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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.

Background Patients with cancer have an increased risk of venous thromboembolism (VTE) and associated morbidity and mortality. Renal dysfunction is more common in patients with cancer, leading to heightened risks of bleeding and thrombotic complications. In the AVERT trial, thromboprophylaxis with apixaban resulted in a significantly lower rate of VTE and higher rate of major bleeding compared to placebo among intermediate-to-high-risk ambulatory cancer patients starting chemotherapy. As apixaban depends on some degree of renal clearance, there may be concerns regarding the safety and efficacy of apixaban thromboprophylaxis in patients with renal insufficiency. In this post-hoc analysis of AVERT, we evaluated the efficacy and safety of apixaban thromboprophylaxis according to renal function at randomization. Methods Eligible patients were randomized to apixaban (2.5mg twice daily) or placebo. First dose of study drug was given within 24 hours of the first chemotherapy administration with the intended treatment period of 180 days. For this subgroup analysis, the efficacy and safety of apixaban thromboprophylaxis was evaluated accordingly to renal function (calculated creatinine clearance [CrCl] by Cockcroft-Gault Equation) at randomization. Patients with CrCl < 30 mL/min were excluded from the trial. The primary efficacy outcome was objectively confirmed major VTE (proximal deep vein thrombosis or pulmonary embolism) within 180 days (±3 days) following randomization. The primary efficacy outcome was evaluated by modified intention-to-treat analysis, which included all patients who had undergone randomization and received at least one dose of study medication on or before day 180 (±3 days). The primary safety outcome was major bleeding defined by the International Society on Thrombosis and Haemostasis criteria. The primary safety outcome was evaluated by on-treatment analysis, when events were counted only if they occurred on study drugs or up to two days after discontinuation of the study drugs. Secondary outcomes included clinically relevant non-major bleeding and overall mortality. Results A total of 574 patients underwent randomization, with 563 patients included in the original primary efficacy and safety analysis (288 apixaban and 275 placebo). Upon randomization, 66 (11.5%) patients had CrCl < 60 mL/min and 508 (88.5%) patients had CrCl ≥ 60 mL/min. Patients with CrCl < 60 mL/min were significantly older, more female, had lower weight and fewer with body mass index (BMI) > 35 kg/m 2 and poorer ECOG performance status (Table 1). In patients with CrCl < 60 mL/min, VTE occurred in no patient on apixaban compared to 1 on placebo, and major bleeding episode occurred in 1 on apixaban and 0 on placebo. In patients with CrCl ≥ 60 mL/min, VTE occurred in 13 out of 257 (5.1%) in the apixaban group and 28 out of 242 (11.6%) in the placebo group [HR 0.41 (95% CI 0.26-0.64), p=0.0001] (Table 2). There were no significant differences between apixaban and placebo groups in major bleeding and clinically relevant non-major bleeding events. Overall mortality was significantly lower in the apixaban group (HR 0.25 [95% CI 0.13-0.45], p Conclusions In the AVERT trial, patients with CrCl < 60 mL/min were significantly older, more likely to be female, with lower weight or BMI and poorer ECOG performance status. There were very few VTE or major bleeding events in patients with CrCl < 60 mL/min. In patients with CrCl ≥ 60 mL/min, apixaban thromboprophylaxis was associated with a significantly lower rate of VTE and overall mortality compared to placebo, with no significant differences in the rates of major bleeding or clinically relevant non-major bleeding events. Figure 1 Figure 1. Disclosures Wang: Servier: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding. Carrier: Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Sanofi: Honoraria; Servier: Honoraria; Pfizer: Honoraria, Research Funding; Bayer: Honoraria. Wells: Daiichi Sankyo: Honoraria; BMS/Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria. OffLabel Disclosure: apixaban for primary thromboporphylaxis in ambulatory cancer patients receiving chemotherapy

Background Venous thromboembolism (VTE) is a common complication in ambulatory patients with cancer initiating systemic chemotherapy. Central venous catheters (CVCs) used for chemotherapy administration are associated with a heightened risk of VTE in this patient population. Primary thromboprophylaxis using a direct oral anticoagulant decreases the risk of VTE without significantly increasing the risk of major bleeding complications in ambulatory cancer patients at intermediate-to-high risk of VTE with a Khorana risk score of ≥ 2. We sought to determine the efficacy and safety of apixaban in intermediate-to-high risk patients with cancer and a CVC. Methods This post-hoc analysis was done using the AVERT trial data, which was a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban for primary thromboprophylaxis in intermediate-to-high risk patients with cancer initiating chemotherapy. The primary efficacy outcome was major VTE within 180 days of randomization and the primary safety outcome was major bleeding. The hazard ratios (HRs) for the primary efficacy and safety outcomes in patients with and without CVC were calculated using a Cox regression model controlling for age, gender, and study center. Results A total of 217 patients were included in the subgroup analyses with 126 and 91 patients receiving apixaban or placebo, respectively. The baseline characteristics are depicted in Table 1. Major VTE occurred in 6 (4.8%) patients in the apixaban group and 17 (18.7%) patients in the placebo group (HR 0.26; 95% CI, 0.14-0.47; p Conclusions Primary thromboprophylaxis with apixaban in patients with cancer and a CVC seems to reduce the risk of VTE without increasing the risk of major bleeding. Future studies are needed to confirm these findings. Figure 1 Figure 1. Disclosures Wells: BMS/Pfizer: Research Funding; Bayer: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Servier: Honoraria. Carrier: Bristol Myers Squibb: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aspen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Honoraria; Servier: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; LEO Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background Venous thromboembolism (VTE) is a leading cause of mortality in patients with cancer and is associated with significant morbidity and healthcare expenditure. The risk of VTE is also increased following the insertion of a central venous catheter (CVC) for chemotherapy deliverance and supportive care. The risks and benefits of primary thromboprophylaxis in patients with cancer and newly inserted CVC are unclear. Objective We sought to assess the rates of VTE and major bleeding complications to determine the safety and efficacy of primary thromboprophylaxis in adult patients with cancer and a CVC. Methods A systematic search of MEDLINE, EMBASE, and all EBM was conducted. Randomized controlled trials (RCTs) of adult patients with cancer and a CVC receiving primary thromboprophylaxis or observation/placebo were included. The primary efficacy and safety outcomes were total VTE and major bleeding episodes, respectively. Results A total of 9 RCTs (3155 patients) were included in the analysis. The total rates of VTE were significantly lower in patients receiving primary thromboprophylaxis compared to those not receiving primary prevention (7.6% vs. 13%; Odds Ratio (OR) 0.51, 95% CI 0.32 to 0.82, p < 0.01, I² = 52%) (Figure 1). The rate of major bleeding complication was not increased in patients receiving thromboprophylaxis (0.9% vs. 0.7%; OR 1.12, 95% CI 0.29 to 4.40, p = 0.87, I² = 32%) (Figure 2). Conclusions Primary thromboprophylaxis significantly reduced the risk of VTE without increasing the risk of major bleeding complications in patients with cancer and CVC. Future studies are needed to confirm these findings. Figure 1 Figure 1. Disclosures Wang: Servier: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding. Ikesaka: LEO Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wells: Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Bayer: Honoraria; BMS/Pfizer: Research Funding; Servier: Honoraria. Carrier: Servier: Honoraria; Boehringer Ingelheim: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aspen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; LEO Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Immediate initiation of anticoagulant therapy is imperative when acute venous thromboembolism (VTE) is diagnosed; 3 months is the minimum duration of treatment. Subsequently, the choice between anticoagulant agents and the continuation of treatment should be guided by the etiology of the VTE event.

Introduction: Apixaban 2.5mg twice daily has been shown to significantly reduce the risk of venous thromboembolism (VTE) compared to placebo for the primary thromboprophylaxis of VTE in ambulatory cancer patients initiating chemotherapy, who are at intermediate-high risk of VTE, with a Khorana score of ≥2 (hazard ratio, 0.41; 95% confidence interval, 0.26 to 0.65; P Method: We conducted a cost-utility analysis of apixaban (2.5mg twice daily) compared to usual care, whereby no apixaban is prescribed, from the perspective of Canada's healthcare system. Our target population was ambulatory cancer patients starting chemotherapy with an intermediate-high risk of VTE. We developed a Markov model with a cycle length of 1-week to simulate costs and quality-adjusted life years (QALYs) for patients receiving either apixaban or usual care over 6 months (Figure 1). To estimate the baseline time varying risk of VTE among ambulatory cancer patients undergoing chemotherapy, we created pseudo patient-level data from survival curves reported for patients in the placebo arm of the AVERT trial using 'WebPlotDigitizer'. We fitted parametric survival models to the patient-level data points to extrapolate VTE risk beyond the trial follow-up period (median follow-up 183 days). The best model was selected based on a visual inspection and the Akaike Information Criterion. The relative risk of VTE, clinically relevant non-major bleeding, and major bleeding (using the International Society of Thrombosis and Haemostasis criteria) as a result of apixaban was obtained from the AVERT trial using the on-treatment analysis. We conducted a targeted literature search to obtain the risk of complications among cancer patients receiving low-molecular-weight heparin for the initial treatment and secondary prevention of VTE using a meta-analysis technique. Hazard ratio for increased risk of death due to cancer was estimated as a weighted average of the age-standardized mortality rate by tumor type, based on the proportion of patients with each tumor type in the AVERT trial. Costs were obtained from published Canadian sources. Baseline health utility values for patients on chemotherapy and in remission were calculated as a weighted average of utility values by tumour type, also based on the proportion of patients with each tumour type in the AVERT trial. Utility values for chemotherapy and remission for each tumour type, as well as event specific disutility values, were obtained from the published literature. Both costs and QALYs were discounted using an annual rate of 1.5%, as recommended by the Canadian Agency for Drugs and Technologies in Health. We conducted deterministic and probabilistic sensitivity analyses to assess robustness of study findings. Results: Over a 6-month period, apixaban was associated with a lower health system cost (C$25,987 vs C$26,268) and a slight increase in QALYs (0.3339 vs 0.3337) compared to usual care (Table 1). The probability that apixaban was cost-saving compared to usual care was 90%; however, this probability decreased with the greater willingness to pay (WTP) values partly due to the high uncertainty in the difference in QALYs. At a WTP threshold of C$50,000/QALY, the probability of apixaban being cost effective was 57% (Figure 2). Over 1 year, apixaban reduced health care system costs by C$1,113 and improved QALYs by 0.0005 units compared to usual care. At a WTP threshold of C$50,000/QALY, the probability of apixaban being cost effective increased to 70%. Our results were robust to the change in time horizon; however, they were more sensitive to the relative risk of VTE, the relative risk of major bleeding, the costs amassed in the post-VTE period, and the treatment cost of acute VTE. Probabilistic sensitivity analysis indicated a high-level uncertainty around cost effectiveness estimates, which may be driven by the wide confidence intervals around estimates for relative risk of complications in patients receiving thromboprophylaxis with apixaban. Conclusion: From a publicly funded health system's perspective apixaban is a cost saving option for thromboprophylaxis among ambulatory cancer patients initiating chemotherapy. Disclosures Wells: BMS/Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria; Daiichi Sankyo: Honoraria. Carrier:Servier: Honoraria; Bayer: Honoraria; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Leo Pharma: Honoraria, Research Funding. OffLabel Disclosure: Apixaban can be used as postoperative prophylaxis of DVT/PE and for treatment of DVT/PE. We performed a cost-utility analysis of apixaban 2.5mg BID for the primary thromboprophylaxis of ambulatory cancer patients initiating chemotherapy, at intermediate-high risk of venous thromboembolism.

Background: The risk of venous thromboembolism (VTE) is increased in cancer patients, which can result in significant increases in mortality, morbidity and healthcare expenditures. The recent AVERT trial (N Engl J Med 2019 Feb 21;380(8):711-719), showed that prophylactic apixaban lowered the rate of VTE when compared to placebo in cancer patients starting chemotherapy. However, the risk-benefit ratio of primary thromboprophylaxis in patients initiating chemotherapy for recurrent disease compared to those with newly diagnosed patients who are chemotherapy naïve is unknown. Methods: This is a post-hoc analysis of the AVERT trial. The AVERT trial assessed apixaban therapy vs. placebo for prophylaxis among patients with cancer who were intermediate-to-high risk for VTE (Khorana score ≥2; the Khorana score is ranged from 0 to 6 with higher scores reflecting an increased risk of VTE) and were initiating chemotherapy. It was a randomized, placebo-controlled, double-blind clinical trial. The primary efficacy outcome was VTE and the main safety outcomes were major bleeding episodes. Secondary outcome measures included clinically relevant non-major bleeding (CRNMB). The severity of major bleeding was stratified from category 1 to 4, with category 4 being the most severe type. We performed time-to-event analysis on the primary efficacy and main safety end-points in patients with recurrent and new diagnosed cancers. The hazard ratio (HR) for the outcomes were estimated using a Cox regression model controlling for age, gender, and center. Results: A total of 574 patients were randomized in the AVERT trial. 563 were included in the modified intention-to-treat analysis. 237 and 232 patients with newly diagnosed cancer were allocated to the apixaban and placebo groups, respectively. Similarly, 51 and 43 patients with recurrent cancer were allocated to the apixaban and placebo groups, respectively. Baseline demographics and clinical characteristics are depicted in Table 1A and Table 1B. In patients with newly diagnosed cancers, the use of apixaban was associated with a significantly lower risk of VTE (HR: 0.45; 95% CI: 0.27-0.76; p = 0.002) and a higher rate of major bleeding complications (HR: 2.10; 95% CI: 1.09-4.08; p = 0.028) but not of CRNMB (HR: 1.06; 95% CI: 0.61-1.82) (Table 2A). A majority of the major bleeding complications were of category 2. In patients with recurrent cancer, apixaban was associated with a significant lower rate of VTE (HR: 0.26; 95% CI: 0.13-0.53; p < 0.001) without an associated significant increased risk of major bleeding complication (HR: 1.82; 95% CI: 0.36-9.15; p = 0.466) but with a significant increase rate of CRNMB (HR: 2.78; 95% CI: 0.58-1.34; p = 0.006) (Table 2B). Major bleeding episodes were split evenly between severity category 1 and 2. Conclusion: The risk-benefit ratio of primary thromboprophylaxis with apixaban might differ between patients with recurrent or newly diagnosed cancers. Apixaban was associated with a lower rate of VTE compared to placebo in both groups. Patients with recurrent cancer initiating chemotherapy may potentially have a more favorable risk benefit profile, as shown through the HR and the prevalence of major bleeding episodes. However, more trials are required to confirm these findings to help tailor thromboprophylaxis in this patient population. (AVERT ClinicalTrials.gov number, NCT02048865.) Disclosures Wells: BMS/Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria; Daiichi Sankyo: Honoraria. Carrier:Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Servier: Honoraria; Bayer: Honoraria; Pfizer: Honoraria, Research Funding. OffLabel Disclosure: Apixaban can be used as postoperative prophylaxis of DVT/PE and for treatment of DVT/PE. This study will show whether the prophylactic effects of apixaban will be more effective when used with patients with recurrent cancer or patients with newly diagnosed cancer.

Background: Ambulatory cancer patients initiating chemotherapy are at increased risk of venous thromboembolism (VTE). The Khorana score (0 = low, 1-2 = intermediate, 3-6 = high) helps clinicians to stratify these patients according to their underlying risk of VTE. The CATS score, which incorporates additional points for elevated biomarkers (d-dimer, p-selectin), may enhance VTE risk stratification by adding up to two additional points to the Khorana score. We sought to evaluate the incidence of VTE in patients with a Khorana score of ≥ 2 and elevated biomarkers. Methods: The AVERT trial compared apixaban to placebo for the primary prevention of VTE in ambulatory cancer patients with a Khorana score of ≥ 2. D-dimer and p-selectin measurements were performed at randomization. Patients with d-dimer or p-selectin over the 75th percentile received 1 additional point each per elevated measurement (d-dimer ≥ 2.06 ug/mL and p-selectin ≥ 44.5 ng/mL). Cumulative 6-month VTE incidences according to Khorana and CATS scores were calculated using Kaplan-Meier analysis. VTE was assessed among patients receiving placebo (control group) according to modified intention to treat analysis, whereas bleeding events were assessed among patients receiving apixaban according to per-protocol analysis. For both the Khorana and CATS scores, the highest risk groups were merged into pooled high-risk groups (Khorana ≥ 3, CATS ≥ 4) given the low number of patients in higher risk strata. Hazard ratios for VTE were calculated by univariate and multivariable Cox regression analyses. The linear association between risk scores, VTE incidence and incidence of overall bleeding was tested for statistical significance. Results: A total of 466 patients were included in the analysis, 229 and 237 patients in the placebo and apixaban arms, respectively. There were 73 (31.9%) and 86 (36.3%) patients with Khorana scores ≥ 3 in the control and apixaban arms, respectively, whereas there were 52 (22.7%) and 66 (27.9%) patients with CATS scores ≥ 4 in the control and apixaban arms, respectively. Mean age was 61.0 ± 11.8 and 60.6 ± 12.6 years in the control and apixaban arms, respectively. A minority of patients, 11.5% in the control arm and 15.1% in the apixaban arm, had ECOG scores of ≥ 2. The 6-month cumulative incidence of VTE was 13% (95% CI 7 to 23) in patients with a Khorana score of ≥ 3 and 20% (95% CI 11 to 35) in patients with a CATS score of ≥ 4, respectively (Figures 1 and 2). The linear trend for association of CATS risk scores with VTE was statistically significant (p = 0.0015). The linear trend for association of Khorana risk scores with VTE did not achieve statistical significance (p = 0.059). There was a total of 7 overall bleeding events (8.1%; 95% CI 2.4 to 13.9) in patients with a Khorana score of ≥ 3, two of which were major (2.3%; 95% CI 0 to 5.5). There were 7 overall bleeding events (10.6%; 95%CI: 3.2 to 18.0) in patients with a CATS score of ≥ 4, two of which were major (3.03%; 95%CI: 0 to 7.17). Neither increasing Khorana (p = 0.85, p = 0.69) or CATS scores (p = 0.58, p = 0.54) were significantly associated with either increased major or overall bleeding, respectively. Conclusion: Incorporation of d-dimer and p-selectin enhances VTE risk stratification in ambulatory cancer patients with a Khorana score of ≥ 2. Disclosures Carrier: BMS: Honoraria, Research Funding; Leo Pharma: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Servier: Honoraria. Key:Uniqure BV: Research Funding. Wells:BMS/Pfizer: Honoraria, Research Funding; Bayer: Honoraria; Sanofi: Honoraria; Daiichi Sankyo: Honoraria.

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

Venous thromboembolism (VTE) is a common condition that can lead to complications such as postphlebitic syndrome, chronic pulmonary artery hypertension, and death. The approach to the diagnosis of has evolved over the years and an algorithm strategy combining pretest probability, D-dimer testing, and diagnostic imaging now allows for safe, convenient, and cost-effective investigation of patients. Patients with low pretest probability and a negative D-dimer can have VTE excluded without the need for imaging. The mainstay of treatment of VTE is anticoagulation, whereas interventions such as thrombolysis and inferior vena cava filters are reserved for special situations. Low-molecular-weight heparin has allowed for outpatient management of most patients with deep vein thrombosis at a considerable cost savings to the health care system. Patients with malignancy-associated VTE benefit from decreased recurrent rates if treated with long-term low-molecular-weight heparin. The development of new oral anticoagulants further simplifies treatment. The duration of anticoagulation is primarily influenced by underlying cause of the VTE (whether provoked or not) and consideration of the risk for major hemorrhage. Testing for genetic and acquired thrombophilia may provide insight as to the cause of a first idiopathic deep vein thrombosis, but the evidence linking most thrombophilias to an increased risk of recurrent thrombosis is limited.

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.

Transforming growth factor–β1 (TGF-β1) and plasminogen activator inhibitor–type 1 (PAI-1) might play a role in the development of fibrosis and stenosis of hemodialysis vascular accesses. We studied polymorphisms in the TGFβ1 (869T>C; 915G>C), and PAI-1 (4G/5G) genes in 416 hemodialysis patients (107 access thrombosis cases, 309 controls), to determine if they are related to vascular access thrombosis. Three TGF-β1 production haplotypes (low, intermediate, and high) were defined according to the combination of polymorphisms found. The adjusted odds ratio (OR) and 95% confidence interval (CI) for access thrombosis in low TGF-β1 producers was 7.31 (2.15-24.88; P = .001). The interaction between low TGF-β1 production haplotype and the 4G/4G PAI-1 genotype was strongly associated with access thrombosis (adjusted OR 19.3; 95% CI 2.82-132.40; P = .003). Mean access thrombosis–free survival times in years (95% CI) were 14.65 (12.05-17.25), 11.96 (8.67-15.25), and 4.94 (3.06-6.83) in high, intermediate, and low TGF-β1 producers, respectively (P = .044). Analysis of the synergy index and the case-only cross-product supported the presence of an interaction. We concluded that low TGF-β1 production haplotype is a risk factor for hemodialysis access thrombosis and that in the presence of the 4G/4G PAI-1 genotype there is an additional increase in risk.

Background: Observation stays are intended to assess patients for short periods (i.e., Objective: To compare LOS, hospital treatment costs, and readmissions in PE patients managed through observation stays treated with either rivaroxaban or parenterally-bridged warfarin. Methods: US Premier Hospital claims data spanning 11/2012-9/2015 was used to identify patients with a primary diagnosis code for PE (415.1x) managed through an observation stay and having ³1 claim for a PE-related diagnostic test on day 0-2. Rivaroxaban users, allowing ²2 days of prior parenteral therapy, were 1:1 propensity-score matched to patients parenterally bridged to warfarin. LOS, the proportion of encounters lasting >2-midnights, total hospital costs and risk of readmission for venous thromboembolism (VTE) or major bleeding during the same month or 2 months subsequent to the index event were compared between propensity-score-matched treatment cohorts. Results: A total of 401 rivaroxaban patients were matched to 401 patients receiving parenteral bridging to warfarin.Rivaroxaban use was associated with a shorter LOS (-0.25 days), fewer encounters lasting >2 midnights (21.1% vs. 32.7%) and lower total hospital costs (-$240) vs. parenteral bridging to warfarin (p²0.03 for all) (Table). Readmission was similar between cohorts (p>0.99 for both VTE and major bleeding readmission). Conclusion: Shorter LOS and lower hospital costs occurred with rivaroxaban vs. parenteral bridging to warfarin in PE observation stay patients. This was achieved without increasing short-term risk of VTE or major bleeding readmission. Table Table. Disclosures Peacock: Portola: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Research Funding. Fermann:Janssen Pharmaceuticals: Other: Advisory Board, Speakers Bureau; Pfizer: Research Funding. Baugh:Janssen Pharmaceuticals: Consultancy; Roche Diagnostics: Other: Advisory Board. Wells:Janssen Pharmaceuticals: Consultancy; Bristol Myers Squib: Research Funding; Pfizer: Research Funding; Bayer Healthcare: Other: Advisory Board, Speakers Bureau; Itreas: Other: Writing Committee. Ashton:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment. Crivera:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment, Equity Ownership. Wildgoose:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment, Equity Ownership. Schein:Johnson & Johnson: Employment, Equity Ownership, Other: Own in excess of $10,000 of J&J stock. Coleman:Boehringer-Ingelheim Pharmaceuticals, inc.: Consultancy, Research Funding; Bayer Pharmaceuticals AG: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Research Funding.

Background: Both the simplified Pulmonary Embolism Severity Index (sPESI) and the multivariable In-hospital Mortality for Pulmonary embolism using Claims daTa (IMPACT) rule classify patients' risk of early post-pulmonary embolism (PE) complications. Objective: To externally validate sPESI and IMPACT for predicting 90-day all-cause mortality and readmission rates among PE patients treated within the Veterans Health Administration (VHA). Methods: We used VHA data from 10/1/2010-9/30/2015 to identify adult patients with: (1) ≥1 inpatient diagnosis for acute PE (International Classification of Diseases-9th Revision-Clinical Modification codes=415.1x), (2) continuous medical and pharmacy enrollment for ≥12-months prior to the index PE (baseline period), (3) a minimum of 90-days of post-event follow-up or until death (whichever came first), and (4) ≥1 claim for an anticoagulant during the index PE stay. Patients were excluded if they had a claim for PE or an anticoagulant during the baseline period. We classified patients as low-risk for early post-PE complications if their sPESI score=0 or their absolute in-hospital mortality risk estimated by IMPACT was Results: Of6,746 eligible PE patients, 851 (12.6%) died and 1,359 (20.1%) were readmitted for any reason within 90-days. Hospitalization for recurrent VTE and major bleeding occurred in 375 (5.6%) and 116 (1.7%), respectively.sPESI classified 1,918 (28.4%) as low-risk, while 1,024 (15.2%) were low-risk per IMPACT. Both tools displayed sensitivity >90% and NPVs >96% for all-cause 90-day mortality, but low specificity and PPVs (Table). IMPACT's sensitivity for all-cause readmission was numerically higher than sPESI, but both had comparable NPVs. Similar trends were observed for accuracy in predicting readmissions due to recurrent VTE or major bleeding. Conclusion: In this external validation study utilizing VHA data, IMPACT classified patients for 90-day post-PE outcomes with similar accuracy as sPESI. While not recommended for prospective clinical decision-making, IMPACT appears useful for identification of PE patients at low-risk for early mortality or readmission in retrospective claims-based studies. Table. Test characteristics for sPESI and IMPACT for 90-day post-pulmonary embolism outcomes CI= confidence interval; IMPACT=In-hospital Mortality for Pulmonary embolism using Claims data; NPV=negative predictive value; PPV=positive predictive value; sPESI=simplified Pulmonary Embolism Severity Index; VTE=venous thromboembolism Table. Test characteristics for sPESI and IMPACT for 90-day post-pulmonary embolism outcomes CI= confidence interval; IMPACT=In-hospital Mortality for Pulmonary embolism using Claims data; NPV=negative predictive value; PPV=positive predictive value; sPESI=simplified Pulmonary Embolism Severity Index; VTE=venous thromboembolism Disclosures Kumar: Johnson & Johnson: Employment. Wells:Itreas: Other: Served on a Writing Committee; Janssen Pharmaceuticals: Consultancy; Bayer Healthcare: Other: Speaker Fees and Advisory Board; BMS/Pfizer: Research Funding. Peacock:Comprehensive Research Associates LLC: Equity Ownership; Cardiorentis: Consultancy, Research Funding; The Medicine's Company: Consultancy, Research Funding; Banyan: Research Funding; Emergencies in Medicine LLC: Equity Ownership; Abbott: Research Funding; Alere: Consultancy, Research Funding; Prevencio: Consultancy; Janssen: Consultancy, Research Funding; Portola: Consultancy, Research Funding; Pfizer: Research Funding; Roche: Research Funding; ZS Pharma: Consultancy, Research Funding; Ischemia Care: Consultancy; Phillips: Consultancy. Fermann:Janssen Pharmaceuticals: Other: Advisory Board, Speakers Bureau; Pfizer: Research Funding. Wang:Janssen Pharmaceuticals: Research Funding. Baser:Janssen Pharmaceuticals: Research Funding. Schein:Johnson & Johnson: Employment, Equity Ownership, Other: Own in excess of $10,000 of J&J stock. Crivera:Johnson & Johnson: Employment, Equity Ownership, Other: Owns excess of $10,000 in stock. Coleman:Boehringer-Ingelheim Pharmaceuticals, inc.: Consultancy, Research Funding; Bayer Pharmaceuticals AG: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Research Funding.

Background: Recent studies have indicated that genetic factors such as polymorphisms in the CYP2C9 and the VKORC1 genes play an important role in vitamin K antagonist (VKA) response and perhaps bleeding. There are also data to suggest, especially for factor V Leiden, that thrombophilia may confer a decreased risk of bleeding (which could explain its persistence and high prevalence in the population). The influence of major genetic factors on risk of bleeding have not previously been evaluated in large prospective cohort studies of patients with VTE on extended (treatment after the first 3 to 6 months) VKA therapy. Aims: We sought to determine the effect of genetic variants that influence warfarin metabolism and thrombophilias on the rates of major bleeding during extended VKA therapy in patients with VTE disease. Methods: The Bleeding Risk study is a multicentre, multinational prospective cohort study of patients on extended VKA for unprovoked VTE, or provoked VTE with prior VTE. Patients were enrolled after at least 3 months of VKA. All major bleeding events during long term VKA were captured and adjudicated. A blood sample was taken from each patient at their first study visit and analysed in a central lab to identify the following genetic variant types: CYP2C9*2 (C/T), CYP2C9*3 (T/G), 1639G-A (G/A), Factor V Leiden (G/A: FVL), CYP4F2 (G/A), and Prothrombin gene 20210 variant (PGV). Rates of major bleeding were then evaluated for patients with each genetic variant in isolation and in combination. Results: 2290 of the 2514 patients enrolled at 12 sites have contributed over 7000 years of observation and were included in this analysis. The mean patient age was 60.2±14.7 years, 64% were male, 92% Caucasian, average BMI was 31.3, and 9% of patients were on antiplatelet agents. Patients were followed for a mean of 2.8 years (range, 0.1 to 6.8 years. 121 patients (4.8%) experienced at least one episode of major bleeding. The annual rate of bleeding was 1.7 per 100 patient-years of observation. The CYP2C9*2 variant heterozygous/homozygous versus wildtype (476 patients vs 1584) was protective against bleeding (Incidence risk ratio 0.5, p =0.01), CYP2C9*3 variant heterozygous/homozygous versus wildtype (215 patients vs 1845) was associated with major bleeding (Incidence risk ratio 2.0, p =0.01), VKORC1 and CYP4F2 had no association with major bleeding, and CYP2C9*3 variant heterozygous/homozygous in combination with wildtype CYP2C9*2 (186 patients) was associated with major bleeding (Incidence risk ratio 3.24, p =0.02). Both FVL (19% of patients) and PGV (8% of patients) had no effect on major bleeding, with p values > 0.35 for comparison of the wildtype to heterozygous/homozygous. Conclusion: This is the largest study we are aware of to determine if warfarin metabolic genotype variants and common thrombophilias influence major bleeding risk in patients followed long-term with extended duration VKA therapy for VTE. The thrombophilias do not influence bleeding risk but those with CYP2C9*3 hetero/homozygous inheritance had double the risk and CYP2C9*2 hetero/homozygous inheritance half the risk. There appears to be an interaction between the CYP2C9*2 and *3 genotypes. Disclosures Wells: BMS/Pfizer: Research Funding; Bayer Healthcare: Other: Speaker Fees and Advisory Board; Janssen Pharmaceuticals: Consultancy; Itreas: Other: Served on a Writing Committee. Kovacs:LEO Pharma: Honoraria; Bayer: Honoraria, Research Funding; Daiichi Sankyo Pharma: Research Funding; Pfizer: Honoraria, Research Funding. Anderson:Bayer Healthcare: Research Funding. Rodger:Canadian Agency for Drugs and Technologies in Health: Consultancy; Boehringer Ingelheim: Research Funding.

Introduction. Upper extremity deep vein thrombosis (UEDVT) is a relatively uncommon event with potentially serious complications. Its clinical outcomes are not well studied. The objective of this study was to assess the incidence of post-thrombotic syndrome (PTS) and functional disability in patients with UEDVT. Patients and methods. This was a pre-specified analysis of a prospective cohort study at 5 Canadian centres. We enrolled adult patients with a symptomatic UEDVT confirmed by compression ultrasound involving the brachial or more proximal veins, with or without a pulmonary embolism (PE). Exclusions included pregnancy, dialysis catheter thrombosis, active or high bleeding risk, platelet count Results. Between 2009 and 2012, we enrolled 141 patients: 75 with spontaneous and 66 with CVC related UEDVT. Mean age was 51 years and 55% were males. There were 78, 59 and 56 patients with evaluable data at 12, 18 and 24 months, respectively. The percentage of patients with ipsilateral PTS is shown in Table 1. There was no difference between patients with spontaneous or CVC- related UEDVT. Functional disability scores are shown in Table 2. Overall, patients developing PTS had higher functional disability at all time points, compared to patients without PTS. Conclusion. In this prospective cohort study PTS occurred in approximately one fifth of patients after UEDVT and was associated with more functional disability, although the majority of cases were mild according to the modified Villata score. No differences were observed between CVC-related and spontaneous UEDVT. Disclosures Lazo-Langner: Bayer: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Research Funding. Wells:Itreas: Other: Served on a Writing Committee; BMS/Pfizer: Research Funding; Bayer Healthcare: Other: Speaker Fees and Advisory Board; Janssen Pharmaceuticals: Consultancy. Carrier:BMS: Research Funding; Leo Pharma: Research Funding. Kovacs:Daiichi Sankyo Pharma: Research Funding; LEO Pharma: Honoraria; Bayer: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.

Background: The American College of Chest Physicians (ACCP) guidelines for venous thromboembolism (VTE) disease recommend treatment with anticoagulation for at least 3 months in patients with VTE. Moreover, the EINSTEIN-extension study assessed the effect of rivaroxaban on the risk of VTE recurrences in patients who had completed 6 to 12 months of treatment for VTE. Results showed that rivaroxaban significantly reduced the risk of VTE recurrences with a small increased risk of major bleeding. The objective of this study was to assess the risk of VTE recurrences and major bleeding associated with extended rivaroxaban treatment in a real-world setting among all VTE patients (i.e., unprovoked, provoked, and cancer related). Methods: A retrospective study was conducted using Truven Health Analytics MarketScan Databases from 02/2011 to 04/2015. The study included adult patients who initiated rivaroxaban therapy within 7 days after their first VTE and continuously used rivaroxaban for at least 3 months. The end of the initial 3-month rivaroxaban treatment was defined as the index date and patients were categorized into discontinued (treatment ended) and continued cohorts. Patients were followed from index date until end of continuous treatment for the continued cohort or end of data or re-initiation of oral anticoagulant therapy for the discontinued cohort. The outcomes included VTE recurrences identified as a primary diagnosis documented during a hospitalization and major bleeding events identified by a validated algorithm (Cunningham et al., 2011). Kaplan-Meier rates for VTE recurrences and major bleeding events at 3, 6, 9, and 12 months after the index date were compared between cohorts with adjustment for baseline confounding using the inverse probability of treatment weights (IPTW) method based on propensity score. Patients with unprovoked VTEs, defined as not having recent surgery, cancer, pregnancy or estrogen therapy, were also evaluated. Sample sizes of patients with provoked VTEs and cancer were too small to analyze these populations. A sensitivity analysis was also conducted among VTE patients receiving rivaroxaban for at least 6 months. Results: Among the 3-month treatment population, a total of 5,933 (63.4% unprovoked VTE) and 1,536 (68.4% unprovoked VTE) rivaroxaban users formed the continued and discontinued cohorts, respectively. The mean (SD) observation period was 149.3 (124.4) days in the continued cohort and 211.1 (191.6) days in the discontinued cohort. The Kaplan-Meier analysis (Figure 1) showed that patients in the continued cohort had significantly lower rates of VTE recurrences after an additional 3 months (0.70% vs. 1.70%), 6 months (1.41% vs. 2.34%), 9 months (1.82% vs. 3.01%), and 12 months (1.97% vs. 3.01%; all p-values < 0.05) of treatment. No statistically significant differences in the cumulative event rates for major bleeding (Figure 2) were observed between the continued and the discontinued cohort at 3 months (0.58% vs. 0.82%), 6 months (0.91% vs. 0.88%), 9 months (1.33% vs. 1.18%), and 12 months (1.44% vs. 1.44%; all p-values > 0.05). Among the 6-month treatment population, a total of 2,676 (65.9% unprovoked VTE) and 1,127 (70.4% unprovoked VTE) rivaroxaban users formed the continued and discontinued cohorts, respectively. The mean (SD) observation period was 158.5 (130.6) days in the continued cohort and 206.5 (171.5) days in the discontinued cohort. Patients in the continued cohort had lower rates of VTE recurrences after an additional 3 months (0.82% vs. 1.41%), 6 months (1.22% vs. 2.69%), 9 months (1.35% vs. 3.02%), and 12 months (1.72% vs. 3.70%; except at 3 months all p-values < 0.05) of treatment. No differences in the cumulative event rates for major bleeding were observed between the continued and the discontinued cohorts. Similar results were found among patients with unprovoked VTE for the 3- and 6-month analyses. The interaction term between the cohort variable (Continued vs. Discontinued) and the type of VTE (unprovoked vs. other types of VTE) was non-significant in both populations (p-value > 0.05), which suggests that the benefit of extended treatment do not depend on the type of VTE events. Conclusions: Our study results suggest that all patients with VTE who continued rivaroxaban therapy after the first 3-month and 6-month treatment periods had significantly lower risk of VTE recurrences without an increased risk of major bleeding. Disclosures Khorana: Halozyme: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Leo: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Janssen Scientific Affairs, LLC: Consultancy, Honoraria, Research Funding. Berger:AZ: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Wells:BMS/Pfizer: Research Funding; Itreas: Other: Served on a Writing Committee; Janssen Pharmaceuticals: Consultancy; Bayer Healthcare: Other: Speaker Fees and Advisory Board. Seheult:Janssen Scientific Affairs, LLC: Consultancy. Ashton:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment. Laliberté:Janssen Scientific Affairs: Research Funding. Crivera:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment, Equity Ownership. Lejeune:Janssen Scientific Affairs: Research Funding. Schein:Johnson & Johnson: Employment, Equity Ownership, Other: Own in excess of $10,000 of J&J stock. Wildgoose:Janssen Scientific Affairs, LLC, Raritan, New Jersey: Employment, Equity Ownership. Lefebvre:Janssen Scientific Affairs: Research Funding. Kaatz:Bristol Myer Squibb: Honoraria; Pfizer: Honoraria; CSL Behring: Honoraria; Boehringer Ingelheim: Consultancy; Pfizer: Consultancy; Janssen: Consultancy; Daiichi Sankyo: Consultancy; Bristol-Myers Squibb: Consultancy; Boehringer Ingelheim: Honoraria; Janssen: Honoraria.

Background: While tools exist to predict the risk of major bleeding in patients on oral anticoagulation therapy (OAT) for venous thromboembolism (VTE), these have focused on the higher risk period during the first 3 months of OAT therapy (risk of major bleeding 2.4% in first 3 months vs. 2% per year thereafter), and have not been developed or evaluated for bleeding risk after the first 3 months of therapy (extended OAT). It is widely considered that a bleeding risk tool that is able to identify patients with an annual rate of major bleeding over 3% is needed, as this is the cut-point at which the risk of continued anticoagulant therapy exceeds the benefit. Aims: We sought to evaluate if the rates of major bleeding were over 3% when four existing, previously published tools (RIETE,outpatient bleeding risk index (OBRI), ACCP and HAS-BLED) classified VTE patients during extended OAT as being high risk for major bleeding, and to assess if the differences in major bleeding risk between high risk and not high risk patients were statistically significantly different. Methods: The Bleeding Risk study was a multicentre, multinational prospective cohort study of patients on extended OAT for unprovoked VTE, or provoked VTE with prior VTE, designed to generate a new prediction tool for major bleeding. Patients were enrolled after at least 3 months of OAT. All major bleeding events during long term OAT were captured and adjudicated. We applied each of the 4 tools above to determine the risk for major bleeding according to patient scores. Not all variables in these tools were collected, including drug and alcohol history, and INR control. Results: 2514 patients enrolled at 12 sites have contributed over 7000 years of observation. The mean patient age was 60.2±14.7 years, 64% were male, 92% Caucasian, average BMI was 31.3, and 9% of patients were on antiplatelet agents. Patients were followed for a mean of 2.8 years (range, 0.1 to 6.8 years. 121 patients (4.8%) experienced at least one episode of major bleeding. The annual rate of bleeding was 1.7 per 100 patient years of observation. The proportion of patients classified as high risk of major bleeding by the RIETE (score of 3 or 4), OBRI (score of 3), ACCP (score ≥ 2) and HAS-BLED (score ≥ 3) scores were 12.3%, 13.3%, 28.0% and 23.1%, with major bleeding rates of 3.9%, 3.2%, 3.4% and 3.4% per year, respectively. The major bleeding rates of patients who were classified as not high risk of bleeding were 1.4%%, 1.5%, 1.1% and 1.2% per year, respectively. All differences were statistically significant with p values < 0.0001. Conclusion: Despite the potential to underestimate risk due to missing variables, all currently available prediction tools are able to identify patients with a 3% or higher risk of major bleeding per year. , The HAS-BLED and ACCP scores were able to identify the highest proportions of patients as high risk for major bleeding. Disclosures Wells: BMS/Pfizer: Research Funding; Bayer Healthcare: Other: Speaker Fees and Advisory Board; Janssen Pharmaceuticals: Consultancy; Itreas: Other: Served on a Writing Committee. Kovacs:Bayer: Honoraria, Research Funding; LEO Pharma: Honoraria; Daiichi Sankyo Pharma: Research Funding; Pfizer: Honoraria, Research Funding. Anderson:Bayer Healthcare: Research Funding. Rodger:Boehringer Ingelheim: Research Funding; Canadian Agency for Drugs and Technologies in Health: Consultancy.

The clinical relevance of antiphospholipid antibodies (APLA) in patients without systemic lupus erythematosus who have venous thromboembolism (VTE) in unknown. Limited evidence suggests that there is an association between the presence of APLA and both initial and recurrent episodes of VTE and that patients with APLA and VTE are resistant to warfarin therapy. Unselected patients with a first episode of clinically suspected deep vein thrombosis or pulmonary embolism were evaluated with objective tests for VTE and with laboratory tests for APLA; the latter included tests for the lupus anticoagulant (LA) and anticardiolipin antibodies (ACLA). Patients with VTE were treated with anticoagulant therapy and observed during and after discontinuation of anticoagulants for symptomatic recurrence of VTE. There was a strong association between LA and VTE (odds ratio, 9.4; 95% confidence interval [CI], 2.1 to 46.2) and 9 to 65 (14%; 95% CI, 7% to 25%) patients with VTE had LA. There was no association between the presence of ACLA and VTE (odds ratio, 0.7; 95%CI, 0.3 to 1.7) because of the high frequency of positive ACLA assays in patients without VTE. None of the 16 patients with VTE and APLA developed recurrent VTE while receiving warfarin therapy. There was no difference in rates of recurrent VTE in patients with or without APLA after anticoagulant therapy was discontinued. The strong association between LA and VTE suggests that testing for LA in patients with VTE is useful. The measurement of ACLA in patients with VTE has no clinical usefulness because the results are abnormal in a high proportion of patients without VTE. Although the presence of APLA in patients with VTE was not associated with resistance to a conventional intensity of warfarin or an increased risk of recurrent VTE after discontinuation of warfarin, a larger study should address these issues in a subgroup of patients with VTE and LA.

Rivaroxaban is an ideal potential alternative for treatment of heparin-induced thrombocytopenia because it is administered orally by fixed dosing, requires no routine coagulation monitoring and has been proven effective in the treatment of venous and arterial thromboembolism in other settings. The Rivaroxaban for HIT Study prospectively evaluated the efficacy and safety of patients with suspected or confirmed HIT who were treated with rivaroxaban [NCT01598168 - investigator sponsored study funded by Bayer] Methods: Canadian multicenter, single-arm, prospective cohort study of patients with confirmed or suspected HIT (4Ts score ≥4) treated with rivaroxaban 15 mg bid until the diagnosis was supported or refuted using the local HIT assay. Participants with HIT (positive local assay result) received rivaroxaban 15 mg bid until platelet recovery (or until Day 21 if the patient had acute thrombosis; HITT) then stepped down to rivaroxaban 20 mg daily until Day 30. Central testing with the serotonin-release assay (SRA) was performed (not in real-time at all centres). HIT positive was defined as a 4Ts score ≥4 plus serotonin release ≥50%. The primary outcome measure was the incidence of new symptomatic, objectively-confirmed venous and arterial thromboembolism in the combined cohort of patients with suspected and confirmed HIT at 30 days. Secondary objectives included incidence of symptomatic thromboembolism while on treatment with rivaroxaban (combined cohort) and the following outcomes among SRA-positive participants while on treatment with rivaroxaban: incidence of venous and arterial thromboembolism, incidence of major bleeding, and time to platelet recovery. Sample size of 200 participants (10 to 30 with SRA-confirmed HIT) was based on feasibility and an anticipated thrombotic event rate in the study population (combined cohort) of 6.5% at 30 days (5% in HIT negative; 11% in HIT positive while on rivaroxaban). Results: 22 participants (12 HIT positive) were enrolled between January 2013 and July 2015. The study was terminated early due to poor recruitment, but after enrolling the minimum expected number of HIT positive participants. Of the 12 HIT positive participants (SRA, mean release 95%), 3(25%) had HITT at time of study entry and 6 had received at least one dose of fondaparinux prior to study enrolment. Half of the HIT positive participants were enrolled in study after the SRA result had already been reported as positive. After 371 days of exposure to rivaroxaban (combined cohort), 1 HIT positive participant had possible symptomatic recurrent VTE (4.5%, 95% CI: 0 to 23.5%), 1 HIT positive participant had major bleeding (9 days after rivaroxaban was held) and there were 4 deaths (cancer 2, sepsis 1, end-stage COPD 1). The single episode of possible recurrent VTE was extension of previously documented apheresis catheter-related arm DVT in a HIT positive participant who presented on Day 7 with worsening arm pain. A repeat ultrasound showed extension of DVT; however a baseline scan had not been performed at time of study entry. Interestingly, the same participant failed treatment with fondaparinux prior to study enrolment (development of erythematous plaques at injection sites and failure of platelets to rise). His apheresis catheter was removed on Day 8, rivaroxaban was continued and complete resolution of his symptoms as well as platelet recovery was achieved. One HIT positive participant presented with evidence of bilateral lower limb arterial ischemia (HIT-related acute arterial thrombosis on documented chronic peripheral vascular disease) at the time of study enrolment. Despite achieving platelet recovery, he underwent bilateral below knee amputation on Day 16. Out of the 12 HIT positive participants, 11 achieved platelet recovery with mean time to recovery 9 days. The single participant who did not achieve platelet recovery received only 2 doses of rivaroxaban before it was held due to a transient rise in liver enzymes. Rivaroxaban was never restarted because he bled while receiving fondaparinux as an alternative. Conclusions: Rivaroxaban appears to be effective for treating patients with confirmed HIT, although lack of a comparator and a small sample size are limitations of our findings. The advantages of rivaroxaban over other agents currently used to treat HIT such as ease of administration, lack of routine coagulation monitoring and low cost make it an attractive option. Disclosures Linkins: Pfizer: Honoraria; Bayer: Honoraria, Research Funding. Off Label Use: rivaroxaban has not been approved for treatment of heparin-induced thrombocytopenia. Warkentin:W.L. Gore: Consultancy, Research Funding; Instrumentation Laboratory: Consultancy, Honoraria; Pfizer: Consultancy. Pai:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS-Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Shivakumar:Bayer: Honoraria. Wells:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS-Pfizer: Research Funding. Wu:Pfizer Canada: Membership on an entity's Board of Directors or advisory committees; Leopharma: Membership on an entity's Board of Directors or advisory committees.

Introduction . Upper extremity deep vein thrombosis (UEDVT) is a relatively uncommon event with potentially serious complications. Its optimal treatment and clinical outcomes are not well studied. The objective of our study was to assess the safety and efficacy of a standardized management protocol for UEDVT as well as its long term complications. Patients and methods . We conducted a prospective cohort study at 5 Canadian centres and enrolled adult patients with a symptomatic UEDVT confirmed by compression ultrasound involving the brachial or more proximal veins, with or without a pulmonary embolism (PE). Exclusions included pregnancy, dialysis catheter thrombosis, active or high bleeding risk, platelet count

Background: Most pulmonary embolism (PE) research has focused on acute and short-term outcomes such as mortality and PE recurrence. Whether long-term morbidity such as exercise limitation, impaired quality of life (QOL) and persistent dyspnea occurs after PE is largely unstudied. To address this knowledge gap, we performed the ELOPE study, a prospective, observational, multicenter cohort study of long-term outcomes after acute PE (www.clinicaltrials.gov NCT01174628). Objectives: The objectives of the ELOPE (Evaluation of Long-term Outcomes after PE) Study were: (1) to describe and quantify degree of exercise limitation, QOL impairment and persistent dyspnea at 1 year after PE; and (2) to identify predictors of poor functional status at 1 year. Methods: Patients ≥18 years old with a 1st episode of acute PE diagnosed within the previous 10 days screened at 5 Canadian recruiting centers were potentially eligible to participate. Exclusion criteria were subsegmental-only PE, preexisting severe cardiopulmonary comorbidity, previous proximal DVT, contraindication to CT pulmonary angiography (CTPA), life expectancy After the Baseline (B) visit, patients attended follow-up (FU) visits at 1, 3, 6 and 12 months to measure QOL (SF-36, PEmbQoL), dyspnea (UCSD SOBQ), and 6-minute walk test (6MWT) [all FU visits]; undergo CTPA [B, 12], echocardiogram [B, 12], Q scan [6, 12], cardiopulmonary exercise testing (CPET) [1, 12] and pulmonary function tests [1, 12]; and measure biomarkers (BNP, ddimer, troponin) [B, 6]. The primary study outcome was maximal aerobic capacity defined by peak oxygen uptake (VO2) as a percent of predicted maximal VO2 (VO2max) on 1-year CPET, with For the present analysis, we summarized demographic and clinical characteristics of study subjects, the proportion of patients with VO2max Results: 984 patients were screened for participation; of these, 150 were eligible and 100 (67%) consented to participate. Mean (SD) age was 50 (15) years, 57% were male, 80% were outpatients and 33% had concomitant DVT. PE was provoked in 21% and unprovoked in 79%; none were cancer-related. At 1 year, 40/86 (46.5%) of patients had 80% predicted VO2max at 1 year. Independent baseline predictors of abnormal VO2max at 1 year included: male sex (relative risk (RR)= 3.2 [95% CI 1.3-8.1]; p=0.015), age (RR 0.98 [95% CI 0.96-0.99] per 1 year age increase; p=0.002), BMI (RR 1.1 [95% CI 1.01-1.2] per 1 kg/m2 BMI increase; p=0.023), and smoker (RR 1.8 [95% CI 1.1-2.9]; p=0.023). In addition, VO2max Conclusions: PE is a common and serious cardiovascular illness, yet clinically relevant information on characteristics and determinants of long-term outcome after PE have been lacking. Results of the ELOPE Study indicate that almost half of PE patients can be considered to have a "post-PE syndrome" characterized by exercise limitation at 1 year, which influences their QOL and degree of dyspnea. Predictors of this post-PE syndrome include male sex, younger age, higher BMI and smoking. CPET testing or 6MWT testing at 1 month may help to identify patients with a higher risk of post-PE syndrome at 1 year. Funding: Canadian Institutes of Health Research (MOP-93627) Disclosures Wells: Bayer: Honoraria; BMS/Pfizer: Research Funding.

Background: Biomarkers such as brain natriuretic peptide (BNP), high-sensitivity cardiac troponin (hsTnT) and d-dimer (DD) are useful for acute or short-term risk stratification after pulmonary embolism (PE) to predict right ventricular dysfunction, recurrent PE or death. However, whether acute or convalescent levels of these biomarkers predict longterm functional limitation after PE has not been evaluated. To address this knowledge gap, we performed the ELOPE (Evaluation of Longterm Outcomes after PE) Study, a prospective, observational, multicenter cohort study of long-term outcomes after acute PE (www.clinicaltrials.gov NCT01174628). Objectives: To describe levels of NT-proBNP, hsTnT and d-dimer at baseline and 6 months in patients with acute PE, and to assess the relationship between biomarker levels and functional status at 1 year. Methods: Patients ³ 18 years old with a 1st episode of acute PE diagnosed within the previous 10 days screened at 5 Canadian recruiting centers were potentially eligible to participate. Exclusion criteria were subsegmental-only PE, preexisting severe cardiopulmonary comorbidity, previous proximal DVT, contraindication to CT pulmonary angiography (CTPA), life expectancy Patients attended study visits at baseline, 1, 3, 6 and 12 months. Blood samples to assay NT-proBNP (serum), hsTnT (serum) and DD (plasma) were obtained at baseline and 6 months. NT-proBNP and hsTnT were measured using the cobas® 8000 modular analyzer (Roche Diagnostics, Laval, Quebec); cut-off for normal is The primary outcome for the ELOPE Study was maximal aerobic capacity as defined by peak oxygen uptake (VO2) as a percent of predicted maximal VO2 (VO2max) on a cardiopulmonary exercise test (CPET) performed at the 1-year visit, with For each biomarker at baseline and 6 months, we calculated median (IQR) values, % of values above the cutoff, and univariate relative risk (RR) for VO2max Results: 984 patients were screened for participation; of these, 150 were eligible and 100 (67%) consented to participate. Mean (SD) age was 50 (15) years, 57% were male, 80% were outpatients, and 33% had concomitant DVT. PE was provoked in 21% and unprovoked in 79%; none were cancer-related. Table. Median biomarker values, % of values above cutoff, and univariate RR for VO2max cut-off* 8 (10.1%) 4 (5.8%) 8 (10.1%) 5 (7.2%) 62 (78.5%) 8 (11.6%) Univariate RR for VO2 max In a multiple model adjusted for age and sex, baseline NT-proBNP >300 pg/mL was associated with a relative risk (RR) of 2.31 (95% CI 1.10, 4.86; p=0.027) for VO2max Conclusion: In a prospective cohort of patients with a first episode of PE without preexisting severe cardiopulmonary comorbidity, baseline NT-proBNP >300 pg/mL predicted a greater than 2-fold increased risk of abnormal CPET at 1 year after PE. This finding may allow early identification of PE patients at increased risk of poor longterm outcome after PE. Further analyses are in progress to assess the relationship between changes in biomarker levels from baseline to 6 months and 1-year CPET result. Funding: Canadian Institutes of Health Research (MOP-93627) Disclosures Wells: BMS/Pfizer: Research Funding; Bayer: Honoraria.

Background The post-thrombotic syndrome (PTS) is a frequent complication of deep venous thrombosis (DVT). Identifying predictors of PTS is important to counsel DVT patients on their expected prognosis and to identify patients who may benefit from closer monitoring or preventive strategies. Objective In a secondary analysis of the SOX Trial, we aimed to identify predictors of developing PTS during 2 years follow-up after a first episode of proximal DVT. Methods The study cohort consisted of participants in the SOX Trial, a multicenter (24 centres in Canada and U.S.) randomized placebo controlled trial of active elastic compression stockings vs. placebo stockings worn for 2 years after a first, symptomatic proximal DVT. PTS, the primary study endpoint, was diagnosed at or after the 6 month visit based on patient-reported pain and swelling of ≥ 1 month duration that were typical in character, i.e. worse at end of day or after prolonged sitting/standing and improved after rest/leg elevation (Ginsberg criteria). Cumulative incidences of PTS were compared in subgroups defined by sex, age category, body mass index (BMI) category, anatomic extent of index DVT, type of DVT (cancer-associated, secondary risk factor-associated, unprovoked) and 1-month Villalta score category (score 0-4: none; 5-9, mild; 10-14, moderate; >14, severe), using Cox regression. Losses to follow-up, withdrawals and deaths were censored as of last date of follow-up. Results are presented as cumulative incidence by 750 days follow-up and hazard ratios (HR) with 95% confidence intervals (CI). Results Among the 803 participants in the SOX Trial, 60% were male, mean age was 55.1 years, and 87% were out-patients. In analyses adjusted for intervention group (i.e. allocation to active vs. placebo stockings), iliac vein DVT (HR 2.26 [95% CI 1.12, 4.53]; reference category: popliteal DVT) and Villalta score category at 1 month after DVT (score 5-9, HR 2.74 [95% CI 1.62, 4.64]; score 10-14, HR 5.81[95% CI 2.99, 11.29]; score >14, HR 7.59 [95% CI 3.31, 17.44]; reference category: score Conclusions In a large prospective cohort of patients with proximal DVT who were participants in the SOX Trial, Villalta score category (which reflects severity of venous symptoms and signs) at 1 month after DVT was strongly predictive of development of PTS during 2 years follow-up. This confirms a similar finding that we first observed in the VETO cohort study (Kahn SR et. al., Annals Intern Med 2008). More extensive DVT was also associated with PTS. Patients with these risk factors may benefit from closer monitoring after proximal DVT, and in the case of iliac vein DVT, from more aggressive strategies to treat acute DVT. Disclosures: No relevant conflicts of interest to declare.

Background Acute deep venous thrombosis (DVT) is associated with leg pain and discomfort. Elastic compression stockings (ECS) have the potential to improve DVT-related leg pain by reducing the diameter of distended veins, increasing venous blood flow and reducing venous hypertension. To date, however, the effect of ECS on DVT-related leg pain has not been studied. In the SOX Trial, a randomized trial of active ECS vs. placebo ECS to prevent the post-thrombotic syndrome, we measured leg pain intensity at baseline and at several time-points during follow-up. Objective In a secondary, non-prespecified analysis of the SOX Trial, to determine whether active ECS, compared with placebo (sham) stockings, are effective to reduce leg pain associated with acute proximal DVT. Methods We did a multicenter (24 centres in Canada and U.S.) randomized placebo controlled trial of active ECS vs. placebo ECS after a first, symptomatic proximal DVT. Active ECS were knee length, 30-40 mm Hg (Class II) graduated ECS. Placebo ECS were manufactured to appear identical to active ECS but lacked therapeutic compression. Study stockings were worn on the DVT-affected leg daily and continued for up to 2 years. Exclusion criteria were >10 days since DVT diagnosis, not planned to be treated with anticoagulants, known peripheral arterial disease or limb phlegmasia, anticipated lifespan < 6 months, inability of patient or caregiver to apply ECS, thrombolysis to treat DVT, geographically inaccessible for follow-up visits or unable to give informed consent. Leg pain intensity was assessed on a 10-point Visual Analog Scale (0, no pain; 10, worst possible pain) via patient self-report at baseline, 14 days, 1 month and 60 days after randomization. We compared mean pain scores at each time point in the active ECS vs. placebo ECS groups using t-tests. We repeated this analysis, restricted to patients who reported daily stockings use at the 1 month visit (the first visit at which frequency of stocking use was assessed). We conducted pre-specified subgroup analyses by age, sex, and extent of DVT. Results are presented as mean difference (95% confidence interval [CI]) in pain intensity score between groups. All statistical tests were 2-sided and significance was set at P Results 410 patients were randomized to active ECS and 396 to placebo ECS. One and 2 patients, respectively, were found to be ineligible soon after randomization and excluded from the analysis. Mean time from DVT diagnosis to randomization was 4.7 days. Baseline characteristics were similar in the 2 groups (60% male, mean age 55.1 years, highest proximal extent of DVT was iliac or femoral vein in 70% and popliteal vein in 30%, 87% were out-patients). Pain scores diminished over time in both groups. There were no differences between groups in pain scores at any time-point (Table), and no evidence for subgroup interaction by age category, sex or anatomical extent of DVT (not shown). Conclusions In a large randomized placebo-controlled trial in patients with symptomatic proximal DVT, leg pain improved at each follow-up visit to a similar degree in patients randomized to active ECS and placebo ECS, and we did not find evidence for benefit of active ECS to reduce pain associated with acute proximal DVT. As our first follow-up assessment was 14 days after DVT, we were unable to evaluate if active ECS had a beneficial or detrimental effect on pain scores during the first 2 weeks after DVT. Disclosures: No relevant conflicts of interest to declare.

Background The Pulmonary Embolism Severity Index (PESI) has been validated in the setting of standard treatment of pulmonary embolism with initial low molecular weight heparin followed by vitamin K antagonists. We evaluated the proposed simplified PESI in a large, phase III randomized trial involving patients with symptomatic pulmonary embolism with or without deep vein thrombosis, who were treated with rivaroxaban or standard therapy. Methods The EINSTEIN PE study was an open-label, randomized, phase III study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin overlapping with and followed by a vitamin K antagonist (warfarin or acenocoumarol, target international normalized ratio 2.0–3.0) for 3, 6, or 12 months in patients with acute, symptomatic pulmonary embolism. At baseline, the simplified PESI score was assessed, with 1 point each assigned for age >80 years, history of cancer, chronic cardiopulmonary disease, heart beat ≥110 beats per minute, systolic blood pressure Results It was possible to calculate the simplified PESI score in 4831 of the 4832 included patients, of whom 2589 (53.6%) had a PESI score of 0; 1775 (36.7%) had a score of 1; and 467 (9.7%) had a score of 2 or 3. No patient had a simplified PESI score greater than 3. Incidences of outcomes in relation to time period, simplified PESI score and treatment are presented in the following table. Conclusions Among patients with a simplified PESI score of 0 or 1, major clinical outcome events were rare during the first 30 days of treatment and were similar in patients treated with rivaroxaban or standard therapy. Patients with a simplified PESI score of 2 or more in both treatment groups had more frequent adverse outcomes both initially and in the long term. Disclosures: Fermann: Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Radiometer: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cubist: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cardiorentis: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Prins:Bayer HealthCare: Consultancy; Sanofi-aventis: Consultancy; Boehringer Ingelheim: Consultancy; GlaxoSmithKline: Consultancy; Daiichi Sankyo: Consultancy; Leo Pharma: Consultancy; Thrombogenics: Consultancy; Pfizer: Consultancy. Wells:BMS/Pfizer: Research Funding; Pfizer: Honoraria; Bayer Schering Pharma: Honoraria; Boehringer Ingelheim: Honoraria; Bayer HealthCare Pharmaceuticals: Honoraria; Biomerieux: Honoraria. Pap:Bayer Pharma AG: Employment. Lensing:Bayer Pharma AG: Employment.

Introduction The post thrombotic syndrome (PTS) is a chronic complication of deep venous thrombosis (DVT). It is not understood why up to 50% of DVT patients develop PTS despite optimal anticoagulation. In the Bio-SOX Study, we investigated whether markers of inflammation, one of the putative pathophysiologic processes leading to PTS, are of value in predicting the development of PTS in DVT patients. Objective To assess whether markers of inflammation measured at three time points after DVT diagnosis are predictors of risk of PTS. Methods The Bio-SOX is a sub-study of the SOX Trial, a multicenter, randomized controlled trial of elastic compression stockings for the prevention of PTS. Eight hundred and three patients with a first, symptomatic, proximal DVT were randomly allocated to receive active or placebo stockings to be worn daily, starting within 2 weeks of DVT diagnosis. During the SOX trial we prospectively collected blood samples from participants at baseline, one and six months. We measured plasma concentrations of C-reactive protein (CRP), interleukin (IL)-6, IL-10 and intercellular adhesion molecule (ICAM)-1 using validated established methods. Differences between median biomarker levels in PTS positive and negative patients (as defined by the Villalta scale applied over time starting at the 6 month visit) were assessed using the Wilcoxon rank-sum test. Multivariable logistic regression models were used to calculate crude and adjusted odds ratios (OR) of PTS by biomarker levels. Results Among study patients, 60.1% were male and mean age was 55.1 years. There were 334 cases of Villalta-defined PTS during follow up, with no significant difference in incidence between the active and placebo stockings groups. Median values of biomarkers between cases and noncases of PTS showed statistically significant differences in CRP and IL-6 at one and six months, ICAM-1 at all time points, and IL-10 at six months post DVT (Figure 1). Table 2 summarizes crude and adjusted ORs for PTS, using the median as a cut-off value. ICAM-1 was associated with PTS at all time points, IL-10 at six months, and CRP at 1 month post DVT, though this association was attenuated after adjustment. Conclusion The Bio-SOX Study is the first large scale prospective study we are aware of that evaluated the predictive role of biomarkers measured at baseline and relevant time points after acute DVT in the development of PTS. Findings suggest that inflammation plays an important role in PTS development. Among the studied biomarkers, ICAM-1 appeared to be most strongly associated with PTS development. ICAM-1 is an endothelial- and leukocyte-associated transmembrane protein important in stabilizing cell-cell interactions and facilitating leukocyte endothelial transmigration. Its expression and secretion by activated endothelial cells is induced by thrombin. Future therapeutic trials should be aimed at targeting this pathway. Disclosures: No relevant conflicts of interest to declare.

Abstract 3332 Background: Post thrombotic syndrome (PTS) is the most common complication of deep vein thrombosis (DVT). Symptoms and signs assessed by the Villalta PTS scale are non-specific and may have causes other than PTS, especially primary venous insufficiency. This may lead to an overestimate of patients categorized as having PTS. To date, the frequency and predictors of PTS in patients with DVT who are free of primary venous insufficiency have not been evaluated. Methods: Using data from the REVERSE prospective multicentre cohort study, we analyzed the prevalence and risk factors for PTS in patients who had a first, unprovoked, unilateral proximal DVT 5–7 months previously and did not have clinically significant primary venous insufficiency (defined as the absence of moderate or severe venous ectasia in the contralateral leg). At the time of enrolment in the REVERSE study, PTS was evaluated in the DVT-affected leg using the Villalta scale and was considered to be present if Villalta score >4. Independent predictors of PTS were assessed using a multivariable logistic regression model adjusting for age, sex, and use of compression stockings and included all variables achieving a p value ≤ 0.10 in univariate analysis. Results: Between October 2001 and March 2006, 664 patients were enrolled in the REVERSE study after having received a 5–7 month course of anticoagulant therapy. Of these, 452 had DVT with or without concomitant pulmonary embolism (PE) as the index event. Of these, 131 patients were excluded from this sub-study for the following reasons: previous secondary DVT/PE (n=24), presence of moderate or severe venous insufficiency in the contralateral leg (n=54), no PTS assessment (n=53). Among the remaining 321 sub-study patients, 48% (n=155) reported using compression stockings. The overall prevalence of PTS 5–7 months after DVT was 27.4% (n=88). The distribution of PTS severity category was as follows: mild PTS (Villalta score, 5–9) in 80% (n=70) of cases, moderate PTS (Villalta score, 10–14) in 17% (n=15) of cases and severe PTS (Villalta score ≥15 or ipsilateral leg ulcer) in 3.4% (n=3) of cases. In univariate analysis, age, sex, concomitant PE at presentation, thrombophilia (mutation of factor II or V, elevated factor VIII or hyperhomocysteinemia, presence of a lupus anticoagulant) and levels of the inflammatory marker C reactive protein or elevated ddimer before stopping anticoagulant therapy did not influence the risk of developing a PTS at 5–7 months (all p>0.10). Obesity (OR=2.3 [1.3 – 4.0]), household income When restricting our analysis to the 226 patients without any signs, even mild, of contralateral venous insufficiency, the prevalence of PTS decreased slightly to 24.8% (n=56). Only obesity remained an independent predictor of PTS (OR=2.3 [1.2 – 4.4]). Poor INR control, ultrasonographic features described above and household income Conclusions: In a population of patients with a first unprovoked proximal DVT and without significant primary venous insufficiency, obesity and ultrasonographic evidence of DVT sequelae at 5–7 months after DVT independently influenced the risk of PTS. Mild clinical expression of primary venous insufficiency was also found to be a predictor of PTS and could therefore play a role in PTS pathophysiology. Nevertheless, it had a limited impact on the assessment of the overall prevalence of ipsilateral PTS according to the Villalta scale. Disclosures: Crowther: Pfizer: Consultancy, Honoraria; Leo Pharma: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; BI: Honoraria; CSL Behring: Consultancy; Octaphram: Consultancy; Artisan: Consultancy.

Abstract 2299 Introduction: The duration of anticoagulation after unprovoked venous thromboembolism (VTE) has been characterized as the most important unanswered question in clinical thrombosis management. This has led to research to identify predictors of recurrent VTE to identify high-risk patients who might warrant indefinite anticoagulation. Many clinicians assume that a family history of VTE is a predictor of recurrent VTE. This study aims to assess the value of family history as a predictor for recurrent VTE. Methods: Prospective multi-center multi-national cohort study recruited patients with a first objectively proven unprovoked VTE who completed 5 to 7 months of anticoagulation therapy. A detailed family history of VTE was completed for every subject. The information recorded included the number of affected relatives, whether they were first or second degree relatives and if the VTE was unprovoked or secondary. Patients were then followed for recurrent VTE. Results: 664 subjects were enrolled between October 2001 and March 2006, 649 subjects were followed for a mean duration of 3.8 years (3.6–3.98 95% C.I.). The mean age of subjects in this cohort was 53 years (min-max 18–95) and 49% of subjects were females. A family history of VTE in at least 1 first-degree relative was recorded for 112 (17.3%) subjects. A total of 142 (21.9%) suspected VTE events were adjudicated as recurrences. The recurrence rate was 5.94% (4.89–7.15 95% C.I.) per patient-year for patients without any family history of VTE, and it was 4.82% (3.02–7.30 95% C.I.) per patient-year in patients with a family history of VTE in at least 1 first-degree relative. In secondary analyses, neither a family history of unprovoked VTE, multiple unprovoked VTE, in first-degree nor second-degree relatives was a predictor of recurrent VTE. A multivariate analysis was performed to adjust for known risk factors for VTE recurrence, but the adjusted hazard ratios were again not significantly different. Conclusion: A family history of VTE is not a predictor for recurrent VTE, and therefore should not be used to segregate unprovoked VTE patients in high- and low-risk categories. Table 1 . Family history of venous thromboembolism (VTE), including first-degree relatives (FDR) and second-degree relatives (SDR), among patients with a single VTE and those with recurrent VTE. Family History Patients without recurrent VTE (n = 507) Patients with recurrent VTE (n = 142) Recurrence Rate per Patient-Year (%) Hazard Ratio (95% C.I.) Adjusted Hazard Ratio (95% C.I.) [1] Negative No FDR or SDR with any type of VTE 390 112 5.94 (4.89–7.15) – – Positive Any relative (FDR&SDR) with any type of VTE 117 30 5.09 (3.43–7.26) 0.883 (0.590–1.322) 0.872 (0.569–1.337) Any relative (FDR&SDR) with an unprovoked VTE 66 15 4.82 (2.69–7.94) 0.827 (0.482–1.417) 0.799 (0.451–1.413) Two or more relatives (FDR&SDR) with any type of VTE 32 6 4.23 (1.55–9.21) 0.716 (0.315–1.628) 0.861 (0.374–1.981) Two or more relatives (FDR&SDR) with unprovoked VTE 13 2 4.18 (0.51–15.11) 0.677 (0.167–2.741) 0.860 (0.208–3.548) [1] Adjustment has been done for age, sex, BMI, factor V Leiden, prothrombin gene variant, HER (Hyperpigmentation, Edema and Redness), D-Dimer, hormone replacement therapy, oral contraceptives. Table 2 . Family history of venous thromboembolism (VTE), including first-degree relatives (FDR) only, among patients with a single VTE and those with recurrent VTE. Family History Patients without recurrent VTE (n = 507) Patients with recurrent VTE (n = 142) Recurrence Rate per Patient-Year (%) Hazard Ratio (95% C.I.) Adjusted Hazard Ratio (95% C.I.) [1] Negative No first degree relative with any type of VTE 417 120 5.95 (4.93–7.11) – – Positive Any first degree relative with any type of VTE 90 22 4.82 (3.02–7.30) 0.844 (0.536–1.331) 0.859 (0.533–1.384) Any first degree relative with unprovoked VTE 49 12 5.18 (2.68–9.05) 0.883 (0.488–1.598) 0.875 (0.464–1.650) [1] Adjustment has been done for age, sex, BMI, factor V Leiden, prothrombin gene variant, HER (Hyperpigmentation, Edema and Redness), D-Dimer, hormone replacement therapy, oral contraceptives. Disclosures: No relevant conflicts of interest to declare.

Abstract 712 Background & Objective: Risk factors for the post-thrombotic syndrome (PTS) remain poorly understood. In a prospective multinational multicenter cohort study of patients with a first episode of unprovoked deep venous thrombosis (DVT), we sought to evaluate whether subtherapeutic anticoagulation was associated with the development of PTS. Methods: The study population was derived from the REVERSE study, a prospective cohort study done to develop a clinical prediction rule to identify patients with unprovoked venous thromboembolism (VTE) at low risk of recurrent VTE. Patients with a first unprovoked VTE (index event) were treated with standard anticoagulant therapy with a target INR of 2–3 for a period of 5–7 months. Patients were then enrolled in the REVERSE study, anticoagulation was stopped, and patients were monitored for VTE recurrence. For the present study, patients with DVT as their index VTE event were assessed for PTS at enrollment into the REVERSE study, using the validated Villalta scale. PTS was defined by a score of > 4. Mild PTS was defined by a score of 5–9, moderate PTS by a score of 10–14 and severe PTS was defined by a score of ≥15 or presence of an ipsilateral leg ulcer. Using international normalized ratio (INR) data from the full period of warfarin anticoagulation, time in therapeutic range (TTR) was calculated by the Rosendaal method of linear interpolation. TTR data were analyzed to evaluate whether there was an association between sub-therapeutic INR values during various time windows since the index DVT and development of PTS. Based on published trials of warfarin anticoagulation for VTE, INR Results: 646 patients were enrolled into the REVERSE study, of whom 410 had DVT as their index event. Of these, 61 were excluded for insufficient INR or PTS data. Hence, the study population comprised 349 patients. The average age was 54.2 years, and 55.6% of the patients were male. Patients were on oral anticoagulation for a mean (SD) of 199 (17) days. Ninety-seven patients (27.8%) developed PTS; of these, 77 (74.7%) had mild PTS, 16 (15.5%) had moderate PTS and 4 (3.9%) had severe PTS. For the study population, the overall mean (SD) TTR during oral anticoagulation was 64.3% (19.4%) and the overall mean (SD) percentage time spent with an INR under 2 was 23.7% (18.7%). For the time window ‘first 3 months of anticoagulation', patients who developed PTS had an INR of 20% of the full time period was 33.5% compared to 21.6% in those with an INR below 2 for ≥20% of the time (p=0.02). In univariate analysis, the OR for development of PTS if the INR was Conclusion: Subtherapeutic warfarin anticoagulation after a first unprovoked DVT may be a risk factor for the development of PTS. Careful attention to INR control may have value in preventing PTS. Further study of the risk of PTS associated with oral or parenteral anticoagulants that offer more predictable anticoagulation than warfarin may be of value. Disclosures: No relevant conflicts of interest to declare.

Abstract 3180 Introduction: Pulmonary embolism (PE) is a continuous risk up to 3 months after surgery. Management of anticoagulation can be challenging in those diagnosed with PE after a major surgical procedure. The aim of this study is to evaluate the outcomes and characteristics of patients diagnosed with PE after a major surgery. Methods: A retrospective cohort of consecutive patients with suspected acute PE that underwent computed tomographic pulmonary angiography (CTPA) or lung ventilation/perfusion scans between 1 January 2007 and 31 December 2008 was constructed by two independent investigators by reviewing each patient's diagnostic images. Patients were included in the study if they had a major surgical procedure (admitted to the hospital for more than 24 hours) and developed PE within 12 weeks of the operation. Patients' follow-up for the first 3 months was recorded. Outcomes included major bleeding, as defined by the ISTH guidelines; recurrent venous thromboembolism (VTE), including PE or deep vein thrombosis (DVT); and mortality. The number of days between treatment initiation and major hemorrhage, recurrent VTE, or death, was recorded. Results: Out of the 842 patients diagnosed with PE at the Ottawa Hospital within the timeframe of the study, 160 (19%) were diagnosed during the post-operative period and were eligible for this study. The mean age (SD) in years was 63 (±15.5), 53% were males, 37% had a cancer related surgery, 37% had orthopedic procedures, and 31% had emergency procedures. The mean time (SD) from surgery to PE diagnosis was 13 (±11) days. All patients were followed-up until the end of their treatment; six patients were transferred to end of life care. Initial treatment was low molecular-weight heparin (LMWH) in 124 (78%) patients, unfractionated heparin (UFH) was given intravenously in 27 (17%) patients, and 5 (3%) requiered an inferior vena cava (IVC) filter to be inserted as the initial treatment. During the 90 days of follow up, there were 17 major bleeding events (12%), 6 recurrent VTEs (4%), and 15 deaths (9%). Of the 17 bleeding events, 13 of them (76%) occurred within the first two weeks of initiation of therapy. No bleeding events occurred after the first month. Two patients died (11.7%) from bleeding, one intracranial and one gastrointestinal (GI). Bleeding was from the GI tract in 47% of cases. Of the 5 patients with IVC filters, 3 developed recurrent DVT in the first two weeks after IVC insertion. The other 3 recurrent VTEs occurred on patients receiving anticoagulation. All cause mortality was 8.7% at 3 months. Within the first 14 days, 8 patients died (5%): 3 patients from PE. Outcomes did not vary by type of surgery, initial treatment or by presence of malignancy. Conclusions: Major bleeding is a common and deadly complication in patients diagnosed with PE after a major surgical procedure. The reported rates of bleeding in this population have varied widely in the literature (between 2 to 9%), according to the type of surgery or population. Our results suggest that alternative triaging and treatment strategies may be indicated in these patients. Disclosures: No relevant conflicts of interest to declare.

Abstract 4202 Background: It is unknown whether patients with cancer who develop VTE after a surgical procedure have the same risk of recurrent VTE as clinical patients cancer-associated thrombosis. VTE recurrence risk in non-cancer patients with VTE after surgery is approximately 1% in the 3 months following completion of anticoagulation. It is unknown whether surgical patients with cancer follow the low risk of recurrence as other provoked VTEs or whether they have the high recurrence risk typical of cancer patients. Methods: We performed a post-hoc analysis of a single centre retrospective cohort study conducted at the Thrombosis Unit of the Ottawa Hospital. The charts of patients with cancer and VTE followed from 2002 to 2004 and from 2007 to 2008 were reviewed. We sought to compare the risk of recurrent VTE between patients with cancer who developed a first VTE after major surgery with all other patients with cancer-associated thrombosis. We included patients > or = 18 years of age with active malignancy and objectively diagnosed index VTE [pulmonary embolism (PE), proximal deep venous thrombosis (DVT) of the legs or arms, PE + DVT; unusual site thrombosis]. After the first VTE, all patients received a minimum of 6 months of anticoagulation. In the surgery group, index VTE was considered associated with the intervention if it occurred within the first 3 months after the procedure. Results: 543 patients were included. 121 patients had VTE after surgery and 17 (13.1%) developed a recurrence during therapeutic anticoagulation. Of 422 clinical patients, 61 (14.7%) had a recurrent VTE (Table). The relative risk of recurrent VTE comparing patients who had and who did not have surgery was non-significant (RR= 0.97 (95%CI: 0.587 – 1.574; p= 1.000) suggesting that patients with cancer who undergo surgery have similar risk of developing a recurrent VTE during anticoagulation as patients with cancer-associated VTE who do not undergo surgery. VTE recurrence occurred predominantly within the first 6 months of anticoagulation [Surgery: 9 of 17 patients (52.9 %); no surgery: 45 of 61 (73.7%) patients (p=0.1377)] (Figure). There was no significant difference in VTE recurrence risk according to anticoagulant strategy, tumor site, histology, TNM stage, age or gender between surgery and no surgery groups. Conclusion: Patients with cancer who develop VTE after surgery have similar risk of developing a recurrent VTE during the anticoagulation period as clinical patients with cancer-associated VTE. Disclosures: Rodger: Pfizer: Research Funding; Leo Pharma: Research Funding; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Institutes of Health Research: Research Funding; Heart and Stroke Foundation: Research Funding.

Abstract 1102 Introduction: The management of saddle pulmonary embolism (PE) is controversial. Evidence about outcomes and management strategies is scarce in the literature due to the small prevalence of saddle PE. Historically it has been recommended that this group of patients should be treated aggressively. Purpose: To determine the prevalence and outcomes of patients diagnosed with saddle PE. Methods: Retrospective cohort study of consecutive patients with saddle PE diagnosed at the Ottawa Hospital between January 2007 and December 2008. Patients were included if a thrombus was present on computed tomographic pulmonary angiography (CTPA) in the main pulmonary arteries spanning the bifurcation of the main pulmonary trunk. These cases were each matched with two non-saddle controls with proximal PE (thromboemboli in the main pulmonary arteries) based on age, sex, systolic blood pressure greater than or less than 90 mmHg, and the presence or absence of cancer. Demographics, prognostic factors, treatment, and outcomes were collected. Patients were followed over a 30 day period following the diagnosis. RESULTS: A total of 32 (5%) of 724 patients with PE had a saddle event. Baseline characteristics are depicted in Table 1. Differences between the saddle case group and non-saddle control group include the presence of right ventricular dilation (59% of saddle cases vs. 22% of controls, p-value: 0.0007) and in the proportion of patients managed as outpatients (7% of saddle cases vs. 33% of controls, p-value: 0.02). At 30 days no differences were found in patients with saddle PE or proximal PE for all cause mortality (6% vs. 10%; OR: 0.64; 95% CI: 0.08–3.2), PE related mortality (0% vs. 6%; OR: 0.52; 95% CI: 0.01–6.1), major bleeding (3% vs. 5%; OR: 0.65; 95% CI: 0.02–6.4), or recurrent venous thromboembolism (6% vs. 10%; OR: 0.64; 95% CI: 0.08–3.2). Conclusions: Patients with saddle PE do not have a worse 30-day prognosis than patients with proximal PE matched by age, sex, systolic blood pressure, and presence of cancer. Disclosures: No relevant conflicts of interest to declare.

Abstract 3125 Poster Board III-62 VTE is the most frequent complication of OS and it can be prevented through anticoagulant prophylaxis. Numerous studies have evaluated different agents for this purpose and there are new agents currently under development or recently approved for this indication. We conducted a systematic review of randomized controlled trials (RCT) evaluating administration of anticoagulants for VTE prophylaxis in OS and performed a MA of proportions to estimate the overall incidence of major VTE (proximal VTE, pulmonary embolism (PE), or death from PE), total VTE (proximal and distal VTE, PE or death from PE), symptomatic VTE and major bleeding episodes (as defined by the International Society on Thrombosis and Hemostasis). We included RCT comparing currently approved anticoagulants (head-to-head or placebo-controlled) for VTE prophylaxis in OS (hip and knee arthroplasty and hip fracture surgery) using systematic evaluation of VTE (ultrasound or venography, pulmonary angiography, CT pulmonary angiography, or ventilation perfusion scan). Heterogeneity of proportions was evaluated using a chi2 test and pooled estimates of proportions were obtained using either a fixed or a random effects model in which the weights were estimated as proposed by Laird and Mosteller. We retrieved 74 studies including180 research arms and enrolling 71,012 patients. The total number of events and evaluable patients, percentage of events and 95% CI, and number of study arms included are shown in the table. We found differences in the percentage of VTE and bleeding events associated with the use of different anticoagulants for VTE prophylaxis after OS. Due to the nature of the analysis no effect measure can be estimated. These estimates might help to design future studies. Major VTE Total VTE Symptomatic VTE Major Bleeding Cases / Evaluable Pts. (N) Percentage (95% CI) Study arms (N) Cases / Evaluable Pts. (N) Percentage (95% CI) Study arms (N) Cases / Evaluable Pts. (N) Percentage (95% CI) Study arms (N) Cases / Evaluable Pts. (N) Percentage (95% CI) Study arms (N) All patients LMWH 993/23692 5.96 (5.81, 6.11) 72 4068/22610 20.29 (20.04, 20.55) 80 193/19431 1.32 (1.27, 1.37) 35 476/28725 1.98 (1.93, 2.02) 70 UFH 234/2407 13.39 (12.86, 13.93) 14 596/2537 22.54 (22, 23.08) 17 11/339 3.24 (3.06, 3.43) 4 70/2849 2.75 (2.61, 2.89) 16 Warfarin 269/5677 6.28 (6.09, 6.46) 12 1317/4203 31.05 (30.44, 31.66) 12 71/4146 1.95 (1.83, 2.08) 6 96/6751 1.78 (1.69, 1.87) 12 Fonda 96/3673 3.81 (3.53, 4.09) 7 223/3477 6.82 (6.57, 7.07) 6 69/6398 1.06 (1.01, 1.1) 8 121/6576 1.63 (1.55, 1.71) 9 Riva 50/5025 2.02 (1.86, 2.19) 8 242/4595 13.05 (12.16, 13.94) 8 29/6252 0.46 (0.45, 0.48) 6 31/6643 0.63 (0.59, 0.68) 8 Dabi 149/4091 3.64 (3.59, 3.69) 6 834/4051 22.96 (21.91, 24.01) 6 26/3664 0.71 (0.67, 0.75) 4 67/5419 1.21 (1.17, 1.26) 6 Placebo 193/710 24.26 (23.17, 25.34) 10 379/816 49.35 (48.08, 50.62) 11 19/198 12.02 (10.32, 13.72) 3 12/753 1.59 (1.5, 1.68) 7 Total 1984/45275 129 7659/42289 140 418/40428 66 873/57716 128 Total Hip Arthroplasty LMWH 653/15978 6 (5.85, 6.16) 50 1817/14480 15.58 (15.35, 15.82) 55 81/11552 0.7 (0.69, 0.72) 19 306/18010 1.97 (1.92, 2.02) 45 UFH 187/1739 14.3 (13.64, 14.96) 11 354/1836 20.13 (19.46, 20.8) 13 11/246 4.47 (4.21, 4.73) 3 52/1451 3.2 (3.01, 3.39) 11 Warfarin 77/2758 4.28 (4.08, 4.48) 6 265/1273 20.82 (20.59, 21.04) 6 32/1833 1.75 (1.69, 1.81) 2 47/2856 2.23 (2.09, 2.37) 5 Fonda 28/1799 2.96 (2.58, 3.33) 3 85/1695 5.01 (4.91, 5.12) 2 15/2255 0.67 (0.63, 0.7) 2 69/2349 2.94 (2.87, 3.01) 3 Riva 25/2938 2.21 (1.95, 2.46) 5 73/2749 9.72 (8.92, 10.53) 5 10/3468 0.29 (0.27, 0.31) 3 14/3795 0.49 (0.44, 0.54) 5 Dabi 72/1803 3.99 (3.88, 4.11) 2 124/1766 7.02 (6.77, 7.27) 2 21/2293 0.92 (0.91, 0.93) 2 38/2309 1.65 (1.58, 1.72) 2 Placebo 105/414 26.01 (24.76, 27.27) 7 174/418 45.43 (43.74, 47.13) 7 4/147 2.72 (2.46, 2.98) 2 3/388 0.77 (0.69, 0.86) 5 Total 1147/27429 84 2892/24217 90 174/21794 33 529/31158 76 Total Knee Arthroplasty LMWH 277/6916 4.45 (4.34, 4.55) 25 2062/7326 30.72 (30.37, 31.07) 32 83/4902 1.69 (1.66, 1.73) 11 89/7808 1.14 (1.12, 1.16) 26 UFH 42/638 6.58 (6.39, 6.78) 3 226/638 35.42 (35.05, 35.79) 3 0/93 NE 1 3/318 0.94 (0.84, 1.05) 2 Warfarin 192/2919 8.1 (7.88, 8.32) 9 1052/2930 39.36 (38.69, 40.02) 9 39/2056 1.9 (1.84, 1.96) 3 28/3407 0.82 (0.79, 0.85) 8 Fonda 23/452 9.3 (7.93, 10.67) 2 45/361 12.47 (12.12, 12.81) 1 3/517 0.58 (0.51, 0.65) 1 12/601 2 (1.88, 2.11) 2 Riva 25/2087 1.2 (1.15, 1.24) 3 169/1846 18.55 (16.47, 20.63) 3 19/2784 0.68 (0.65, 0.71) 3 17/2848 0.6 (0.57, 0.63) 3 Dabi 77/2288 3.37 (3.32, 3.41) 4 710/2285 30.98 (30.42, 31.55) 4 5/1371 0.36 (0.32, 0.41) 2 29/3110 0.93 (0.89, 0.98) 4 Placebo 88/296 27.12 (24.54, 29.7) 4 205/398 55.19 (53.53, 56.84) 5 15/51 29.41 (28.16, 30.66) 1 9/365 2.47 (2.31, 2.62) 4 Total 724/15596 50 4469/15784 57 164/11774 22 187/18457 49 LMWH Low molecular weight heparin, UFH unfractionated heparin, Riva Rivaroxaban, Dabi Dabigatran etexilate Disclosures Lazo-Langner: Boehringer Ingelheim: Honoraria. Rodger:Bayer: Research Funding; Leo Pharma: Research Funding; Pfizer: Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Biomerieux: Research Funding; GTC Therapeutics: Research Funding.

Abstract 3984 Poster Board III-920 Background Exercise training is an effective treatment for lower limb arterial claudication and may also have the potential to improve the post-thrombotic syndrome (PTS). Objectives We conducted a randomized, allocation concealed, controlled, assessor-blinded multicenter pilot trial to provide preliminary data on the effectiveness of a 6-month exercise training program in improving the PTS. Methods Patients aged 18-75 years with unilateral DVT diagnosed >6 months previously and ipsilateral PTS (Villalta criteria) were screened for participation in the trial at 2 centres in Canada (Montreal & Ottawa). Eligible, consenting patients were randomized to Active Training (AT) , a 26-week trainer-supervised program consisting of leg strengthening, leg stretching and aerobic exercise, or Attention Control (AC) , a 1-hour presentation on PTS + monthly phone follow-ups. Participants had study visits at Baseline (T0), 3 mths (T3) and 6 mths (T6) to measure generic (SF-36) and venous disease-specific (VEINES-QOL) quality of life (QOL), PTS severity (Villalta scale), leg strength (number of heel lifts) and leg flexibility (stretch angle, in degrees, for quadriceps, hamstring, gastrocnemius and soleus muscles). Within-subject changes from T0 to T6 were compared in AT vs. AC using repeated measures two-way ANOVA. Results From 2007-2008, 43 patients were recruited (21 randomized to AT, 22 to AC). Mean age was 47 years, 44% were male, and 49% had moderate or severe PTS. At 3 and 6 mths, PTS severity category improved in 65% of AT vs. 26% of AC (p=0.02) and 61% of AT vs. 46% of AC (p=ns), respectively. Other results are shown in Table (for all outcomes except Villalta score, + change signifies improvement from T0 to T6). Outcome measure Active Training Within subject change, T6-T0, Mean (SD) Attention Control Within subject change, T6-T0, Mean (SD) Between-group (AT vs. AC), within subject difference, T6- T0, Mean (95% CI) P value for interaction between treatment group and time P value, age and sex adjusted VEINES-QOL score 6.0 (5.1) 1.4 (7.2) +4.6 (0.54, 8.7) 0.027 0.052 SF-36 Physical Component Score 5.6 (7.7) 0.2 (7.6) +5.4 (0.5, 10.4) 0.03 0.09 Villalta score -3.6 (3.7) -1.6 (4.3) -2.0 (-4.6, 0.6) 0.14 0.12 Number heel lifts 5.2 (10.6) -2.5 (10.6) +7.7 (0.7, 14.7) 0.03 0.04 Stretch angle quadriceps (°) 10.2 (20.5) 0.3 (6.6) +9.9 (-1.0, 20.7) 0.04 0.04 Stretch angle hamstring (°) 2.7 (11.0) -3.7 (22.7) +6.4 (-5.8, 18.5) 0.29 0.47 Stretch angle gastroc (°) 4.6 (8.0) 2.3 (8.9) +2.2 (-3.4, 7.8) 0.43 0.35 Stretch angle soleus (°) 3.3 (10.7) 2.6 (8.5) +0.7 (-5.7, 7.0) 0.83 0.88 Conclusion In our pilot trial, exercise training improved PTS severity, QOL, leg strength and leg flexibility in patients with PTS. Exercise training appears to be a promising modality to treat PTS, and a large, adequately powered trial is warranted. Funded by Canadian Institutes of Health Research Disclosures: No relevant conflicts of interest to declare.

Background: Clinical outcome studies have shown that it is safe to withhold anticoagulant therapy in patients with suspected pulmonary embolism (PE) who have a negative D-dimer result and a low pre-test probability (PTP) either using a PTP model or clinical gestalt. Purpose: To assess the safety of the combination of a non-high PTP using the Wells or Geneva models with a negative VIDAS© D-dimer result to exclude PE. Data Source: A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews. Study Selection: Seven studies (6 prospective management studies and 1 randomized controlled trial) reporting failure rates at three months were included in the analysis. Non-high PTP was defined has “unlikely” or “low/intermediate” PTP using either, the Wells’ score, the Geneva, Revised Geneva Score, or gestalt estimation. Data extraction: Two reviewers independently extracted data onto standardized forms. Data Synthesis: A total of 5,622 patients with non-high PTP were assessed using the VIDAS© D-dimer. PE was ruled out by a negative VIDAS© D-dimer test in 40% (95% confidence intervals (CI) 38.7 to 41.2%) of patients. The three-month thromboembolic risk in patients left untreated was 0.14% (95% CI 0.05 to 0.4%). Table 1. Accuracy Indices Total non-high PTP and negative VIDAS© D-Dimer Wells’ “unlikely” PTP and negative VIDAS© D-dimer Geneva* “low/intermediate” and negative VIDAS© D-dimer Number of patients 5,622 2,017 3,208 Sensitivity (%, 95% CI) 99.7 (99.0– 99.9) 98.7 (96.2– 99.6) 100.0 (99.4–100) Specificity (%, 95% CI) 47.4 (46.0– 48.9) 57.3 (55.0– 59.6) 40.8 (38.9– 42.7) NPV (%, 95% CI) 99.9 (99.6– 100) 99.7 (99.1– 99.9) 100.0 (99.6– 100) Conclusion: The combination of a non-high PTP with a negative VIDAS© D-dimer result, effectively and safely exclude PE in an important proportion of outpatients with suspected PE.

Background: The optimal duration of anticoagulation treatment in patients with unprovoked VTE is unknown. In order to counsel VTE patients on the risks and benefits of discontinuing anticoagulants, clinicians need to balance the long-term risk of recurrent VTE with major bleeding on anticoagulants. For all VTE patients on oral anticoagulant, the case-fatality rate of major bleeding was previously reported to be 13.4% (95% confidence intervals (CI): 9.4% to 17.4%). A major knowledge gap exists regarding the case-fatality rate of recurrent pulmonary embolism (PE) during and following anticoagulation therapy for VTE. Purpose: To summarize the case fatality rate of recurrent VTE during and following anticoagulation therapy. Data Source: A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews. Study Outcome: We selected 62 studies that reported the rates of fatal PE in patients with recurrent VTE. Fatal PE was defined as confirmed autopsy report; death preceding with confirmed deep vein thrombosis (DVT) or non-fatal PE; sudden death not explained by a condition other than PE. Measurements: Pooled case fatality rates were generated. Ninety-five percent CI were calculated for each case fatality rate using averaged, inverse variance-weighted estimates from each study. Data Synthesis: 30,885 VTE patients were included (17,650 DVT, 8801 PE and 4434 DVT or PE Limitations: Unable to determine the case fatality rate by etiology of VTE (i.e. provoked, unprovoked). Conclusion: Case fatality rates for recurrent VTE are elevated during and following anticoagulation treatment for VTE but appear lower than the case-fatality rate for major bleeding with oral anticoagulants. This information must be considered by clinicians when counseling patients on whether to continue or discontinue anticoagulant therapy following VTE. Not only must absolute recurrent VTE and major bleeding rates be compared between groups that continue and discontinue anticoagulants but the relative consequences (i.e. case fatality rates) must be also considered with more weight placed on major bleeding episodes. Initial event During anticoagulation Treatment (%, 95% CI) Following anticoagulation Treatment (%, 95% CI) DVT 10.6 (8.3–13.0) 7.3 (5.0–9.7) PE 12.3 (5.9–18.7) 12.5 (6.4–28.7) Any event 10.2 (7.9–12.5) 9.0 (7.3–10.8)

Introduction: Venous thromboembolism (VTE) is a serious and sometimes fatal condition, encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE). Evidence suggests that major orthopaedic surgery, such as total hip replacement (THR) and total knee replacement (TKR), is associated with a high risk of postoperative VTE. Because of this risk, the American College of Chest Physicians (ACCP) guidelines recommend that these patients receive prophylaxis with anticoagulant therapy. However, the degree to which these guidelines are followed in routine practice is variable. In addition, few studies have documented the relationship between the variability in guideline alignment and VTE rates. Therefore, a retrospective database analysis was conducted to determine the extent to which the ACCP guidelines for VTE prophylaxis are followed after THR/TKR and evaluate the incidence of VTE of those who received ACCP recommended prophylaxis according to the guidelines (‘ACCP’) and those who did not (‘non-ACCP’). Methods: In order to fully evaluate VTE prophylaxis patterns and outcomes, patients should be followed from the time of surgery through to hospital discharge and subsequently to care in the community. To our knowledge, a single database that captures this information for a specific patient in these three phases is not yet available. Therefore, a claims database associated with a large US health plan was linked to the Premier database, which provides details of inpatient medication use. Patients age ≥18 years undergoing TKR/THR between April 1, 2004 and December 31, 2007 and enrolled in the health plan 90 days prior to and 90 days following discharge from index hospitalization (or until death) were included in the analysis. Patients were considered to have received ACCP-guideline prophylaxis if they: initiated prophylaxis in hospital with LMWH, fondaparinux, or VKA initiated prophylaxis within one day of surgery (for THR patients) and were prescribed prophylaxis for a minimum of ten days, or until the occurrence of a bleeding event, a VTE-related event, or death. In addition, the number of DVTs and PEs occurring in ACCP and non-ACCP patients was recorded. Multivariate logistic regression was used to assess whether there was a significant relationship between ACCP guideline prophylaxis and the probability of a DVT or PE following THR/TKR. Results: Of the 30,644 eligible patients from the health plan, 3,497 patients could be linked to the inpatient database. Except for geographic indicators, there were no significant differences in patient demographics or baseline co-morbidities between those included and excluded from the final study sample. Of the 3,497 linked patients, 1,395 received ACCP guideline prophylaxis (40%). The number of DVTs occurring in the ACCP and non-ACCP groups were 27 and 62, respectively. Thus, 2.01% of ACCP and 3.76% of non-ACCP patients have a DVT following surgery and up to the end of 90-day followup (p=0.0521), suggesting that non-ACCP patients were almost twice as likely as ACCP patients to have a DVT. The number of PEs occurring in the ACCP and non-ACCP groups were 2 and 25, respectively. Thus, 0.14% of ACCP and 1.19% of non-ACCP patients experienced a PE following the date of surgery and up to the end of 90-day follow-up (p Conclusions: By following patients from surgery through to care in the community, this study offers a unique perspective on ‘real-world’ prophylaxis patterns and clinical outcomes related to such patterns in THR and TKR patients. It suggests that: only 40% of THR/TKR patients receive prophylaxis that is in alignment with ACCP guidelines and that patients receiving prophylaxis according to the ACCP guidelines were less likely to have a DVT or PE than those not receiving ACCP guideline prophylaxis, the latter were almost twice as likely to have a DVT and more than eight times as likely to experience a PE.

Introduction: Cancer patients with venous thromboembolism (VTE) are at high risk of treatment failures (i.e. recurrent VTE while on therapeutic anticoagulants). Management of these treatment failures is controversial/poorly studied. Whereas some clinicians recommend inferior vena cava (IVC) filter insertion, others do not. We sought to assess the efficacy and safety of escalating the dose of low-molecular weight heparin (LMWH) in the management of treatment failure recurrent VTE in cancer patients. Methods: Retrospective cohort study of outpatients with cancer and treatment failure recurrent VTE seen at the Ottawa Hospital Thrombosis Unit from January 2007 to June 2008. Patients were followed for three months following the treatment failure event. Results: Thirty cancer patients had recurrent VTE despite ongoing anticoagulation. The mean age was 60.7 years. Twenty two patients (73.3%) were on LMWH treatment at the time of the recurrent event. Of these 22 patients, 4 (18.2%) were on full (100%) therapeutic doses, 15 (68.2%) on 75% of therapeutic doses and 3 (13.6%) on prophylactic doses of LMWH. All 4 patients on full therapeutic dose were treated by increasing the weight-adjusted dose of LMWH by 20% for 6 weeks. Patients on 75% of therapeutic doses were treated by increasing the weight-adjusted LMWH by 25% for 6 weeks (4/15 patients) or 3 months (11/15 patients). All three patients on prophylactic doses were treated with one month of full therapeutic doses of LMWH followed by 75% thereafter. No patients had an IVC filter inserted or a major bleeding episode. One patient had a minor bleeding episode (4.5%; 95% CI: 1.1–21.9%), 2 patients died (9.1%; 95% CI: 2.8–28.0) (no VTE-related death) and one patient (4.5%; 95% CI: 1.1–21.9%) had a second treatment failure event during the three-month follow-up period while on full therapeutic doses of LMWH. Eight patients (26.7%) were on vitamin-K antagonist at the time of the recurrent VTE due to treatment failure. Five (62.5) patients had a therapeutic INR on the day of the recurrent VTE. All patients were treated with LMWH at full doses for a month followed by 75% thereafter. One patient (12.5%; 95%CI 2.8–48.3) had a minor bleeding episode during follow-up. Conclusion: Escalading the dose of LMWH following a recurrent VTE due to treatment failure seems to be a safe and effective method to prevent further recurrence in cancer patients. Our data challenges the concept of using IVC filters in this setting.

Introduction: Initiation of warfarin therapy is a clinical challenge. A 10 mg warfarin initiation nomogram was recently validated in a randomized controlled trial. We sought to determine the efficacy and safety of this 10 mg warfarin initiation nomogram in “real-life” daily practice. Methods: A retrospective cohort including all outpatients beginning concurrent treatment with warfarin and low-molecular-weight-heparin (LMWH) over a 24 month period in our Thrombosis Unit was reviewed. Results: 841 patients were included, of them 640 (76.1%) were started on the nomogram. The nomogram was entirely followed in 324 patients (38.5%). The efficacy and safety profile was similar to that observed in the original clinical trial: 86% of patients managed according to the nomogram reached the INR target of 2.0 to 3.0 within 5 days. Mean duration of LMWH treatment was 6.0 ± 1.9 days, and 3.7% of patients had an INR ≥ 5.0 in the first four weeks of treatment. Conclusion: The 10-mg nomogram effectively results into an early therapeutic INR with a good safety profile in “real life” daily practice.

Introduction: Rivaroxaban is a novel, oral, direct Factor Xa inhibitor under regulatory review for prevention of venous thromboembolism (VTE) after total hip and knee replacement surgery. The efficacy and safety of rivaroxaban for VTE prevention following total hip replacement (THR) was assessed in two, large, randomized, controlled trials. RECORD1 compared rivaroxaban (10 mg once daily) with subcutaneous (sc) enoxaparin (40 mg once daily) over 35 days. The primary outcome (deep vein thrombosis, non-fatal pulmonary embolism, and all-cause mortality) occurred in 1.1% of rivaroxaban patients and in 3.7% of enoxaparin patients (RRR 70%; p Methods: An economic model was developed to assess the cost-effectiveness of rivaroxaban versus both durations of enoxaparin after THR in Canada. The analyses were conducted from the perspective of the Ontario (Canadian) Ministry of Health. The incidence of clinical events and their consequences on resource use and quality of life (QoL) were modeled for rivaroxaban and enoxaparin over five years. The incidence of VTE during the period of prophylaxis was based upon RECORD1 and RECORD2, and the incidence of VTE up to 90 days following surgery was extrapolated based on epidemiological data (Quinlan et al., 2007). The incidence of recurrent VTE and post-thrombotic syndrome (PTS) beyond this period was based on clinical data (Prandoni et al., 1997). To calculate resource use we assumed that 19% of patients receiving enoxaparin prophylaxis and those eventually treated for VTE on an outpatient basis would require daily home nursing visits to administer the injections (Harrison et al., 1998). This is likely to be an underestimate in light of other studies and clinical experience of VTE practice in Canada. The costs associated with clinical events (major bleed, VTE and PTS) and home visits was derived from published Canadian sources and expressed in Canadian dollars (C$). Rivaroxaban and enoxaparin costs were included. Utility values, used to demonstrate the impact of clinical events on QoL, were also derived from published literature (Haentjens et al., 2004; Rasanen et al., 2007). Results: When rivaroxaban and enoxaparin were both administered for 35 days, rivaroxaban was associated with improved clinical outcomes and an average cost saving of C$282.58 per patient. Savings were driven mainly by reduced outpatient administration. Sensitivity analyses showed that rivaroxaban remained more effective and less expensive than enoxaparin in more than 98% of the simulations. When 35 days’ rivaroxaban were compared with 10–14 days enoxaparin, rivaroxaban cost an extra C$90.34 per patient. However, when the improved efficacy with rivaroxaban compared with the 10–14 day enoxaparin regimen was adjusted for QoL, rivaroxaban produced a gain in quality adjusted life years (QALYs) of 0.0027. This translates to an incremental cost per QALY of C$33,323, which is below the commonly-referenced threshold of C$50,000/QALY. Another frequently used VTE prophylaxis in Canada is Fragmin. As Fragmin has a similar efficacy and safety profile to enoxaparin, and has a higher price than enoxaparin in Canada, rivaroxaban is even more cost-effective versus Fragmin. Conclusions: Rivaroxaban is cost-effective versus 10–14 days’ and 35 days’ enoxaparin for the prevention of VTE following THR in Canada. This is driven by improved efficacy, with respect to clinical event costs and QoL, and the reduction in home nurse visits with use of oral rivaroxaban.

Background: Identifying previously undiagnosed malignancy in patients with newly diagnosed venous thromboembolism (VTE) is important. Malignancy screening can potentially diagnose more cancers and at earlier stage, thereby preventing malignancy associated morbidity and perhaps mortality. Purpose: To summarize the period prevalence of previously undiagnosed malignancy at baseline (within 1 month of VTE diagnosis), 6 and 12 months following VTE. To quantify the additional value of an “extensive” malignancy screening strategy at baseline compared to a more “limited” screen (history, physical exam and simple widely available tests) at baseline. Data Source: A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews. Study Selection: We selected 36 studies that reported the prevalence of undiagnosed malignancies at baseline, at 6 and 12 months. Fourteen articles and one abstract also met inclusion criteria for the assessment of “extensive” versus “limited” malignancy screening. Data extraction: Two reviewers independently extracted data onto standardized forms. Data Synthesis: The period prevalence of previously undiagnosed malignancy in patients with unprovoked VTE is 6.1% (95% confidence intervals (CI): 5.0 to 7.1) at baseline and 10.0% (95% CI: 8.6 to 11.3) from baseline to 12 months. An “extensive” malignancy screening strategy using computed tomography of the abdomen/pelvis significantly increases the proportion of previously undiagnosed malignancy detected from 49.4% (95% CI: 40.2 to 58.5) (limited screening alone) to 69.7% (95% CI: 61.1 to 77.8) in patients with unprovoked VTE. Limitations: Unable to determine complication rates, cost-effectiveness and difference in morbidity and mortality associated with “extensive” screening strategies. Conclusion: Previously undiagnosed malignancies are frequent in patients with unprovoked VTE. Malignancy screening using an “extensive” screening strategy detects more malignancies compared to a limited screening strategy. Computed tomography of the abdomen/pelvis should be considered in the diagnostic work up of previously undiagnosed malignancy in patients with unprovoked VTE.

Warfarin is the most widely used anticoagulant for the treatment of conditions such as deep vein thrombosis and pulmonary embolism. Warfarin has a narrow therapeutic index, and individual patient response to the drug is highly variable. Models to predict the maintenance dose have been published but not validated in independent populations (Kamali et al, Sconce et al, and Gage et al). Most of the prior data was derived in patients with atrial fibrillation and these may not be applicable to our predominantly ambulatory VTE population. The prior models incorporate a variety of factors that have been predicted to have an effect on warfarin dosing, such as age, height, and polymorphisms in the vitamin K epoxide reductase complex subunit 1 (VKORC1) and cytochrome P450 (CYP450) 2C9 enzyme. We enrolled 51 consecutive VTE patients on stable doses of warfarin as defined in the prior studies. As in those studies we excluded patients with known or suspected non-compliance, known liver disease and known congestive heart failure. All previously suggested predictive variables were collected. Mean warfarin dose, mean INRs, and gene polymorphisms were determined by previously described standard methods. In addition we are testing the recently identified coding VKORC1 Asp36Tyr polymorphism which predisposes to warfarin resistance. This study aimed to examine the accuracy of three previous models to predict individual warfarin dosing in pursuit of the development of a more accurate regression model. Preliminary results with the first 51 patients, through correlation analysis, indicate that none of the previous models provide an accurate prediction of warfarin maintenance dose. The mean maintenance dose of the patient population was 6.23mg. The doses predicted by the previous models were significantly lower at 4.4mg, 5.3mg, and 4.5mg for Kamali, Gage, and Sconce, respectively. The Pearson correlation coefficients were 0.047, 0.27, and 0.50, respectively. A preliminary model has been developed with a Pearson correlation coefficient of r=0.78, and a p-value

Background: The incidence of venous thromboembolism (VTE) following hematopoietic stem cell transplantation (HSCT) is not well described, particularly with the emerging trend towards increased ambulatory care in the transplant setting. HSCT involves high dose chemotherapy and/or radiation and is often associated with periods of immobilization. In addition, vascular damage and inflammation are common following transplantation and may further increase the risk of VTE. We sought to quantify the incidence of VTE in both allogeneic and autologous HSCT recipients and characterize the factors influencing these events. Methods: A retrospective analysis involving 589 patients (382 autologous, 207 allogeneic recipients undergoing transplantation between 2000–2005) was performed in order to identify the incidence of symptomatic acute deep proximal vein thrombosis (DVT) or pulmonary embolism (PE) in HSCT recipients. Only patients who provided signed informed consent regarding the utilization of their medical information for research purposes were included. All diagnostic imaging reports of CT pulmonary angiography, ventilation / perfusion (VQ) scanning and duplex ultrasound of the upper and lower extremities performed within the first year after HSCT were reviewed. A diagnosis of VTE was confirmed by reviewing the clinical record and verifying a moderate to high pre-test probability according to the Wells’ criteria. Non-catheter related events were the designated primary outcome. Symptomatic catheter-related events (superficial and deep veins) were secondary outcomes. Statistical analysis included comparison of mean values using Student’s t test and comparison of proportions using the chi squared analysis. Results: A total of 7 patients developed VTE following HSCT unrelated to central venous catheters (4 PE and 3 DVT) for an incidence of 1.2%. A total of 5 patients had VTE events in the allogeneic group (2.4%) and 2 autologous recipients suffered VTE events (0.52%, p=0.043). An increased number of PEs occurred in the allogeneic group compared with autologous recipients (4 vs 0, p=0.006). Symptomatic catheter-related thrombosis (superficial and deep venous occlusion combined) was not different between the allogeneic and autologous groups (7.25% vs. 5.50%, p= 0.4). Three allogeneic recipients (60%) had GVHD at the time of VTE diagnosis and only 1 patient had relapsing disease (20%) while both patients in the autologous cohort (100%) had progression of their disease at the time of VTE diagnosis. All VTE events unrelated to central venous catheters occurred after hematopoietic engraftment with a trend towards earlier occurrence in the allogeneic setting compared to autologous recipients (mean 153 days vs. 312 days, respectively, p=0.080). The mean platelet count at the time of VTE was 121 (50–174). Conclusion: HSCT patients have a high incidence of non-catheter related VTE compared to historical reports of the general and cancer populations. Allogeneic recipients have an increased risk of VTE and of PE in comparison to autologous transplant patients. VTE occurred exclusively in HSCT patients after hematopoietic recovery. Perhaps thrombocytopenia and the emphasis on ambulatory patient status in our program were protective against the development of VTE. Our study supports the notion that GVHD may contribute to the development of VTE in allogeneic transplant recipients. Moreover, progression of the underlying malignancy may be a dominant risk factor in the development of VTE in autologous recipients.

AC proph after OS results in a decrease in the incidence of VTE with an associated increase in the risk of major bleeding (MB). Several AC agents and schedules are used; however the optimal timing of initiation has not been determined. It is likely that the proximity to the time of surgery might influence both the efficacy and safety of the AC thus altering their risk-benefit profile. Using a clinical cost-effectiveness approach we compared different AC and timings of VTE proph in patients undergoing OS. A meta-analysis of 55 randomized trials was done to estimate the risk (MB) and benefit (averted VTE) of proph in OS using placebo (plac) or different AC (ximelagatranxim, low molecular weight heparin-LMWH, unfractionated heparin-UFH, warfarin-warf and fondaparinux-fonda) and timings of initiation (defined as preoperative (preop) if the first dose of the AC was administered >2 hrs before surgery, perioperative (periop)if between 2 hrs before or up to 12 hrs after the surgery and postoperative (postop) if starting 12 hrs or more after surgery). Means and variances of the MB and VTE estimates were used to parameterize Monte Carlo simulations for a beta distribution using 1,000 replications. Incremental risk, benefit and risk-benefit ratios (compared to placebo) were calculated from the replications. All AC/timing combinations were compared across a range of benefit-risk tradeoff values (risk acceptance) by calculating the percentage of replications with the highest net clinical benefit (NCB; e.g. incremental benefit - incremental risk · tradeoff) for each AC/timing combination. A higher NCB represents a better risk-benefit profile. In addition all anticoagulants were pooled together according to the initial timing of administration and NCB was calculated using random re-sampling of the replications. Analyses were done separately for major VTE (mVTE; proximal deep vein thrombosis (DVT) + pulmonary embolism), and total VTE (tVTE; mVTE + distal DVT) and a sensitivity analysis was done after excluding xim. The reference tradeoff was estimated from the case-fatality rate-ratios of VTE to MB (mVTE/MB=0.39; tVTE/MB=0.10). At the reference tradeoff value, the AC/timing combination with the highest probability of having the best risk-benefit profile was postop xim analyzed by both mVTE and tVTE (99 and 58%, respectively). After excluding xim the AC/timing combination of choice was postop LMWH if analyzed by mVTE (60%) or preop LMWH if analyzed by tVTE (59%). When all AC were pooled those administered postop had the highest probability of having the best risk-benefit profile analyzed by mVTE (48%) and the choice was indifferent between preop (45%) and postop (40%) if analyzed by tVTE. After excluding xim from the pooled analysis the choice was indifferent between preop (40%) and postop (35%) if analyzed by mVTE and if analyzed by tVTE the choice was preop (55%) followed by postop (27%). Our results suggest that: postop administration of AC proph has the best risk-benefit profile; the results are influenced by the event defining benefit (mVTE or tVTE); in some analyses preop administration was best, and; periop administration always had the worst risk-benefit profile. We conclude that periop AC proph after OS should not be used.

Background: Central venous catheters (e.g., PICC lines and Hickman-type catheters) in patients with cancer are associated with development of DVT in 1–3%. Patient management varies from immediate removal of the line, with or without anticoagulation, to the extreme of thrombolytic therapy. This multicenter cohort clinical trial was designed to assess the safety and effectiveness of a management strategy for central venous catheter-related UEDVT in cancer patients consisting of dalteparin and warfarin as a means of salvaging the line without the need for line removal. Methods: Patients greater than 18 years-of-age with an active malignancy and who had symptomatic, acute, objectively documented UEDVT were eligible. Patients were excluded if the catheter was a dialysis catheter, they had active bleeding or a high risk for major bleeding, platelet count 177μmol/l, if they were currently on therapeutic doses of warfarin, inability to infuse through the catheter after a trial of intraluminal thrombolytic therapy (2mg TPA), had AML or ALL or bone marrow/stem cell transplant planned in the next 3 months or if they did not provided written informed consent. Four centers in Canada participated. Patients were treated with dalteparin 200 IU/kg per day for 5–7 days and simultaneously initiated on warfarin with a target INR of 2.0–3.0. Patients were followed for 3 months for recurrent venous thromboembolism, major hemorrhage and survival of the central venous catheter. Results: There were 74 patients (48 males) enrolled from November 2002 to December 2005. The average age was 58 years. Seventy-one UEDVTs were diagnosed by ultrasound and three by CT. There were 57 PICC lines, 14 portacaths and 3 Hickman catheters. Sixty-four patients (86%) completed three-month follow-up. Of the 10 who did not, 7 died (6 due to cancer and 1 due to a major bleed) and 3 others were no longer evaluable (2 patients were treated with LMWH only and another patient had the line removed against protocol). There were no episodes of recurrent venous thromboembolism and 3 (4%) major bleeds. For the endpoint of line survival, 42 (57%) of the lines were in situ and still functional at three months. No lines were removed due to infusion failure or recurrence/extension of DVT. In the 32 patients who had line removal before the study three-month endpoint, 21 were due to the end of therapeutic need, 2 were due to infection and 9 for other reasons such as falling out, skin irritation, patient request, etc. Hence, 63 (85%) patients were able to maintain the central line until it was no longer needed, or for at least three months. For the 11 others, none were removed due to venous thrombosis or line failure. Conclusion: Treatment of UEDVTs secondary to central catheters in cancer patients with standard dalteparin/warfarin can allow the central line to remain in situ with little risk of line failure or recurrence/extension of the DVT.