ALBERT

Description: 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

Description: In lymphoma patients, treatment with chimeric CD20 monoclonal antibodies (rituximab) results in a depletion of normal and malignant B cells, persisting for 6 to 9 months. This B-cell depletion leads neither to a decrease in immunoglobulin levels nor an increase in the number of infectious complications. However, the effect of rituximab treatment on the immune responsiveness is unknown. In 11 patients with relapsed, low-grade lymphoma, we investigated the effect of rituximab treatment on the humoral immune response to 2 primary antigens and 2 recall antigens. After rituximab treatment, the humoral immune response to the recall antigens was significantly decreased when compared with the response before treatment. Already before rituximab treatment, none of these patients was able to mount a response to the primary antigens. These findings are relevant regarding the feasibility of rituximab in maintenance treatment and may also offer a rationale for the treatment of antibody-mediated autoimmune diseases with rituximab.

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 3796 Introduction: Systematic reviews have shown that subcutaneous low molecular weight heparins (LMWH) are at least as safe and effective in the treatment of venous thromboembolism (VTE) as intravenous unfractionated heparin (UFH). LMWH allows patients with VTE to be treated as outpatients. However, patients with pulmonary embolism (PE) are still systematically admitted to the hospital for a few days to avoid potential complications. Physicians are reluctant to discharge patients due to insufficient data supporting the safety of outpatient management of PE. This study evaluates the safety of outpatient treatment of acute PE at the Ottawa Hospital. Methods: This is a retrospective cohort study of consecutive patients presenting at the Ottawa Hospital with acute PE diagnosed between January 1, 2007 and December 31, 2008. PE was defined as an arterial filling defect on CTPA or a high probability V/Q scan. Patients diagnosed with PE during hospitalization, patients with chronic PE and patients in whom anticoagulation treatment was not initiated (e.g. palliative care patients, small clinical non-significant PE) were excluded from the analyses. Patients were managed as outpatients if they were hemodynamically stable, did not require supplemental oxygenation and did not have contraindications to low molecular weight heparin therapy. Results: In this cohort of 473 patients with acute PE, 260 (55.0%) were treated as outpatients and 213 (45.0%) were admitted to the hospital. The majority of the patients were admitted because of severe comorbidities (45.5%) or hypoxia (22.1%).No outpatient died of fatal PE during the 3 month follow-up period. At the end of follow-up, the overall mortality was 5.0% (95% CI: 2.7 to 8.4%). The rates of recurrent venous thromboembolism (VTE) in the outpatient group were 0.4% (95% CI: 0.0 to 2.1%) and 3.8% (95% CI: 1.9 to 7.0%) within 14 days and 3 months, respectively. The rates of major bleeding episodes were 0% (95% CI: 0 to 1.4%) and 1.5% (95% CI: 0.4 to 3.9%) within 14 days and 3 months, respectively. Four (1.5%) outpatients were admitted to hospital within the first 14 days because of progressive shortness of breath and pain, a pre-syncopal episode or heparin induced thrombocytopenia. Conclusion: A majority of patients with acute PE can be managed as outpatients with a low risk of mortality, recurrent VTE and major bleeding episodes. Outpatient treatment in PE is feasible and safe in uncomplicated patients. 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.

Description: In previous case control studies factor V Leiden and the prothrombin 20210A mutation have been associated with pregnancy loss, in particular recurrent and late (〉12 weeks of gestation) losses in women carriers1. The prognosis of a second pregnancy after an initial late pregnancy loss in women with inherited thrombophilia is uncertain; the live birth rate reported in different cohort studies varied from 11 to 98%2–4. This has led to a debate about whether low-molecular-weight heparin should be prescribed to women with thrombophilia and pregnancy loss, despite the absence of evidence about its effectiveness from placebo-controlled trials. We determined the live birth rate of the 2nd pregnancy following a first loss in a large family study that included patients with documented venous thromboembolism or premature atherosclerosis and carriership of the factor V Leiden or prothrombin 20210A mutations and their 1st degree relatives. Ectopic or terminated pregnancies and pregnancies lost due to known chromosomal abnormalities were excluded, as well as pregnancies during which anticoagulants were used. A total of 993 women (498 carriers) who had had 2809 pregnancies (1420 in carriers) were analyzed. After an early pregnancy loss in the 1st pregnancy, the live birth rate of the 2nd pregnancy was 77% (95%CI 62–87) in carriers and 76% (95%CI 57–89) in non-carriers. After a late pregnancy loss in the 1st pregnancy, the live birth rate of the 2nd pregnancy was 68% (95%CI 46–85) in carriers and 80% (95%CI 49–94) in non-carriers (OR 0.9, 95%CI 0.5–1.3). We conclude that the pregnancy outcome in women with either factor V Leiden or the prothrombin 20210A mutation is fairly similar to the outcome in women without these mutations. After a late pregnancy loss in the first pregnancy, the live birth rate in the second pregnancy tended to be somewhat lower for carriers than for non-carriers. The live birth rates for both carriers and non-carriers in this study was substantially higher than in some other cohorts, which may be due to the fact that the cohort was not selected based on obstetric indications. Given the observed favourable prognosis after a first pregnancy loss even in women with known thrombophilia and a late loss, low-molecular-weight heparin to improve pregnancy outcome should not be used before results from ongoing randomized placebo controlled trials have shown its effectiveness and safety.

Description: Key Points Estrogen-containing or progestin-only hormonal therapy is not associated with increased recurrent VTE risk in women on anticoagulant therapy. Abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/VKAs.

Description: We performed a randomized dose-ranging study, double-blind for rivaroxaban doses and open-label for the comparator (low-molecular-weight heparin followed by vitamin K antagonists) to assess the optimal dose of rivaroxaban for the treatment of deep vein thrombosis. A total of 543 patients with acute deep-venous thrombosis received rivaroxaban 20, 30, or 40 mg once daily or comparator. Treatment lasted for 84 days. The primary efficacy outcome was the 3-month incidence of the composite of symptomatic venous thromboembolic complications and asymptomatic deterioration in thrombotic burden as assessed by comparison of ultrasound and perfusion lung scanning at day 84 with baseline. The main safety outcome was the composite of major bleeding and clinically relevant nonmajor bleeding. A total of 449 (83%) of the 543 patients could be included in the per-protocol population. The primary efficacy outcome occurred in 6.1%, 5.4%, and 6.6% of the rivaroxaban 20-, 30-, and 40-mg treatment groups, respectively, and in 9.9% of those receiving standard therapy. The main safety outcome occurred in 5.9%, 6.0%, and 2.2% of the rivaroxaban 20-, 30-, and 40-mg treatment groups, respectively, and in 8.8% of those receiving standard therapy. These results with simple fixed-dose oral regimens justify phase 3 evaluations (www.ClinicalTrials.gov no.NCT00395772).

Description: Current guidelines discourage combined oral contraceptive (COC) use in women with hereditary thrombophilic defects. However, qualifying all hereditary thrombophilic defects as similarly strong risk factors might be questioned. Recent studies indicate the risk of venous thromboembolism (VTE) of a factor V Leiden mutation as considerably lower than a deficiency of protein C, protein S, or antithrombin. In a retrospective family cohort, the VTE risk during COC use and pregnancy (including postpartum) was assessed in 798 female relatives with or without a heterozygous, double heterozygous, or homozygous factor V Leiden or prothrombin G20210A mutation. Overall, absolute VTE risk in women with no, single, or combined defects was 0.13 (95% confidence interval 0.08-0.21), 0.35 (0.22-0.53), and 0.94 (0.47-1.67) per 100 person-years, while these were 0.19 (0.07-0.41), 0.49 (0.18-1.07), and 0.86 (0.10-3.11) during COC use, and 0.73 (0.30-1.51), 1.97 (0.94-3.63), and 7.65 (3.08-15.76) during pregnancy. COC use and pregnancy were independent risk factors for VTE, with highest risk during pregnancy postpartum, as demonstrated by adjusted hazard ratios of 16.0 (8.0-32.2) versus 2.2 (1.1-4.0) during COC use. Rather than strictly contraindicating COC use, we advocate that detailed counseling on all contraceptive options, including COCs, addressing the associated risks of both VTE and unintended pregnancy, enabling these women to make an informed choice.