ischemic stroke, defined as any new focal neurologic deficit that persists for 24 hours or any new focal neurologic deficit of any duration that occurs with evidence of acute infarction on computed tomography (CT) or magnetic resonance imaging (MRI) of the brain; (2) systemic embolism, defined as symptomatic embolism to upper or lower extremity or abdominal organ, confirmed intraoperatively or by objective imaging studies (e.g. CT angiography) and (3) transient ischemic attack, defined as symptomatic focal neurologic deficit (lasting typically 1 hour) that occurs with no evidence of acute infarction on CT/MRI of the brain. Second, the depiction of the pre-procedure interruption interval for dabigatran-treated patientswith a CrCl 50 mL/min is incorrect in Figure 1 (pg. 2418) of the paper, as the arrow should extend so it reflects 2 days off treatment (i.e., day -2 and day -1). The incorrect (currently published) version is shown below, with incorrect area shaded in red: (Figure Presented).

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.

Background We aimed to evaluate health-related quality of life (QOL), dyspnea, and functional exercise capacity during the year following the diagnosis of a first episode of pulmonary embolism. Methods This was a prospective multicenter cohort study of 100 patients with acute pulmonary embolism recruited at 5 Canadian hospitals from 2010-2013. We measured the outcomes QOL (by Short-Form Health Survey-36 [SF-36] and Pulmonary Embolism Quality of Life [PEmb-QoL] measures), dyspnea (by the University of California San Diego Shortness of Breath Questionnaire [SOBQ]) and 6-minute walk distance at baseline and 1, 3, 6, and 12 months after acute pulmonary embolism. Computed tomography pulmonary angiography was performed at baseline, echocardiogram was performed within 10 days, and cardiopulmonary exercise testing was performed at 1 and 12 months. Predictors of change in QOL, dyspnea, and 6-minute walk distance were assessed by repeated-measures mixed-effects models analysis. Results Mean age was 50.0 years; 57% were male and 80% were treated as outpatients. Mean scores for all outcomes improved during 1-year follow-up: from baseline to 12 months, mean SF-36 physical component score improved by 8.8 points, SF-36 mental component score by 5.3 points, PEmb-QoL by −32.1 points, and SOBQ by −16.3 points, and 6-minute walk distance improved by 40 m. Independent predictors of reduced improvement over time were female sex, higher body mass index, and percent-predicted VO 2 peak Conclusions On average, QOL, dyspnea, and walking distance improve during the year after pulmonary embolism. However, a number of clinical and physiological predictors of reduced improvement over time were identified, most notably female sex, higher body mass index, and exercise limitation on 1-month cardiopulmonary exercise test. Our results provide new information on patient-relevant prognosis after pulmonary embolism.

We aimed to determine the frequency and predictors of exercise limitation after pulmonary embolism (PE) and to assess its association with health-related quality of life (HRQoL) and dyspnea.One hundred patients with acute PE were recruited at five Canadian hospitals from 2010 to 2013. Cardiopulmonary exercise testing (CPET) was performed at 1 and 12 months. Quality of life (QoL), dyspnea, 6-min walk distance (6MWD), residual clot burden (perfusion scan, CT pulmonary angiography), cardiac function (echocardiography), and pulmonary function tests (PFTs) were measured during follow-up. The prespecified primary outcome was percent predicted peak oxygen uptake (VoAt 1 year, 40 of 86 patients (46.5%) had percent predicted VoAlmost half of patients with PE have exercise limitation at 1 year that adversely influences HRQoL, dyspnea, and walking distance. CPET or 6MWD testing at 1 month may help to identify patients with a higher risk of exercise limitation at 1 year after PE. Based on our results, we believe that the deconditioning that occurs after acute PE could underlie this exercise limitation, but we cannot exclude the fact that this may have been present before PE.ClinicalTrials.gov; No.: NCT01174628; URL: www.clinicaltrials.gov.

To cite this article: Levine MN, Gu C, Liebman HA, Escalante CP, Solymoss S, Deitchman D, Ramirez L, Julian J. A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer. J Thromb Haemost 2012; 10: 807–14. Summary. Background: Cancer patients receiving chemotherapy are at increased risk for thrombosis. Apixaban, a factor Xa inhibitor, is oral and does not require laboratory monitoring. Objectives: A pilot study was conducted to evaluate whether apixaban would be well tolerated and acceptable in cancer patients receiving chemotherapy. Patients/ Methods: Subjects receiving either first-line or second-line chemotherapy for advanced or metastatic lung, breast, gastrointestinal, bladder, ovarian or prostate cancers, cancer of unknown origin, myeloma or selected lymphomas were randomized to 5 mg, 10 mg or 20 mg once daily of apixaban or placebo in a double-blind manner for 12 weeks. Use of the study drug began within 4 weeks of the start of chemotherapy. The primary outcome was either major bleeding or clinically relevant non-major (CRNM) bleeding. Secondary outcomes included venous thromboembolism (VTE) and grade III or higher adverse events related to the study drug. Thirty-two patients received 5 mg, 30 patients 10 mg, 33 patients 20 mg, and 30 patients placebo. In these groups, there were 0, 0, 2 and 1 major bleeds, respectively. The corresponding data for CRNM bleeds were 1, 1, 2, and 0. The rate of major bleeding in the 93 apixaban patients was 2.2% (95% confidence interval 0.26– 7.5%). There were no fatal bleeds. Three placebo patients had symptomatic VTE. Conclusions: Apixaban was well tolerated in our study population. These results support further study of apixaban in phase III trials to prevent VTE in cancer patients receiving chemotherapy.

Summary. Background: Few studies have evaluated the long-term economic consequences of deep vein thrombosis (DVT).None of them have incorporated prospectively collectedclinical data to ensure accurate identification of incident casesof DVT and DVT-related health outcomes of interest, such aspost-thrombotic syndrome (PTS). Objectives: To prospectivelyquantify medical and non-medical resource use and costsrelated to DVT during 2 years following diagnosis, and toidentify clinical determinants of costs. Methods: Three hun-dred and fifty-five consecutive patients with acute DVT wererecruited at seven Canadian hospital centers. Resource use andcost information were retrieved from three sources: weeklypatient-completed cost diaries, nurse-completed case reportforms, and the Quebec provincial administrative healthcaredatabase (RAMQ). Results: The rate of DVT-related hospi-talization was 3.5 per 100 patient-years (95% confidenceinterval [CI] 2.2–4.9). Patients reported a mean (standarddeviation) of 15.0 (14.5) physician visits and 0.7 (1.2) otherhealthcare professional visits. The average cost of DVT was$5180 (95% CI $4344–6017) in Canadian dollars, with 51.6%of costs being attributable to non-medical resource use.Multivariate analysis identified four independent predictorsof costs: concomitant pulmonary embolism (relative increasein cost [RIC] 3.16; 95% CI 2.18–4.58), unprovoked DVT(RIC 1.65; 95% CI 1.28–2.13), development of PTS duringfollow-up (RIC 1.35; 95% CI 1.05–1.74), and management ofDVT in the inpatient setting (RIC 1.79; 95% CI 1.33–2.40).Conclusions: The economic burden of DVT is substantial. Theuse of measures to prevent the occurrence of PTS andfavoring outpatient care of DVT has the potential to diminishcosts.Keywords: cohort study, cost determinants, deep vein throm-bosis, economic burden, post-thrombotic syndrome.IntroductionDeepveinthrombosis(DVT)isacommonandseriousvascularcondition[1].TheclinicalburdenofDVToftenextendsbeyondthe initial event, with increased risks of recurrent venousthromboembolism (VTE), bleeding while on anticoagulanttherapy, and development of the chronic post-thromboticsyndrome (PTS).Few studies have evaluated the long-term economic conse-quences of DVT. Studies to date have relied on retrospectiveadministrative claims database analysis [2–5] or Markovmodeling [6], and assessed medical costs only. Non-medicalcosts, including productivity losses that impact on patients,their families, and society, have not been adequately consid-ered. None has incorporated prospectively collected clinicaldata to ensure accurate identification of incident cases of DVTand DVT-related health outcomes of interest, such as PTS.We conducted a study to prospectively quantify medicaland non-medical costs associated with DVT during the

See also Watson HG. RVO – Real value obscure. This issue, pp 1116–8; Carrier M, Rodger MA, Wells PS, Righini M, Le Gal G. Residual vein obstruction to predict the risk of recurrent venous thromboembolism in patients with deep vein thrombosis: a systematic review and meta-analysis. This issue, pp 1119–25. Summary. Objectives: There is growing interest in using residual vein obstruction (RVO) to guide the duration of oral anticoagulant therapy (OAT) for unprovoked deep vein thrombosis (DVT). We sought to determine if RVO as determined by compression ultrasonography (CUS) after completion of 5–7 months of anticoagulation for unprovoked DVT is associated with an increased risk of recurrent venous thromboembolism (VTE). Materials and Methods: This was a multicentre multinational prospective cohort study undertaken in tertiary care centers. Patients with a first ‘unprovoked’ major VTE were enrolled over a 4-year period and completed a mean 18-month follow-up in September 2006. All 452 patients with DVT had baseline CUS at inclusion to assess any RVO before stopping OAT at 5–7 months. During follow-up off OAT, all episodes of suspected recurrent VTE were independently adjudicated with reference to baseline imaging. Results: Forty-five out of 231 patients with abnormal CUS (19.5%) had recurrent VTE during follow-up, as compared with 32 out of 220 patients with normal CUS (14.6%), and one patient had inadequate CUS. There was no significant association between an abnormal CUS at inclusion and the risk of recurrent VTE: hazard ratio 1.4 (95% confidence interval, 0.9–2.1), P = 0.19. None of the different degrees of clot resolution on baseline CUS was statistically significantly associated with the risk of recurrent VTE. Conclusion: In our study, the presence of RVO at the time of OAT withdrawal was not associated with a statistically significant higher risk of recurrent VTE. RVO assessment may not be useful to guide duration of anticoagulation.

Background It remains uncertain if patients with atrial fibrillation or mechanical heart valves requiring interruption of warfarin for procedures benefit from post-procedure anticoagulant bridging therapy. Methods In order to determine the efficacy and safety of postoperative LMWH bridging, we conducted a multicenter randomized double-blind controlled trial of patients with atrial fibrillation or a mechanical heart valve who require interruption of warfarin for a planned procedure. We excluded patients with active bleeding within 30 days, platelet count Results Starting in October 2006 we randomized a total of 1471 patients of whom 1167 had atrial fibrillation (without mechanical heart valves) and 304 had mechanical valves (99 also had atrial fibrillation). Last follow up was completed in May 2016. Baseline characteristics were similar between the LMWH and the placebo groups (see Table 1). Due to a randomization program system error at two centres more atrial fibrillation patients were randomized to dalteparin rather than to placebo. Major thromboembolism occurred in 6/820 (0.71%) dalteparin patients and 7/650 (1.11%) placebo patients. Major post-procedure bleeding occurred in 12 (1.46%) dalteparin patients and 16 (2.46%) placebo patients. Findings were similar in patients with atrial fibrillation alone and in patients with mechanical heart valves (with or without atrial fibrillation) (Table 2). Conclusions In patients with atrial fibrillation and/or mechanical heart valves who had warfarin interrupted for a procedure there was no benefit from post-procedure LMWH bridging. Disclosures Kovacs: Bayer: Research Funding; Daiichi Sankyo Pharma Development: Research Funding. Wells:Janssen: Honoraria; Sanofi: Honoraria; BMS: Honoraria, Research Funding; Bayer: Honoraria. Schulman:Boehringer-Ingelheim: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Sanofi: Honoraria; Bayer: Honoraria.

Introduction: The perioperative management of patients who are taking a direct oral anticoagulant (DOAC) for atrial fibrillation (AF) and require an elective surgery/procedure is uncertain. No studies have addressed the timing of perioperative DOAC interruption and resumption, and if perioperative heparin bridging and coagulation function testing are needed. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study hypothesized that a simple, standardized perioperative management strategy, based on DOAC-specific interruption and resumption intervals, that foregoes perioperative heparin bridging and coagulation function testing, is safe for patient care, with associated low rates of major bleeding (1%) and arterial thromboembolism (0.5%). We postulated that this management yields a high proportion of patients (>90%) with a minimal to no DOAC level at surgery/procedure. Methods: PAUSE is a prospective study with 3 parallel DOAC cohorts of patients with AF taking apixaban, dabigatran or rivaroxaban and requiring anticoagulant interruption for an elective surgery/procedure. Patients were managed using a standardized protocol based on DOAC pharmacokinetic properties, procedure-associated bleeding risk (Appendix 1) and creatinine clearance (CrCl). DOACs were interrupted for 1 day before and after surgery for a low bleed risk surgery and 2 days before and after a high bleed surgery; longer interruption was done in patients on dabigatran with a CrCl Results: We enrolled 3007 patients from 23 sites in Canada, the U.S. and Europe (Appendix 4). The patient characteristics were (Figure 2): mean age 72.5 years; 66.1% male; 33.5% high bleeding risk surgery/procedure, with 1257 patients in the apixaban cohort, 668 in the dabigatran cohort and 1082 in the rivaroxaban cohort (Table 1). DOAC interruption and resumption intervals are shown in Table 2. The 30-day postoperative rate (95% CI) of major bleeding was 1.35% (0-2.00) in the apixaban cohort, 0.90% (0-1.73) in the dabigatran cohort and 1.85% (0-2.65) in the rivaroxaban cohort; the rate (95% CI) of arterial thromboembolism was 0.16% (0-0.48) in the apixaban cohort, 0.6% (0-1.33) in the dabigatran cohort and 0.37% (0-0.82) in the rivaroxaban cohort (Table 3). There were 2541 (84.5%) patients with preoperative DOAC levels measured: a level Conclusions: In patients with AF who were taking a DOAC (apixaban, dabigatran, rivaroxaban) and required anticoagulant interruption for an elective surgery/procedure, using a standardized DOAC-specific perioperative management strategy was safe for patient care, with associated low rates of perioperative MB (90% overall; 98.8% at high bleeding risk) had a minimal or no residual DOAC level at the time of the surgery/procedure. PAUSE is the largest study, to date, that addresses how to manage the common problem of perioperative DOAC management. It is likely to have a practice-changing impact and will inform future practice guidelines in perioperative care. Study Funding: CIHR (313156) and the H&S Foundation of Canada (G-14-0006136). Aniara-Hyphen Biomed (assays). Acknowledgments: We thank Drs. Walter Ageno, David Garcia, Lehana Thabane, Wendt Lim, Lori Linkins, William Ristevski, and Demetrios J. Sahlas. Also, Kayla Lucier, Grace Wang, Tara McDougall, and HRLMP and CRLB. Supported by CanVector and REDCap. Disclosures Douketis: Bayer: Other: Advisory Board; Janssen: Consultancy; BMS: Other: Advisory Board; Biotie: Other: Advisory Board; Daiichi-Sankyo: Other: Advisory Board; Boehringer-Ingelheim: Consultancy, Other: Advisory Board, Research Funding; The Medicines Company: Other: Advisory Board; Sanofi: Consultancy, Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Portola: Other: Advisory Board; Pfizer: Other: Advisory Board. Spyropoulos:Janssen Scientific Affairs, LLC: Consultancy. Carrier:Bayer: Honoraria; Leo Pharma: Research Funding; Pfizer: Honoraria; BMS: Honoraria, Research Funding. Vanassche:Bayer: Consultancy; Boehringer Ingelheim: Consultancy; BMS/Pfizer: Consultancy. Verhamme:Bayer: Honoraria, Research Funding; Medtronic: Honoraria; Portola: Honoraria; Boehringer Ingelheim: Honoraria; Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Shivakumar:Pfizer: Honoraria; Servier: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria. Gross:Pfizer: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria; Servier: Honoraria. Lee:Pfizer: Consultancy, Research Funding; BMS: Research Funding; Servier: Honoraria; LEO Pharma: Consultancy, Research Funding; Bayer: Consultancy, Honoraria. Le Templier:BMS-pfizer: Honoraria. Wu:Leo Pharma: Honoraria; Pfizer: Honoraria; BMS-Pfizer: Honoraria. Coppens:Bayer: Honoraria, Other: Non-financial support, Research Funding; CSL Behring: Honoraria, Other: non-financial support, Research Funding; Uniqure BV: Research Funding. Arnold:Bristol Myers Squibb: Research Funding; UCB: Consultancy; Amgen: Consultancy, Research Funding; UCB: Consultancy; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding. Caprini:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Recovery Force: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizor: Membership on an entity's Board of Directors or advisory committees; Janssen R&D: Membership on an entity's Board of Directors or advisory committees. Summer:Octapharma: Honoraria. Schulman:Daiichi-Sankyo: Honoraria; Bayer: Honoraria; Sanofi: Honoraria; Boehringer-Ingelheim: Honoraria, Research Funding.

SummaryThe use of exogenous oestrogen in women with otherwise unprovoked venous thromboembolism (VTE) could be considered sufficient explanation to classify VTE as provoked if the risk of recurrent VTE after 3–6 months of anticoagulant treatment is similar to the risk of recurrent VTE observed after a surgery or prolonged immobilisation. Our objective was to assess the risk of recurrent VTE in women after a first unprovoked episode on oestrogen. The REVERSE study is a cohort study of patients with a first unprovoked VTE treated with anticoagulant treatment for 5–7 months. The risk of recurrent VTE during follow-up was compared between women users and non users of oestrogen at the time of index VTE. Among the 646 patients included, 314 were women, of them 67 were current users of oestrogen at the time of their VTE: 49 were on oral contraceptives and 18 on post-menopausal hormone replacement therapy (HRT). No significant association was found between oestrogen exposure, either oral contraceptives or HRT, and a lower risk of recurrent VTE after adjustment for age, or analysis restricted to women in the same age range as oestrogen contraceptives and HRT users, respectively. The risk of recurrent VTE is low in women after a first otherwise unprovoked oestrogen-associated VTE. However, this risk is not significantly lower than in women whose VTE was not related to oestrogen use.

Summary. Background/objectives: We prospectively measured change in quality of life (QOL) during the 2 years after a diagnosis of deep vein thrombosis (DVT) and evaluated determinants of QOL, including development of the post-thrombotic syndrome (PTS). Patients/methods: Consecutive patients with acute DVT were recruited from 2001 to 2004 at eight hospitals in Canada. At study visits at baseline, and 1, 4, 8, 12 and 24 months, clinical data were collected, standardized PTS assessments were performed, and QOL questionnaires were self-completed. Generic QOL was measured using the Short-Form Health Survey-36 (SF-36) questionnaire. Venous disease-specific QOL was measured using the Venous Insufficiency Epidemiological and Economic Study (VEINES)-QOL/Sym questionnaire. The change in QOL scores over a 2-year follow-up was assessed. The influence of PTS and other characteristics on QOL at 2 years was evaluated using multivariable regression analyses. Results: Among the 387 patients recruited, the average age was 56 years, two-thirds were outpatients, and 60% had proximal DVT. The cumulative incidence of PTS was 47%. On average, QOL scores improved during follow-up. However, patients who developed PTS had lower scores at all visits and significantly less improvement in QOL over time (P-values for PTS*time interaction were 0.001, 0.012, 0.014 and 0.006 for PCS, MCS, VEINES-QOL and VEINES-Sym). Multivariable regression analyses showed that PTS (P

Risk factors predictive of occult cancer detection in patients with a first unprovoked symptomatic venous thromboembolism (VTE) are unknown. Cox proportional hazard models and multivariate analyses were performed to assess the effect of specific risk factors on occult cancer detection within 1 year of a diagnosis of unprovoked VTE in patients randomized in the Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism (SOME) trial. A total of 33 (3.9%; 95% CI, 2.8%-5.4%) out of the 854 included patients received a new diagnosis of cancer at 1-year follow-up. Age ≥ 60 years (hazard ratio [HR], 3.11; 95% CI, 1.41-6.89; ITALIC! P= .005), previous provoked VTE (HR, 3.20; 95% CI, 1.19-8.62; ITALIC! P= .022), and current smoker status (HR, 2.80; 95% CI, 1.24-6.33; ITALIC! P= .014) were associated with occult cancer detection. Age, prior provoked VTE, and smoking status may be important predictors of occult cancer detection in patients with first unprovoked VTE. This trial was registered atwww.clinicaltrials.govas #NCT00773448.

• A subset of women enrolled in the REVERSE II study underwent a second, blinded assessment for signs of post-thrombotic syndrome (hyperpigmentation, edema, redness).

Venous thromboembolism (VTE) is the second leading cause of death in patients with cancer. These patients are at an increased risk of developing VTE and are more likely to have a recurrence of VTE and bleeding while taking anticoagulants. Management of VTE in patients with cancer is a major therapeutic challenge and remains suboptimal worldwide. In 2013, the International Initiative on Thrombosis and Cancer (ITAC-CME), established to reduce the global burden of VTE in patients with cancer, published international guidelines for the treatment and prophylaxis of VTE and central venous catheter-associated thrombosis. The rapid global adoption of direct oral anticoagulants for management of VTE in patients with cancer is an emerging treatment trend that needs to be addressed based on the current level of evidence. In this Review, we provide an update of the ITAC-CME consensus recommendations based on a systematic review of the literature ranked according to the Grading of Recommendations Assessment, Development, and Evaluation scale. These guidelines aim to address in-hospital and outpatient cancer-associated VTE in specific subgroups of patients with cancer.

SummaryLow-molecular-weight heparin (LMWH) is increasingly being used for prophylaxis of venous thromboembolism (VTE) and prevention of pregnancy associated morbidity in pregnant women with thrombophilia. We sought to determine if the administration of prophylactic doses of LMWH downregulates coagulation activation in high risk pregnant women with thrombophilia. This sub-study was planned as part of a randomized open label controlled trial (Thrombophilia in Pregnancy Prophylaxis Study[TIPPS])in which patients at high risk of pregnancy complications with confirmed thrombophilia are randomized to receive either dalteparin (5,000 units/day until 20 weeks then 5,000 units q12h until 37 weeks or onset of labor) or no treatment. Blood samples were collected at baseline, day 7–9 (after starting study drug), week 20 (before increasing study drug), week 36 (prior to stopping study drug) and at the time of admission to the labor and delivery unit. Samples were not drawn at fixed times in relation to drug injection. These samples were analyzed for levels of thrombin-antithrombin complexes (TAT), prothrombin fragments 1+2 (F1.2), D-dimer and anti-Xa activity. Generalized linear mixed models were used for statistical analysis and model results were controlled for age, smoking status, type of thrombophilia and predisposing risk factors. The effect of dalteparin onTAT levels was defined as the primary outcome. Of 198 patients eligible, 114 were enrolled in TIPPS. Ninety-one were eligible for the TIPPS coagulation activation sub-study and randomized. Thirty-nine patients were analyzed in the treatment group (dalteparin) and 46 patients in the control group (no intervention). Levels of coagulation activation factors F1.2, TAT and D-dimer increased significantly throughout pregnancy in both groups (p

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.).

The presence of antiphospholipid antibodies (aPL) has been shown to be associated with arterial (AT) and venous thrombosis (VT) [1]. However, thrombosis does not occur in all aPL-positive individuals, and predicting which patients may develop thrombotic events remains one of the major clinical dilemmas in this area. Hence, it would be of tremendous clinical value to determine serological markers or tests that can identify patients at high risk of thrombosis. Persistence of anticardiolipin antibody (aCL) positivity has been shown to be of diagnostic importance in identifying systemic lupus erythematosus (SLE) patients at higher risk of thrombosis [2, 3]. aCL persistence has also been associated with a higher incidence of lupus anticoagulant (LA) [3]. Multiple different aPL [e.g. LA, anti-β2-glycoprotein I antibodies (aβ2GPI) and antiprothrombin] are often present in an individual with aCL, but the diagnostic utility of aPL other than aCL and LA remains questionable [4–6]. Other retrospective studies have shown that individuals with more than one aPL are at greater risk of thrombosis than those with a single aPL [7–12]. The mechanism responsible for the development of these multiple aPL remains unknown, but epitope spreading is one potential mechanism that can explain the presence of multiple and related autoantibodies in a given individual [13]. In fact, in patients with SLE, aPL (specifically, aCL) have been shown to precede the development of other autoantibodies and to precede the development of disease by 7 or 8 yr [13]. We propose that autoantibodies in patients with antiphospholipid syndrome also develop and emerge in an ordered pattern, and that clinical symptoms may occur only after multiple autoantibodies have been present for several to many years. In the present study, we were interested in exploring whether the persistent presence of aCL is associated with an increased risk of the development of other aPL. In particular, we focused on whether persistent aCL positivity is associated with an increased risk of the presence of LA and anti-β2GPI antibodies, and evidence for a temporal relationship in the development of these different aPL. Such an association might provide better diagnostic criteria for identifying patients at risk of thrombosis, and a better understanding of the development and pathogenesis of aPL.

Summary. Background: The risk of recurrence is lower after treatment of an episode of venous thromboembolism associated with a transient risk factor, such as recent surgery, than after an episode associated with a permanent, or no, risk factor. Retrospective analyses suggest that 1 month of anticoagulation is adequate for patients whose venous thromboembolic event was provoked by a transient risk factor. Methods: In this double-blind study, patients who had completed 1 month of anticoagulant therapy for a first episode of venous thromboembolism provoked by a transient risk factor were randomly assigned to continue warfarin or to placebo for an additional 2 months. Our goal was to determine if the duration of treatment could be reduced without increasing the rate of recurrent venous thromboembolism during 11 months of follow-up. Results: Of 84 patients assigned to placebo, five (6.0%) had recurrent venous thromboembolism, compared with three of 81 (3.7%) assigned to warfarin, resulting in an absolute risk difference of 2.3%[95% confidence interval (CI) − 5.2, 10.0]. The incidence of recurrent venous thromboembolism after discontinuation of warfarin was 6.8% per patient-year in those who received warfarin for 1 month and 3.2% per patient-year in those who received warfarin for 3 months (rate difference of 3.6% per patient-year; 95% CI − 3.8, 11.0). There were no major bleeds in either group. Conclusion: Duration of anticoagulant therapy for venous thromboembolism provoked by a transient risk factor should not be reduced from 3 months to 1 month as this is likely to increase recurrent venous thromboembolism without achieving a clinically important decrease in bleeding.

Purpose: We sought to determine whether venous thromboembolism in cancer patients is associated with aberrant plasma levels of hemostatic and angiogenic factors. Patients and Methods: Peripheral blood was collected before anticoagulant therapy from cancer patients with acute deep venous thrombosis (DVT; DVT + cancer group, n = 32), those without DVT (cancer control group, n = 36), and patients with acute DVT but no cancer (DVT control group, n = 58). Plasma assays of activation and inhibition of coagulation and fibrinolysis, as well as angiogenesis activation, were then performed. Results: Median levels of thrombin-antithrombin complex, prothrombin fragments 1 + 2, and von Willebrand factor antigen were significantly greater in the DVT + cancer group than in the cancer control and DVT control groups (17.8 ng/mL v 4.6 ng/mL and 9.8 ng/mL, P = .0001 and P = .003, respectively; 3.65 nmol/L v 1.60 nmol/L and 2.71 nmol/L, P < .0001 and P = .011, respectively; and 4.04 U/mL v 2.26 U/mL and 2.06 U/mL, P < .0001, respectively). Median levels of tissue-type plasminogen activator were also significantly higher, while protein C activity was lower in the DVT + cancer group than in the DVT control group (14.6 ng/mL v 9.50 ng/mL, respectively, P = .0005; 0.89 U/mL v 1.11 U/mL, respectively, P = .0008). Conclusion: These data not only support prior observations of coagulation activation in patients with malignancy, but also provide new evidence for enhanced coagulation activation in the setting of acute venous thromboembolism in cancer. Future prospective studies are warranted to determine whether these and other potential markers of hypercoagulability may help to identify cancer patients at highest risk for venous thromboembolism.

Observations suggest that traditional anticoagulant therapy, maintaining an international normalized ratio (INR) of approximately 2.0 to 3.0, could be more intensive than is necessary for the long-term prevention of recurrent venous thromboembolism. The value of less-intensive warfarin anticoagulation, with a target INR of 1.5 to 1.9, was therefore examined in a randomized, double-blind study enrolling 738 consecutive patients having one or more episodes of venous thromboembolism. All had completed at least 3 months of conventional oral anticoagulant therapy. Participants were assigned to continue on warfarin with a target INR of either 2.0-3.0 or 1.5-1.9 and were followed up for 2.4 years on average. To be eligible, patients must have had confirmed, symptomatic, proximal deep venous thrombosis or pulmonary embolism with no apparent major risk factor. The mean INR was 1.8 for patients assigned to low-intensity treatment and 2.4 in the usual-intensity group. Nine major bleeding episodes occurred in patients on low-intensity treatment, for a rate of 1.1 per 100 person-years. The 8 such episodes in the traditional treatment group represented a rate of 0.9 per 100 person-years. Including minor bleeding episodes, rates were 4.9 and 3.7 per 100 person-years, respectively. There were no fatal or intracranial bleeds in either treatment group. Older patients were more likely to have major bleeding. Venous thromboembolism recurred at rates of 1.9 events per 100 person-years in the low-intensity group and 0.7 per 100 person-years with traditional treatment, a statistically significant difference. Five episodes in the low-intensity group and 3 in the usual-intensity group occurred after warfarin was discontinued. There was 1 death in the low-intensity group caused by pulmonary embolism and 2 such deaths in the conventional treatment group. These findings show that conventional warfarin anticoagulation is more effective than a low-intensity regimen for preventing recurrent venous thromboembolism; the risk is lowered by approximately two thirds. At the same time, low-intensity treatment does not appear to make bleeding less likely.

Background— The perioperative management of dabigatran in clinical practice is heterogeneous. We performed this study to evaluate the safety of perioperative management of dabigatran using a specified protocol. Methods and Results— Patients treated with dabigatran and planned for an invasive procedure were eligible for inclusion. The timing of the last dose of dabigatran before the procedure was based on the creatinine clearance and procedure-related bleeding risk. Resumption of dabigatran was prespecified according to the complexity of the surgery and consequences of a bleeding complication. Patients were followed up for 30 days for major bleeding (primary outcome), minor bleeding, arterial thromboembolism, and death. We included 541 cases: 324 procedures (60%) with standard risk of bleeding and 217 procedures (40%) with increased risk of bleeding. The last dose of dabigatran was at 24, 48, or 96 hours before surgery according to the protocol in 46%, 37%, and 6%, respectively, of the patients. Resumption was timed according to protocol in 77% with 75 mg as the first dose on the day of procedure in 40% of the patients. Ten patients (1.8%; 95% confidence interval, 0.7–3.0) had major bleeding, and 28 patients (5.2%; 95% confidence interval, 3.3–7.0) had minor bleeding events. The only thromboembolic complication was transient ischemic attack in 1 patient (0.2%; 95% confidence interval, 0–0.5), and there were 4 deaths unrelated to bleeding or thrombosis. Bridging was not used preoperatively but was administered in 9 patients (1.7%) postoperatively. Conclusion— Our protocol for perioperative management of dabigatran appears to be effective and feasible.

Background —At one end of the clinical spectrum of coronary artery disease (CAD) are subjects who have had repeated acute ischemic events, and at the other end are those with long-standing angina who have never been unstable. This study tests the hypothesis that a specific biological profile can distinguish these 2 extreme groups and predict acute coronary events. Methods and Results —Blood levels of lipoprotein(a), homocysteine, tissue plasminogen activator, plasminogen activator inhibitor-1, C-reactive protein (CRP), fibrinogen, and von Willebrand factor were compared in 3 groups of 50 subjects each: (1) those with previous multiple acute coronary events, (2) age-matched subjects with ≥3 years of stable angina and no prior acute coronary events, and (3) matched controls without evidence of atherosclerotic disease and a normal coronary angiogram. All subjects were followed for 4.0 years. Lipoprotein(a), homocysteine, tissue plasminogen activator, and plasminogen activator inhibitor-1 were similar in both CAD groups and significantly higher than in the control group. However, compared with subjects with long-standing stable angina, those with previous multiple coronary events had higher values of CRP (5.7±5.4 versus 3.0±5.2 mg/L, P =0.012), fibrinogen (3.38±0.75 versus 2.92±0.64 g/L, P =0.001), and von Willebrand factor (1.60±0.55 versus 1.25±0.36 U/mL, P =0.0003). On follow-up, myocardial infarction and unstable angina occurred in 42% of the group with multiple events, 4% of the stable angina group ( P P P =0.002). A baseline CRP >3.5 mg/L had a relative risk of 7.6 (2.6 to 21.7, P =0.0002) for subsequent acute events. Conclusions —An inflammatory biological profile distinguished patients with previous multiple acute coronary events from those with long-standing stable angina and predicted acute coronary instability.

Background —Increased levels of markers of hemostasis may assist in the determination of the extent of carotid occlusive disease and the identification of neurologically intact individuals at increased risk of ischemic events. Methods —We conducted a prospective study of 304 subjects, including 82 with a recent (≤7 days) transient ischemic attack (TIA), 157 asymptomatic individuals with a cervical bruit, and 65 control subjects. Baseline evaluation included a neurological assessment, ECG, cervical ultrasonography, and cerebral CT and/or MRI. Levels of markers of coagulation and fibrinolytic activity were also determined. Results were analyzed in relation to the degree of carotid disease and the subsequent occurrence of cerebral and cardiac ischemic events. Results —Over a mean follow-up period of 2.8 years (SD, 1.3 years), 114 ischemic events occurred. Survival analyses showed that prothrombin fragment 1.2 (F 1.2 ) was a predictor of time to cerebral and cardiac ischemic events in the combined TIA and asymptomatic bruit group (relative risk [RR], 1.46; 95% CI, 1.18 to 1.81) as well as in the asymptomatic bruit group separately (RR, 1.70; 95% CI, 1.14 to 2.53). In the TIA group, both F 1.2 (RR, 2.36; 95% CI, 1.19 to 4.68) and severe (≥80%) carotid stenosis (RR, 3.53; 95% CI, 1.19 to 10.51) were predictive of time to ischemic stroke, myocardial infarction, or vascular death. Conclusions —In patients with TIAs and in asymptomatic individuals with cervical bruits, F 1.2 levels were found to be independent predictors of subsequent cerebral and cardiac ischemic events. Our results are consistent with an active role of the coagulation system through upregulation of thrombin in carotid disease progression and in the pathogenesis of ischemic events in patients at risk.

Background Patients who have a first episode of venous thromboembolism in the absence of known risk factors for thrombosis (idiopathic thrombosis) are often treated with anticoagulant therapy for three months. Such patients may benefit from longer treatment, however, because they appear to have an increased risk of recurrence after anticoagulant therapy is stopped. Methods In this double-blind study, we randomly assigned patients who had completed 3 months of anticoagulant therapy for a first episode of idiopathic venous thromboembolism to continue receiving warfarin, with the dose adjusted to achieve an international normalized ratio of 2.0 to 3.0, or to receive placebo for a further 24 months. Our goal was to determine the effects of extended anticoagulant therapy on rates of recurrent symptomatic venous thromboembolism and bleeding. Results A prespecified interim analysis of efficacy led to the early termination of the trial after 162 patients had been enrolled and followed for an average of 10 months....

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

Postpartum factor VIII inhibitors are rare; thus, collecting clinical and treatment data may provide valuable information in guiding patient management. This paper reports the results of a survey of United States and Canadian hemophilia centers on 14 patients with postpartum acquired factor VIII inhibitors. Patients ranged in age from 23 to 40 years. Parity at diagnosis was most frequently the first gestation. Two patients were diagnosed prepartum, but two patients only up to one year postpartum. Initial inhibitor titers ranged from two to 550 Bethesda units (BU), and rose to five to 885 BU. The median duration of the inhibitor was 27 months, with two of the 14 inhibitors unresolved at the time of the survey. A total of 80 bleeding episodes occurred, five of which were life or limb threatening. Three patients received no blood products and were not hospitalized. Of those treated for hemostasis, activated prothrombin complex concentrates and porcine factor VIII were most often reported to be effective. For immunosuppression, all patients received steroids and most received additional treatment. Steroids were reported ineffective more frequently than cyclophosphamide. No adverse fetal events were noted and there was no maternal mortality. These results underline the clinical heterogeneity of the severity of postpartum factor VIII inhibitors, and provide treatment guidelines in the absence of prospective studies.

Reexploration of the mediastinum for bleeding is required in 3% to 7% of patients after cardiac operation, with many proving to have no surgically correctable cause. In spite of a "negative exploration," the bleeding often ceases. We propose the hypothesis that such a negative exploration can be therapeutic by reducing marked fibrinolytic activity in the mediastinal cavity.Fibrinolytic activity in shed mediastinal blood was compared with that in the system blood in 5 patients after cardiac operation by measuring fibrinogen, fibrin degradation product, plasminogen activator inhibitor-1, and alpha2-antiplasmin levels.Fibrinolytic activity in mediastinal blood was markedly increased when compared with paired systemic venous blood. This was indicated by the mediastinal blood's lower fibrinogen levels (0.47 versus 1.91 U/mL; p0.001), very high levels of fibrin degradation products (1,350 versus 200 ng/mL; p0.05), and higher levels of plasminogen activator inhibitor-1 (55.5 versus 28.1 ng/mL; p0.005). Decreased levels of alpha2-antiplasmin were also observed in the mediastinum (0.50 versus 0.61 U/mL; p0.05).Our data confirm that fibrinolytic activity can be extremely high in the mediastinum in response to clot formation. This may explain the hemostatic effects of a negative reexploration, where irrigation and the removal of clots may reduce the fibrinolytic process; this may allow the bleeding ends of capillaries and small vessels to thrombose. Decreased levels of alpha2-antiplasmin observed suggest that lysine analogs, such as epsilon-aminocaproic acid, may have a beneficial role when locally delivered into the mediastinum.

Our aim was to find out whether thrombosis has a key role in distally ischaemic flaps and whether heparin improves flap survival in distally ischaemic myocutaneous and pure skin flaps in pigs. In experiment 1 we measured the concentration of coagulation factors in the venous effluent from both viable flaps and distally ischaemic flaps. In experiment 2 radio-actively labelled blood components (red cells, platelets and fibrinogen) were injected intravenously and the distribution of each tracer was measured. In experiment 3 either heparin or saline was given as a local, continuous direct intra-arterial infusion. Fluor-escein was used in all experiments to estimate the eventual flap survival. Our results indicate that thrombosis is not an important factor in distal ischaemia, and that heparin did not improve survival. Instead, there seems to be selective pooling of formed elements in the ischaemic portion of the flap.

SummaryThe role of ABO blood type as a risk factor for recurrent venous thromboembolism (VTE) in patients with a first unprovoked VTE who complete oral anticoagulation therapy is unknown. The aim of this study was to determine if non-OO blood type is a risk factor for recurrent VTE in patients with a first unprovoked VTE who completed 5–7 months of anticoagulant therapy. In an ongoing cohort study of patients with unprovoked VTE who discontinued oral anticoagulation after 5–7 months of therapy, six single nucleotide polymorphisms sites were tested to determine ABO blood type using banked DNA. The main outcome was objectively proven recurrent VTE. Mean follow-up for the cohort was 4.19 years (SD 2.16). During 1,553 patient-years of follow-up, 101 events occurred in 380 non-OO patients (6.5 events per 100 patient years; 95% CI 5.3–7.7) compared to 14 events during 560 patient years of follow-up in 129 OO patients (2.5 per 100 patient years; 95% CI 1.2–3.7), the adjusted hazard ratio was 1.98 (1.2–3.8). In conclusion, non-OO blood type is associated with a statistically significant and clinically relevant increased risk of recurrent VTE following discontinuation of anticoagulant therapy for a first episode of unprovoked VTE.

An acquired IgG inhibitor to factor XIII was identified in a 30-year-old Vietnamese woman with systemic lupus erythematosus. The IgG fraction was isolated from plasma by chromatography on an agarose gel column and by protein G adsorption. The anti-factor XIII activity, identified within the IgG fraction, inhibited factor XIII from both normal plasma (a2b2) and platelets (a2). A normal level of the b subunit was measured by immunoelectrophoresis of the patient's plasma, but the a subunit was not detected. These results suggested the presence of an IgG immunoglobulin which recognized the a subunit and interfered with its activity.

Measures of markers of in vivo activation of coagulation were assessed in patients on stable long-term oral anticoagulant therapy and analyzed with respect to the International Normalized Ratio (INR). The range of F1+2, FPA, and antithrombin--enzyme complex results (ATM) were significantly lower as compared to normals. Plasmin-antiplasmin complexes were unaffected by anticoagulation. An inverse correlation was evident between F1+2, FPA, and INR values at low intensity anticoagulation, and FPA and complexed antithrombin were correlated at high INRs. The relative ratio of plasma FPA/F1+2 and ATM/F1+2 increased with increasing INR. In conclusion, the interrelationship of these measures changes with intensity of anticoagulation as measured by INR, and appears complex. The utility of using these measures for patient monitoring awaits future clinical trials.