ALBERT

Description: Background: Patients with cancer are at elevated risk for venous thromboembolism (VTE). Active cancer contributes a 4-7 fold increased risk for VTE; however, the incidence of VTE stratified by subpopulations of patients diagnosed with cancer, especially race/ethnicity, is uncertain. Objective: Describe the incidence of VTE among adult patients (age ≥ 18 years) with a cancer diagnosis in Oklahoma County, OK according to age, gender, race, and cancer type. Methods: In collaboration with the Centers for Disease Control and Prevention, we established a population-based surveillance system for VTE in Oklahoma County, OK between April 1, 2012-March 31, 2014 to estimate the incidences of first-time and recurrent VTE events. The Commissioner of Health made VTE a reportable condition and delegated surveillance-related responsibilities to the University of Oklahoma, College of Public Health. Active surveillance involved reviewing imaging studies (e.g., chest computed tomography and compression ultrasounds of the extremities) from all inpatient and outpatient facilities in the county and collecting demographic, treatment and risk factor data on all VTE case-patients. Patients were linked to the Oklahoma Central Cancer Registry. Any patient with a cancer diagnosis since 1997, excluding basal or squamous cell carcinoma, were included in the population-at-risk. Active cancer was defined as metastatic or a diagnosis ≤6 months before their VTE diagnosis. Poisson regression was used to estimate incidence rates (IRs) and 95% confidence intervals (CIs), which are reported per 1,000 person years (PY). Estimates with

Description: Thromboprophylaxis with enoxaparin after total knee replacement is an evidence-based recommended standard of care. The ADVANCE-1 clinical trial was a phase III randomized double-blind multicenter study that evaluated the efficacy and safety of apixaban, an oral direct factor Xa inhibitor, 2.5 mg orally bid compared with enoxaparin 30 mg subcutaneously every 12 hours for preventing venous thromboembolism after total knee replacement. Apixaban (or oral placebo) and enoxaparin (or subcutaneous placebo) were begun 12 to 24 hours post-operatively (mean 20 hours) and continued until mandatory bilateral venography was completed at 12± 2 days. The primary efficacy outcome was the composite of deep-vein thrombosis (DVT) by venography; symptomatic, objectively confirmed DVT or pulmonary embolism (PE); or death from any cause during the treatment period. The secondary efficacy outcome was the composite of objectively confirmed proximal DVT or PE, or death. The primary safety outcome was bleeding, including major bleeding (defined by ISTH criteria), clinically relevant non-major bleeding, and minor bleeding. All outcome events were interpreted by a central independent adjudication committee without knowledge of treatment. The study hypothesis was that apixaban would be as effective as enoxaparin based on a pre-specified non-inferiority margin in which the upper limit of the two-sided 95% CI is 〈 1.25 for relative risk and 〈 5.6% for the absolute risk difference for the primary efficacy outcome. A total of 3195 patients from 129 sites in 14 countries were randomized. The primary efficacy outcome occurred in 104 of 1157 patients (8.99%) given apixaban and in 100 of 1130 (8.85%) given enoxaparin (relative risk 1.02, 95% CI 0.78 to 1.32, one-sided p= 0.064 for non-inferiority, statistical criteria not met). The secondary efficacy outcome occurred in 26 patients (2.05%) given apixaban and in 20 patients (1.64%) given enoxaparin. Symptomatic PE occurred in 16 patients (1.0%) who received apixaban (2 fatal) and in 7 patients (0.44%) given enoxaparin (0 fatal); the majority of the PE in apixaban patients occurred within 48 hours postoperatively. Major or clinically relevant non-major bleeding occurred in 46 of 1596 patients (2.88%) given apixaban, compared with 68 patients (4.28%) given enoxaparin (absolute difference 1.46%, two-sided p=0.034). Major bleeding occurred in 11patients (0.69%) who received apixaban and in 22 patients (1.39%) who received enoxaparin (two-sided p=0.053). Elevated levels of liver transaminase enzymes were uncommon (2% to 3%) in both groups; no patient given apixaban met Hy’s criteria. Myocardial infarction or stroke occurred in only one patient who received apixaban (0.06%) and in 5 patients (0.31%) given enoxaparin. The lower-than-expected incidence of the primary efficacy outcome in the enoxaparin group resulted in an undersized study to meet the pre-defined statistical criteria for non-inferiority in spite of a similar incidence with the apixaban regimen. This is the first phase III trial to demonstrate a potential advantage of the new oral anticoagulants for bleeding. The apixaban regimen resulted in less clinically relevant bleeding than enoxaparin 30 mg given every 12 hours. Maintaining this advantage while optimizing efficacy with an altered dosing regimen, either by earlier postoperative dosing or by a slightly increased dose, would be an important advance in patient care.

Description: Abstract 207 Background: The extent of deep vein thrombosis (DVT) is, for many physicians, an important variable that is considered in decisions on the type and duration of anticoagulant treatment. Although it has been consistently demonstrated that localization of the initial DVT is a powerful and independent predictor of recurrent venous thromboembolism (VTE) after discontinuation of anticoagulation (Baglin T et al. J Thromb Haemost 2010;8:2436–2442), it remains unknown to what extent localization of the initial DVT affects the occurrence of recurrent VTE while patients are on anticoagulation. Data from the EINSTEIN DVT study, which randomized 3,449 patients with proximal DVT, offers an opportunity to investigate this question. Aim: To investigate whether localization of the initial DVT was predictive of the rate of recurrent venous thromboembolic events in the whole cohort of patients in the EINSTEIN DVT study, in those who received rivaroxaban, or in those who received conventional anticoagulation with enoxaparin plus vitamin K antagonists (VKA) followed by VKA alone. Methods: Patients were randomized to rivaroxaban or enoxaparin plus VKA followed by VKA only for intended treatment durations of 3, 6, or 12 months. Patients were grouped into four categories according to the extent of the proximal vein thrombosis that was recorded at baseline: 1) popliteal vein alone; 2) popliteal and superficial femoral vein; 3) popliteal, superficial femoral, and common femoral vein; and 4) all combinations of DVT without popliteal vein involvement. Patients were followed for recurrent events. All baseline and recurrent events were assessed by a central independent adjudication committee that was unaware of treatment allocation. The effect of thrombus location on the incidence of recurrent VTE was assessed using a Cox proportional hazard model. Results: Recurrent VTE occurred in 21/1,040 (2.0%) patients with popliteal vein thrombosis only; in 28/1,002 (2.8%) patients with thrombosis located in the popliteal and superficial femoral vein; in 26/935 (2.8%) patients with thrombosis in the popliteal, superficial femoral, and common femoral vein (± iliac vein); and in 11/370 (3.0%) patients without popliteal vein involvement. None of these differences was statistically significant (p=0.87). The relative effect of rivaroxaban versus enoxaparin/VKA was similar in these subgroups (Table). Conclusions: At baseline, most patients in the EINSTEIN DVT study had thrombosis that involved more than one proximal vein. While patients were on treatment, the extent of the DVT at baseline was not predictive for recurrent VTE irrespective of type of treatment. Patients with extensive thrombosis (i.e. popliteal, superficial femoral, and common femoral vein involvement) had a recurrence rate below 3%, which was similar to the rate of recurrence in patients with thrombosis in only one vein at baseline. In summary, this analysis suggests that the localization and extent of the initial DVT was not predictive of the rate of recurrent venous thromboembolic events in the EINSTEIN DVT patient population while patients were on anticoagulation. Character count: 2670/3800 (spaces excluded) (2983 including table) Disclosures: Prins: Bayer HealthCare: Consultancy, Honoraria. Prandoni:GSK: Membership on an entity's Board of Directors or advisory committees. Lensing:Bayer HealthCare AG: Employment. van Bellen:Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Pap:Bayer HealthCare AG: Employment. Raskob:Bayer: Consultancy, Honoraria; Johnson & Johnson: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Boehringer-Ingelhiem: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Sanofi-Aventis: Consultancy, Honoraria. Büller:Sanofi-aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer HealthCare: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Abstract 192 Thromboprophylaxis after joint replacement surgery is evidence-based standard care. Usually, when thromboprophylaxis regimens with new anticoagulants have been more effective than existing standard practice they have also caused increased bleeding. Apixaban, a novel orally administered factor Xa inhibitor, has been evaluated in three phase 3 randomized, double-blind, double-dummy clinical trials (the ADVANCE studies) for the prevention of venous thromboembolism (VTE) after hip or knee replacement. A pre-specified aim of this program, in order to provide more precise estimates of the incidences of major VTE, bleeding, and the additional safety outcomes of myocardial infarction, stroke, and liver function, was to combine data from the two trials comparing apixaban 2.5 mg twice daily with the same enoxaparin regimen of 40 mg once daily (ADVANCE-2 and 3). Major VTE was defined a priori as the composite of adjudicated symptomatic or asymptomatic proximal deep-vein thrombosis (popliteal, femoral, or iliac vein thrombosis), non-fatal pulmonary embolism, and VTE-related death, counted if they occurred during the intended treatment period for each trial or within 2 days after the last dose of study medication, whichever was longer. The bleeding outcomes of major bleeding (adapted from ISTH criteria), clinically relevant non-major bleeding, and the composite of major and clinically relevant non-major bleeding, were counted if they occurred during the treatment period or within 2 days after the last dose of study medication. In both studies, subcutaneous enoxaparin (or placebo) was started 12±3 hours before operation, and resumed after surgery according to the investigator's standard of care, and oral apixaban (or placebo) was initiated 12 to 24 hours after wound closure (typically on the morning after surgery). Study medications were continued for 10 to 14 days after knee arthroplasty in ADVANCE- 2, and for 32 to 38 days after hip replacement in ADVANCE- 3. In both studies, mandatory bilateral venography was done at the end of the intended treatment period to assess the presence or absence of asymptomatic deep-vein thrombosis, and clinically suspected VTE was confirmed or excluded by objective testing. Patients were followed-up 30±5 and 60±5 days after the last dose of study medication. All venograms and all episodes of suspected VTE, bleeding, myocardial infarction, stroke, or death were adjudicated without knowledge of assigned treatment by an independent central adjudication committee. The site of bleeding was analysed as reported by the investigator. The pooled analysis was stratified by the type of joint replacement (hip or knee) for statistical calculations. A total of 8,564 patients were randomized in the ADVANCE-2 and 3 trials. Major VTE occurred in 23 of 3,394 evaluable patients (0.68%) in the apixaban group and in 51 of 3,394 (1.50%) evaluable patients in the enoxaparin group (absolute risk difference, -0.76%, 95% CI, -1.23% to -0.30%). Major bleeding occurred in 31 of 4,174 patients (0.74%) who received apixaban (18 occurred before the first dose) and in 32 of 4,167 patients (0.77%) given enoxaparin (absolute risk difference -0.02%, 95% CI, -0.40% to 0.35%). Major bleeding at the surgical site occurred in 26 apixaban and 27 enoxaparin patients (absolute risk difference -0.02%, 95% CI, -0.37% to 0.32%). The composite of major or clinically relevant non-major bleeding occurred in 182 patients (4.36%) given apixaban, compared with 206 patients (4.94%) given enoxaparin (absolute risk difference -0.58%, 95% CI, -1.49% to 0.32%); these bleeding events occurred at the surgical site in 135 (3.23%) apixaban patients, and in 155 (3.72%) enoxaparin patients (absolute risk difference -0.49%, 95% CI, -1.27% to 0.30%). Myocardial infarction or stroke during treatment or follow-up occurred in 13 patients (0.31%) in the apixaban group and in 10 patients (0.24%) in the enoxaparin group (absolute risk difference 0.07%, 95% CI, -0.15% to 0.30%). Elevated levels (〉3 times upper normal limit) of enzymes ALT or AST occurred in 2.2% and 2.8% of apixaban patients respectively, and in 3.0% and 2.8% of enoxaparin patients respectively. The apixaban regimen was more effective than enoxaparin 40 mg once daily for preventing major VTE, without increased bleeding, and has the clinical advantages of oral administration and later initiation 12 to 24 hours post-operatively. Disclosures: Raskob: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Johnson and Johnson: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda R and D: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy. Off Label Use: Apixaban is an experimental drug being evaluated in phase 3 clinical trials for the prevention and treatment of thromboembolic disease. Research reults will be discussed. Gallus:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Progen: Membership on an entity's Board of Directors or advisory committees. Pineo:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chen:BMS: Employment. Ramirez:BMS: Employment. Lassen:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Speakers Bureau; Sanofi Aventis: Consultancy; Astellas Pharma: Consultancy; GSK: Consultancy.

Description: Background Hospital discharge data have been used to estimate the burden of venous thromboembolism (VTE) disease. However, most of these databases are de-identified which limits their utility for estimating VTE incidence due to the inability to identify multiple hospitalizations for the same VTE event, and the inability to differentiate between first-time and recurrent VTE events. Objective We aimed to estimate the magnitude of error in estimates of VTE incidence derived from hospital discharge data by comparing the results obtained when patient identifying information is included, thus enabling us to remove duplicate patient events and stratify by first-time and recurrent VTE events, to the estimates obtained using only de-identified data. Methods In collaboration with the Centers for Disease Control and Prevention (CDC) and the Oklahoma State Department of Health (OSDH), we established a pilot surveillance system for VTE events in Oklahoma County, OK during 2012–2014. The OSHD Commissioner of Health made VTE events reportable conditions from 2010 to 2015 which facilitated our acquisition of hospital discharge data with patient identifiers for years 2010–2012 from the OSDH. The data included the inpatient, outpatient surgical, and ambulatory surgery center discharges. A deep vein thrombosis diagnosis was defined as the presence of any of the ICD-9-CM codes 451.1x, 451.81, 451.83, 453.2, 453.4x, 671.3x, and 671.4x. A pulmonary embolism diagnosis was defined as the presence of either of the ICD-9-CM codes 415.1x and 673.2x. Data were de-duplicated and linked across datasets using Link Plus software incorporating patient identifying variables. Duplicate events for the same person caused by hospital transfers were defined a priori as a second hospital admission with a VTE diagnosis code occurring within 72 hours of the previous discharge date with a VTE present on admission (POA) code for the second admission of “Yes” or “Unknown.” Potentially recurrent events were defined as two hospital admissions of the same patient ≥72 hours apart with a VTE diagnosis. Census Bureau estimates for 2010–2012 were used to define the population at risk in Oklahoma County. Incidence rates (IR) and 95% confidence intervals (CI) were calculated using the Poisson distribution and reported as events per 100,000 population per year. Rate differences and excess fractions were calculated to account for the contribution of recurrent and duplicate events to overall estimates and to differentiate between event-based incidence estimates and patient-based estimates. Results We identified 3,299 unique patients with VTE events. The overall event-based IR for VTE events was 249 (95% CI: 241–257). The IR for potentially recurrent events was 35 (95% CI: 32–38) and for duplicate events caused by patient transfers was 13 (95% CI: 11–14). Thus, the rate difference between event-based estimates and patient-based estimates was 48 (95%CI: 44–51) giving a patient-based IR for first-time events of 201 (95% CI: 194–208). The excess fraction was 19.2% (95% CI: 17.8%-20.5%), of which 14.1% (95% CI: 12.9%–15.2%) is attributed to potential recurrent events and 5.1% (95% CI: 4.4%–5.8%) is attributed to duplicate events caused by patient transfers. Conclusions Using event-based estimates for VTE disease resulted in an over-estimate of the incidence rate of first-time VTE events by up to 20%. Included in this excess estimate is the burden caused by potential recurrent events (14%) and duplicate events caused by patient transfers (5%). We designed our case definitions to accurately measure first-time events, and to capture all duplicate events and potential recurrent events. Assuming these data are representative of national trends, applying these excess fractions to estimates from de-identified data may improve the validity of measuring the incidence of first-time VTE events from de-identified hospital discharge data. Disclosures Bratzler: Centers for Disease Control and Prevention: Consultancy; Sanofi Pasteur: Consultancy. Raskob:Bayer Healthcare: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ISIS Pharmaceuticals: Consultancy, Honoraria.

Description: Abstract LBA-1 Background: Apixaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for extended treatment of venous thromboembolism. Objectives: To compare the efficacy and safety of two doses of apixaban (2.5 or 5 mg twice daily) with placebo for the extended treatment of venous thromboembolism in patients who have completed 6 to 12 months of prior anticoagulant therapy. Methods: This randomized, double-blind study (ClinicalTrials.gov number, NCT00633893) compared two apixaban doses (2.5 or 5 mg twice daily) with placebo for 12 months in patients with venous thromboembolism who had completed 6–12 months of anticoagulation. The primary efficacy outcome was symptomatic recurrent venous thromboembolism or all-cause mortality. Secondary efficacy outcomes included (a) the composite of symptomatic venous thromboembolism or venous thromboembolism-related death, and (b) the composite of symptomatic venous thromboembolism, venous thromboembolism-related death, myocardial infarction, stroke, or cardiovascular-related death. The primary safety outcome was major bleeding; the secondary safety outcome was major and clinically relevant non-major bleeding. Results: The study included 2486 patients: 829, 840, and 815 randomized to placebo, apixaban 2.5 mg, and apixaban 5 mg, respectively. Rates of the primary efficacy outcome were 11.6% in the placebo group, compared with 3.8% and 4.2% in the apixaban 2.5 mg and 5 mg groups, respectively (absolute risk differences of 7.8% and 7.4%, respectively; 95% confidence intervals 5.3% to 10.3% and 4.8% to 10%, respectively; p

Description: Initial management of patients with thrombotic thrombocytopenic purpura—hemolytic uremic syndrome (TTP-HUS) is difficult because of lack of specific diagnostic criteria, high mortality without plasma exchange treatment, and risks of plasma exchange. Although severe ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats) deficiency may be specific for TTP, the role of ADAMTS13 activity measurements for initial management decisions is unknown. ADAMTS13 was measured before beginning plasma exchange treatment in 142 (88%) of 161 consecutive patients with clinically diagnosed TTP-HUS with assignment to 1 of 4 categories: less than 5% (severe deficiency), 5% to 9%, 10% to 25%, and more than 25%. Eighteen (13%) of 142 patients had severe ADAMTS13 deficiency. Among 6 predefined clinical categories (stem cell transplantation, pregnant/postpartum, drug association, bloody diarrhea, additional/alternative disorder, idiopathic), severe deficiency occurred only among pregnant/postpartum (2 of 10) and idiopathic (16 of 48) patients. The presenting features and clinical outcomes of the 16 patients with idiopathic TTP-HUS who had severe ADAMTS13 deficiency were variable and not distinct from the 32 patients with idiopathic TTPHUS who did not have severe ADAMTS13 deficiency. Many patients in all ADAMTS13 activity categories apparently responded to plasma exchange treatment. Therefore, severe ADAMTS13 deficiency does not detect all patients who may be appropriately diagnosed with TTP-HUS and who may respond to plasma exchange treatment. (Blood. 2003;102:60-68)

Description: Background: Hospitalized medically ill patients are at risk for venous thromboembolism (VTE) for at least 45 days after discharge. This observation prompted the MAGELLAN and MARINER trials, which evaluated the efficacy and safety of rivaroxaban for extended thromboprophylaxis. In MAGELLAN, rivaroxaban (10 mg once daily) started in hospital and continued for 35 days was compared with a 10±4 day course of enoxaparin (40 mg once daily) followed by placebo. In MARINER, a 45-day course of rivaroxaban (10 mg once daily for those with creatinine clearance [CrCl] ≥50ml/min and 7.5 mg once daily for those with CrCl 30-