In the Hokusai VTE Cancer study, edoxaban was non-inferior to dalteparin for the composite outcome of recurrent venous thromboembolism (VTE) and major bleeding in 1,050 patients with cancer-associated VTE. The absolute rate of recurrent VTE was 3.4% lower with edoxaban, whereas the absolute rate of major bleeding was 2.9% higher. The present analysis focuses on the sites, clinical presentation, course and outcome of bleeding events, and the associated tumour types. Major bleeds and their severity (categories 1-4) were blindly adjudicated by a committee using a priori defined criteria, and data were analysed in the safety population. Major bleeding occurred in 32 of 522 patients given edoxaban (median treatment duration, 211 days) and in 16 of 524 patients treated with dalteparin (median treatment duration, 184 days); no patients had more than one major bleed. There were no fatal bleeds with edoxaban, and two with dalteparin. Severe bleeding at presentation (category 3 or 4) occurred in 10 (1.9%) and 11 (2.1%) patients in the edoxaban and dalteparin groups, respectively. The excess of major bleeding with edoxaban was confined to patients with gastrointestinal cancer. However, severe major bleeding at presentation (category 3 or 4) in this sub-group occurred in 5 of 165 (3.0%) and in 3 of 140 (2.1%) patients given edoxaban or dalteparin, respectively.In conclusion, this analysis suggests that while oral edoxaban is an appropriate alternative to subcutaneous dalteparin for treatment of cancer-associated VTE, the use of edoxaban in patients with gastrointestinal cancer requires careful benefit-risk weighting.

Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and standard anticoagulants in the predefined subgroup of children with cerebral venous thrombosis (CVT) who participated in the EINSTEIN-Jr trial. Children with CVT were randomized (2:1), after initial heparinization, to treatment with rivaroxaban or standard anticoagulants (continued on heparin or switched to vitamin K antagonist). The main treatment period was 3 months. The primary efficacy outcome, symptomatic recurrent venous thromboembolism (VTE), and principal safety outcome, major or clinically relevant nonmajor bleeding,were centrally evaluated by blinded investigators. Sinus recanalization on repeat brain imaging was a secondary outcome. Statistical analyses were exploratory. In total, 114 children with confirmed CVT were randomized. All children completed the follow-up. None of the 73 rivaroxaban recipients and 1 (2.4%; CVT) of the 41 standard anticoagulant recipients had symptomatic, recurrent VTE after 3 months (absolute difference, 2.4%; 95% confidence interval [CI], −2.6% to 13.5%). Clinically relevant bleeding occurred in 5 (6.8%; all nonmajor and noncerebral) rivaroxaban recipients and in 1 (2.5%; major [subdural] bleeding) standard anticoagulant recipient (absolute difference, 4.4%; 95% CI, −6.7% to 13.4%). Complete or partial sinus recanalization occurred in 18 (25%) and 39 (53%) rivaroxaban recipients and in 6 (15%) and 24 (59%) standard anticoagulant recipients, respectively. In summary, in this substudy of a randomized trial with a limited sample size, children with CVT treated with rivaroxaban or standard anticoagulation had a low risk of recurrent VTE and clinically relevant bleeding. This trial was registered at clinicaltrials.gov as #NCT02234843.

In a family-based study called GAIT (Genetic Analysis of Idiopathic Thrombophilia) that included a genome-wide scan we demonstrated that a polymorphism (46C-->T) in the F12 locus jointly influences variability of plasma (Factor XII) FXII levels and susceptibility to thrombotic disease. It then became germane to determine the prevalence of the 46C-->T polymorphism and its relative risk of thrombotic disease. We followed up evidence for genetic linkage with a case-control study, including 250 unrelated consecutive Spanish patients suffering from venous thrombotic disease and 250 Spanish subjects matched for sex and age as a controls. We measured FXII levels and genotyped the 46C-->T polymorphism, as well as a number of classical risk factors for thrombotic disease. We confirmed that individuals with different genotypes for this polymorphism showed significant differences in their FXII levels. Most importantly, the mutated T allele in the homozygous state (genotype T/T) was associated with an increased risk of thrombosis (adjusted OR of 4.82; 95% CI 1.5-15.6), suggesting that the polymorphism itself is an independent risk factor for venous thromboembolism. This study confirms that the 46C-->T polymorphism is a genetic risk factor for venous thrombosis in the Spanish population. In addition, our results confirm that a genome-wide scan coupled with a classical case-control association study is an extremely valuable approach to identify DNA variants that affect complex diseases.

Background Guidance for periprocedural anticoagulant management is mainly based on limited data from Phase III or observational studies and expert opinion. Hypothesis EMIT‐AF/VTE was designed to document the risks of bleeding and thromboembolic events in more than 1000 patients on edoxaban undergoing diagnostic and therapeutic procedures in clinical practice. Methods Routine care in a multinational multicenter, prospective observational study. Participants were adult patients with atrial fibrillation and/or venous thromboembolism treated with edoxaban for stroke prevention or for secondary prevention in venous thromboembolic disease, undergoing a wide range of diagnostic and therapeutic procedures. Edoxaban therapy was interrupted periprocedurally at the treating physician's discretion. Patients were evaluated from 5 days pre‐ until 30 days postprocedure. Primary outcome was the incidence of International Society on Thrombosis and Haemostasis defined major bleeding; secondary outcomes included incidence of clinically relevant non‐major bleeding, acute coronary syndrome, and acute thromboembolic events. Results Outcomes and management are reported for the first procedures in 1155 unselected patients. Five cases of major bleeding (0.4%) and eight of clinically relevant non‐major bleeding (0.7%) were documented, five (38%) of which occurred outside the period of likely edoxaban effect (last edoxaban dose ≥3 days prior to bleeding). Five (0.4%) deaths from any cause, seven acute thromboembolic events (0.6%) including two cardiac deaths (0.2%) in six patients, and one acute coronary event (0.1%) occurred. Conclusions The periprocedural bleeding and acute thromboembolic event risks for patients treated with edoxaban were low. This can help inform both clinical routine and guidelines for the periprocedural management of edoxaban.

Nowadays, most patients under oral anticoagulant therapy (OAT) require invasive procedures such as colonoscopy (CC) or gastroscopy (GC). The goals of the management of OAT are to minimise the risk of thromboembolism and bleeding. We have performed the first prospective, observational study to evaluate these parameters using fixed-dose high-risk thromboprophylactic therapy with sodic bemiparin (Hibor) as bridging therapy. From January 2004 to January 2005, patients under OAT were included. Periprocedure prophylaxis consisted of: Acenocumarol patients: Day -3: withdrawal acenocumarol. Days -2,-1,0: Hibor 3500 UI/d sc and days +1,+2,+3: Hibor 3500 U/I + acenocumarol. And day +5: acenocumarol only. Warfarin patients: Days -5,-4: withdrawal warfarin, -3,-2,-1, 0; Hibor 3500 UI/day sc, days +1,+2,+3,+4: Hibor 3500 UI/day sc and warfarin and day +5; warfarin only. Thromboembolic complications and bleeding were recorded in a 3 month follow-up. We included 100 consecutive patients in the intention-to-treat group. The remaining 98 patients were 50 women and 48 men. Mean age of women was 71.1 (range: 46-87) years and 70.7 (range: 39-86) years in men. Eighty-three took acenocumarol, and 15 warfarin. Thirty-two gastroscopies and 61 colonoscopies were performed and in five patients both were performed. No thromboembolic and bleeding complications related to bemiparin were observed in the 103 endoscopies. Two patients developed pruritus at the punction site. Fixed-dose high-risk thromboprophilactic therapy with bemiparin (Hibor) is safe and effective as a bridging therapy in patients under OAT who require GC or CC.