ALBERT

Description: Whether long-term use of vitamin K antagonists (VKAs) might affect the incidence of cancer is a longstanding hypothesis. We conducted a population-based study including all cancer- and thromboembolism-free patients of our health area; study groups were defined according to chronic anticoagulant use to VKA-exposed and control groups. Cancer incidence and cancer-related and overall mortality was assessed in both groups. 76 008 patients (3231 VKA-exposed and 72 777 control subjects) were followed-up for 8.2 (± 3.2) years. After adjusting for age, sex, and time-to-event, the hazard ratio of newly diagnosed cancer in the exposed group was 0.88 (95% confidence interval [95% CI] 0.80-0.98; P 〈 .015). VKA-exposed patients were less likely to develop prostate cancer, 0.69 (95% CI 0.50-0.97; P = .008). The adjusted hazard ratio for cancer-related and overall mortality was 1.07 (95% CI 0.92-1.24) and 1.12 (95% CI 1.05-1.19), respectively. These results support the hypothesis that anticoagulation might have a protective effect on cancer development, especially prostate cancer.

Description: Key Points Symptomatic extensions, whether or not reaching the SFJ, are common complications of SVT. Their frequency and associated risk of venous thromboembolic complications and medical resource consumption are reduced by fondaparinux.

Description: Abstract 171 Introduction: SVT is a common disease, associated with risks of clinically relevant venous thromboembolic complications. Currently, treatment of isolated SVT (i.e. without concomitant deep-vein thrombosis, DVT, or pulmonary embolism, PE) is based on analgesic agents, topical or oral nonsteroidal anti-inflammatory drugs, elastic stockings and occasionally surgery. Previous clinical trials have suggested the benefit of an extended antithrombotic therapy. Yet the optimal antithrombotic treatment remains unknown. Fondaparinux (Arixtra®) is a synthetic selective inhibitor of factor Xa with a favorable benefit-risk profile in the prevention and treatment of venous and arterial thrombosis in various medical and surgical settings. The large-scale, double-blind, randomized, placebo-controlled, CALISTO trial was designed to evaluate the benefit-risk ratio of fondaparinux 2.5 mg subcutaneously once daily during 45 days in 3000 patients with symptomatic, isolated SVT of the lower limbs documented by compression ultrasound (CUS). Methods: The study concerned male or female patients 18 years of age or greater with acute symptomatic isolated SVT of the lower limbs at least 5 cm long documented by standard CUS. After randomization (Day 1), subjects received fondaparinux 2.5 mg or placebo subcutaneously once daily up to Day 45. Study treatments were administered on an outpatient basis. Follow-up continued up to Day 75. Permitted medications included analgesic agents, topical non-steroidal anti-inflammatory drugs, graduated compression (elastic) stockings, aspirin at low dose (up to 325 mg per day) and other oral antiplatelet agents if the subject was receiving these drugs at the time of screening for a chronic medical condition. The primary efficacy outcome was confirmed symptomatic thromboembolic complications (a composite of PE, DVT, extension of SVT with thrombus head ≤3 cm from the saphenofemoral junction or recurrence of SVT) or all-cause death up to Day 45. Safety outcomes included major bleeding, clinically relevant non-major bleeding and death. All efficacy and safety outcomes were adjudicated by a central adjudication committee, unaware of treatment assignment. Results: The study started in March 2007 and inclusions were completed on May 15th 2009, with the recruitment of 3002 patients. The follow-up of the last patient was completed on July 31st 2009. Overall, on blinded preliminary data available on June 23rd 2009 (n=2994), the median age of patients was 58 [range: 19-92] years; 63.9% were women; 37.0% were obese (BMI ≥30 kg/m2). The main predisposing risk factors for SVT were varicose veins (88.6%) and a history of SVT (11.9%). More than one SVT was observed on baseline CUS in 19.2% of patients. The qualifying SVT predominantly involved the great saphenous vein alone (64.6% of patients). At Day 45, the overall incidence of adjudicated and adjudicated-pending symptomatic thromboembolic complications or death was 4.4% (Table). There was one adjudicated major bleeding. The final results according to treatment groups will be presented during the congress. Conclusions: There is an unmet medical need for an evidence-based anticoagulant treatment for isolated SVT. CALISTO is the first large randomized, controlled trial designed to establish standard anticoagulant therapy in patients with isolated SVT. It also provides a large database on the clinical characteristics of this disease. Disclosures: Décousus: GSK: Consultancy, Research Funding. Leizorovicz:GSK: Consultancy.

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 1161 Background Heterogeneity in clinical practices worldwide for Venous Thromboembolism (VTE) is a major challengs. This concern led us to establish international good clinical practices guidelines (GCPG) for the management VTE in cancer patients (pts). Methods Twenty-four international experts (WG) worked with the methodological support of the French Cancer institute (INCa). All studies on cancer, venous thromboembolism (VTE, pulmonary embolism PE), and anticoagulant drugs (AC) published from 1996 to 2011 were searched using MEDLINE®database. Studies quality was evaluated double-blind manner by the methodologists using the GRADE appraisal grids. Main study outcomes were rates of VTE, major and minor bleeding, thrombocytopenia and death. Extracted data were entered in evidence tables and validated by the WG. High A, Moderate B, Low C, Very low D levels of evidence depended on study design, limitations, inconsistency, indirectness, imprecision and publication bias. Guidelines were classified as Strong (Grade 1) or Weak (Grade 2) based on GRADE. If absence of scientific evidence, the WG consensus judgement was defined as Best Clinical Practice (BCP). The GCP were then evaluated by 45 independent experts worldwide and 3 pt representatives using a specific grid. Results in cancer pts A) For initial treatment of established VTE: low molecular weight heparin (LMWH) is recommended [1B], Fondaparinux and unfractionated heparin (UFH) can be also used [2D]. Thrombolysis may be considered on a case-by-case basis, with attention to contraindication (bleeding risk) [BCP], Vena Cava Filters (VCF) may be considered if contraindication to AC of PE recurrence under optimal AC with periodic reassessment of contraindications to AC.VCF are not recommended for primary VTE prophylaxis [BCP]. For early maintenance (10 days-3 mths) and long-term treatment (〉3 mths) of established VTE: LMWH are preferred over vitamin K antagonist (VKA) [1A]; LMWH should be used at least 3 mths After 3–6 mths, continuation of LMWH or VKA should be based on individual benefit-risk ratio [BCP]. If VTE recurrence, 3 options: switch from VKA to LMWH; increase in LMWH dose in pts treated with LMWH; VCF insertion [BCP]. B) To prevent postoperative VTE: LMWH once a day or low dose UFH 3 times a day are recommended; AC prophylaxis should start 12 to 2 hrs preoperatively and continued at least 7 to 10 days [ 1A]. No evidence support fondaparinux as an alternative to LMWH [2C]. The highest prophylactic dose of LMWH is recommended [ 1A]. Extended prophylaxis (4 weeks) after major laparotomy may be indicated if high VTE and low bleeding risks [2B]. For laparoscopic surgery, LMWH may be recommended as for laparotomy [BCP]. External compressions devices (ECD) are not recommended as monotherapy except if AC is contraindicated [ 2C]. C) In hospitalized medical cancer pts with reduced mobility, prophylaxis with LMWH UFH or fondaparinux [1B] is recommended. For ALL children and adults treated with L-asparaginase, depending on local policy and each pt prophylaxis may be considered [BCP]. In pts receiving chemotherapy, prophylaxis is not recommended routinely [1B]. Primary VTE prophylaxis VTE may be indicated for locally advanced or metastatic pancreatic [1B] or lung [2B] cancer pts treated with chemotherapy and having low bleeding risk. In pts treated by IMiDs with steroids and/or anthracycline, VTE prophylaxis is recommended: low or therapeutic VKA doses, LMWH at prophylactic doses and low-dose aspirin have shown similar effects [2C]. D) A brain tumor per se is not a contraindication to AC for established VTE [2C], for which we prefer LMWH [BCP]. LMWH or UFH are recommended postoperatively to prevent VTE in neurosurgery cancer pts [1A]. If creatinine clearance 50 G/L and no bleeding, full doses AC can be used for established VTE; if platelet 〈 50 G/L, treatment and dose depend on a case-by-case basis [BCP ]; if platelet 〉80 G/L, AC prophylaxis may be used and if 〈 80 G/L, only on a case-by-case basis [BCP]. In pregnant cancer pts, standard treatment for established VTE and prophylaxis should be implemented [BCP]. Conclusion Dissemination and implementation of international GCPG for the management of VTE, the second cause of death in cancer pts, is a major public health priority. Disclosures: No relevant conflicts of interest to declare.

Description: Background: Venous ulcer, the most serious consequence of chronic venous insufficiency (CVI), is associated with a high morbidity, impaired quality of life and high costs. To date, risk factors for venous ulcer after acute VTE have not been characterized. Objective: To identify independent predictors of venous ulcer development one year after an acute VTE event. Methods: Using data from the RIETE international registry, we analysed risk factors for venous ulcers in patients with an objectively confirmed symptomatic acute VTE (DVT and/or pulmonary embolism (PE)) and followed up for at least one year. During follow-up, signs and symptoms of CVI, occurrence of a venous ulcer in the leg ipsilateral to DVT or, in the absence of reported DVT, in any leg were reported by local investigators. Independent predictors of venous ulcers were assessed using a stepwise multivariable model. Results: Of the 34,144 patients included in the RIETE registry, 4,305 were recruited in centres participating in long-term (1 to 3 years) follow-up. Of these, 54% (n=2,337) underwent an assessment for CVI. After a mean (SD) follow-up of 383 (+/-575) days, 55% (n=1297) had signs or symptoms of CVI and 2.5% (n=59) had developed a venous ulcer. History of previous VTE (OR=4.4 [2.6 - 7.7], signs of venous insufficiency (i.e. leg varicosities) at time of VTE event (OR=2.3 [1.3 - 4.0]), diabetes (OR=2.0 [1.0 - 3.8]), obesity (OR=1.8 [1.1 - 3.2]) and male sex (OR=2.7 [1.5 - 4.9]) were independent predictors of an increased risk of venous ulcer. Conversely, older age, presence of an objectively confirmed DVT at study enrolment, anticoagulant duration (1 year), anticoagulant type (extended low molecular weight heparin vs. vitamin K antagonist), or presence of vena cava filter had no significant impact on risk of venous ulcer. When restricting our analysis to the 1790 patients with objectively confirmed DVT only, results remained similar in magnitude. Proximal character of DVT was associated with a 30% non-significant increased risk of - unquestionable - post-thrombotic ulcer but the proportion of distal DVT was low in our population (11%). Conclusions: After an acute VTE event, history of VTE, pre-existing signs of CVI, male sex, diabetes and obesity independently influenced the risk of venous ulcer. VTE therapeutic management (neither duration nor drugs) did not appear to modify this risk. Our results suggest that clinicians should consider strategies aimed to prevent ulcers in high risk patients, such as preventing VTE recurrence, use of compression stockings in those with CVI and encouraging weight loss in obese patients. Disclosures Galanaud: bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daichi: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bertoletti:Daichi: Honoraria; bayer: Honoraria; BMS-Pfizer: Consultancy, Honoraria. Monreal:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; boehringer: Consultancy, Membership on an entity's Board of Directors or advisory committees; daichii: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 543 Background A recurrence occurs in 15–20% of patients with unprovoked venous thromboembolism (VTE) in the two years after the withdrawal of oral anticoagulant treatment. Extending anticoagulant treatment is effective but associated with increased bleeding risk. We assessed the efficacy and safety of aspirin for the prevention of VTE recurrence after a conventional course of oral anticoagulation. Methods Warfasa was an investigator-initiated double-blind randomized placebo-controlled event-driven study. Patients with a first-ever unprovoked VTE who had completed 6–12 months of oral anticoagulant treatment were randomized to receive aspirin, 100 mg daily, or placebo for at least two years. The primary efficacy outcome was objectively confirmed recurrent symptomatic VTE and VTE-related death. Clinically relevant (major and non-major) bleeding were the main safety outcome. All outcome events were blindly adjudicated by an independent committee. Results A VTE recurrence occurred in 27 of the 205 patients who received aspirin and 42 of the 197 patients who received placebo (6.3% versus 11.0% patient-years; hazard ratio, 0.57, 95% CI 0.35 to 0.93) during the study period (mean 24 months) (Figure A). While on study treatment, 22 and 38 patients who received aspirin or placebo, respectively had a recurrence (5.7% versus 10.7% patient-years; hazard ratio, 0.54, 95% CI 0.32 to 0.91) (mean on-treatment period 22 months) (Figure B). One patient in each treatment group had a major bleeding, with a similar incidence of clinically relevant non-major bleeding. Conclusions Aspirin reduces by about 40% the risk of recurrence in patients with unprovoked VTE without increasing bleeding, when given after a 6–12 month anticoagulant treatment. For its safety, practicality and low cost, aspirin is a valid alternative to oral anticoagulants in the extended treatment of VTE. Disclosures: No relevant conflicts of interest to declare.

Description: Key Points The duration of anticoagulation after VTE is uncertain; this management study intended to identify patients with low/high recurrence risk. Patients with persistently negative D-dimers after stopping standard therapy have a low recurrence risk and can stop anticoagulation.

Description: Background: The optimal duration of anticoagulation after a first unprovoked venous thromboembolism (VTE) is uncertain. Anticoagulant therapy is highly effective at reducing the risk of recurrent VTE, but this clinical benefit is not maintained once anticoagulation is stopped. Current guidelines suggest considering indefinite anticoagulation in all patients with unprovoked who have a non-high bleeding risk. However, this is a weak recommendation based on limited evidence. Deciding whether patients with a first unprovoked VTE should be considered for indefinite anticoagulant therapy requires estimation of the long-term risk of recurrent VTE after stopping anticoagulation. This risk however, is poorly established, hindering decision making. Methods: We performed a systematic review and meta-analysis of randomized clinical trials and prospective observational studies to determine the rate of recurrent VTE in the first year, in the second year, between years 2 and 5, and years 5 and 10; and the cumulative incidence for recurrent VTE at 2, 5 and 10 years after stopping anticoagulation in men and women with first unprovoked VTE, who had completed at least 3 months of initial treatment. Studies were identified through a comprehensive literature search using MEDLINE, EMBASE and the Cochrane CENTRAL databases. Data clarifications were requested from authors of eligible studies. Rates of recurrent VTE were calculated for each study from the total number of recurrent VTE events divided by the person-years of follow-up, and then pooled using random-effects meta-analysis. Results: Fourteen studies involving 6, 446 patients were included in the analysis. Among men with a first unprovoked VTE, the pooled rate of recurrent VTE per 100 person-years after stopping anticoagulation was 11.2 events (95% CI, 9.0-13.6) in the first year; 7.4 events (95% CI, 5.5-9.5) in the second year; 4.4 events/year (95% CI, 3.2-5.7) between years 2 and 5, and 3.8 events/year (95% CI, 1.6-6.9) between years 5 and 10 [Table 1]. Among women with a first unprovoked VTE, the pooled rate of recurrent VTE per 100 person-years after stopping anticoagulation was 8.6 events (95% CI, 6.5-11.0) within the first year; 5.2 events (95% CI, 3.5-7.2) in the second year; 3.0 events/year (95% CI, 1.6-4.7) between years 2 and 5, and 2.0 events/year (95% CI, 1.3-2.9) between years 5 and 10 [Table 1]. In men and women respectively, the cumulative incidence for recurrent VTE was 17.8% (95% CI, 14.0%-21.9%) and 13.4% (95% CI, 9.8%-17.4%) at 2 years, 28.2% (95% CI, 22.0%-34.4%) and 20.9% (95% CI, 14.0%-28.5%) at 5 years, and 40.8% (95% CI, 28.0%-53.9%) and 28.5% (95% CI, 19.5%-38.3%) at 10 years after stopping anticoagulant therapy [Table 2]. Conclusions: Among patients with a first unprovoked VTE who have completed at least 3 months of initial treatment, men have a higher long-term risk of recurrent VTE after stopping anticoagulation, and may be given greater consideration for indefinite anticoagulant therapy. Our findings affirm the importance of considering patient's sex in deciding the optimal duration of anticoagulation, and as such, emphasize the need for individualized, patient-centered approach for the long-term management of unprovoked VTE. Disclosures Carrier: BMS: Honoraria, Research Funding; Leo Pharma: Research Funding; Pfizer: Honoraria; Bayer: Honoraria. Weitz:Bristol-Myers Squibb: Honoraria; Daiichi-Sankyo: Honoraria; Ionis: Consultancy, Honoraria; Janssen: Honoraria; Servier: Honoraria; Novartis: Honoraria; Bayer: Honoraria; Boehringer Ingelheim: Honoraria, Research Funding. Schulman:Boehringer-Ingelheim: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Sanofi: Honoraria; Bayer: Honoraria. Couturaud:Pfizer: Research Funding; Bayer: Honoraria, Other: Travel Support; AstraZeneca: Honoraria; Actelion: Other: Travel Support; Intermune: Other: Travel Support; Leo Pharma: Other: Travel Support; Daiichi Sankyo: Other: Travel Support. Becattini:Bayer HealthCare: Other: Lecture Fees; Boehringer Ingelheim: Other: Lecture Fees; Bristol Meyer Squibb: Other: Lecture Fees. Agnelli:Daiichi Sankyo: Other: Personal Fees; Boehringer Ingelheim: Other: Personal Fees; Bayer Healthcare: Other: Personal Fees; Pfizer: Other: Personal Fees; Bristol-Myers-Squibb: Other: Personal Fees. Brighton:Glaxo Smith Klein: Other: Personal Fees; Novo Nordisk: Other: Personal Fees; Bayer: Other: Personal Fees. Lensing:Bayer: Employment. Prins:Pfizer: Consultancy; Daiichi Sankyo: Consultancy. Hutton:Cornerstone Research Group: Honoraria. Palareti:Roche: Membership on an entity's Board of Directors or advisory committees; Werfen: Speakers Bureau; Alfa-Wassermann: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Prandoni:Pfizer: Consultancy; Daiichi-Sankyo: Consultancy; Sanofi: Consultancy; Bayer: Consultancy. Büller:Pfizer: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Sanofi-Aventis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Thrombogenics: Consultancy, Research Funding; Isis: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding. Rodger:Biomerieux: Research Funding.

Description: In contrast with extensive documentation in patients treated with unfractionated heparin (UFH), the incidence of heparin-induced thrombocytopenia (HIT) in medical patients receiving low-molecular-weight heparin (LMWH) is less well defined. In a prospective cohort study, the platelet count was monitored in 1754 consecutive patients referred to 17 medical centers and treated with LMWH for prophylaxis or treatment of thromboembolic disorders. The diagnosis of HIT was accepted in case of a platelet drop of at least 50%, the absence of obvious explanations for thrombocytopenia, and the demonstration of heparin-dependent IgG antibodies. HIT developed in 14 patients (0.80%; 95% CI, 0.43%-1.34%), in all of them within the first 2 weeks, and was more frequent in patients who had (1.7%) than in those who had not (0.3%) been exposed to UFH or LMWH (OR = 4.9; 95% CI, 1.5-15.7). The prevalence of thromboembolic complications in HIT patients (4 of 14; 28.6%) was remarkably higher than that (41 of 1740; 2.4%) observed in the remaining patients (OR = 16.6; 95% CI, 5.0-55.0). Immune thrombocytopenia and related thromboembolism may complicate the clinical course of medical patients treated with LMWH with a frequency that is not different from that observed with the use of UFH. The previous administration of heparin increases the rate of HIT.