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Background: Guidelines suggest indefinite anticoagulation after unprovoked venous thromboembolism (VTE) unless the bleeding risk is high, yet there is no consistent guidance on assessing bleeding risk., Objectives: This study aimed to evaluate the performance of 5 bleeding risk tools (RIETE, VTE-BLEED, CHAP, VTE-PREDICT, and ABC-Bleeding)., Methods: PLATO-VTE, a prospective cohort study, included patients aged ≥40 years with a first unprovoked VTE. Risk estimates were calculated at VTE diagnosis and after 3 months of treatment. Primary outcome was clinically relevant bleeding, as per International Society on Thrombosis and Haemostasis criteria, during 24-month follow-up. Discrimination was assessed by the area under the receiver operating characteristic curve (AUROC). Patients were classified as having a "high risk" and "non-high risk" of bleeding according to predefined thresholds; bleeding risk in both groups was compared by hazard ratios (HRs)., Results: Of 514 patients, 38 (7.4%) had an on-treatment bleeding. AUROCs were 0.58 (95% CI, 0.48-0.68) for ABC-Bleeding, 0.56 (95% CI, 0.46-0.66) for RIETE, 0.53 (95% CI, 0.43-0.64) for CHAP, 0.50 (95% CI, 0.41-0.59) for VTE-BLEED, and 0.50 (95% CI, 0.40-0.60) for VTE-PREDICT. The proportion of high-risk patients ranged from 1.4% with RIETE to 36.9% with VTE-BLEED. The bleeding incidence in the high-risk groups ranged from 0% with RIETE to 13.0% with ABC-Bleeding, and in the non-high-risk groups, it varied from 7.7% with ABC-Bleeding to 9.6% with RIETE. HRs ranged from 0.93 (95% CI, 0.46-1.9) for VTE-BLEED to 1.67 (95% CI, 0.86-3.2) for ABC-Bleeding. Recalibration at 3-month follow-up did not alter the results., Conclusion: In this cohort, discrimination of currently available bleeding risk tools was poor. These data do not support their use in patients with unprovoked VTE., Competing Interests: Declaration of competing interests N.A.M.G., A.-M.L.B., S.S.W., N.K., F.I.M., M.J.L.P., M.t.W, J.M.M.B.O., E.P., V.S.-L., and P.M.M.B. have no competing interests to disclose. M.C. has received research funding from BMS, Pfizer, and LEO Pharma. He has also received Honoria from Bayer, BMS, Pfizer, Servier, and LEO Pharma. A.D. has received research funding from BMS-Pfizer and Honoria from Bayer, BMS-Pfizer, Servier, and LEO Pharma. L.J.-P. has received research funding from LEO Pharma and MSD. He has also received honoraria from Bayer Hispania, Actelion, Pfizer, Rovi, LEO Pharma, Menarini, and MSD. M.D. has received research funding from LEO Pharma and honoraria and consultancy fees from Daiichi Sankyo, Bayer, BMS-Pfizer, Sanofi, and LEO Pharma outside the submitted work. W.A. has received research funding from Bayer and honoraria from Bayer, BMS-Pfizer, Aspen, Sanofi, Janssen, Werfen, LEO Pharma, and Portola. J.B.-W. has received research funding from Bayer, Daiichi Sankyo, Pfizer, and Portola/Alexion. He has also received honoraria from Bayer, Daiichi Sankyo, Pfizer, and Portola/Alexion. T.V. has served as a speaker and/or advisor for Boehringer Ingelheim, Daiichi Sankyo, BMS/Pfizer, Bayer, Sanofi, and LEO Pharma. F.A.K. reports research grants from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Daiichi Sankyo, Actelion, the Dutch Thrombosis Association, and the Dutch Heart foundation. B.C. reports speakers’ fees from Daiichi Sankyo and Sanofi. V.E.A.G. reports lecture fees from Novo Nordisk, and funding of studies by Dutch Thrombosis Foundation, AstraZeneca, and Zambon. H.B. reports consulting fees from Daiichi Sankyo, Bayer Healthcare, BMS/Pfizer, Boehringer Ingelheim, Portola, Medscape, Eli Lilly, Sanofi Aventis, and Ionis. N.v.E. has received advisory board honoraria from Daiichi Sankyo, Bayer, and LEO Pharma, which were transferred to his institute. P.W.K. received research grants from Daiichi Sankyo and Roche Diagnostics., (Copyright © 2024. Published by Elsevier Inc.)

Background: The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain., Purpose: To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups., Data Sources: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021., Study Selection: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment., Data Extraction: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies., Data Synthesis: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs., Limitation: Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs., Conclusion: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE., Primary Funding Source: Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

Aims: Non-vitamin K antagonist oral anticoagulants (NOACs) require dose reductions according to patient or clinical factors for patients with atrial fibrillation (AF). In this meta-analysis, we aimed to assess outcomes with reduced-dose NOACs when given as pre-specified in pivotal trials., Methods and Results: Aggregated data abstracted from Phase III trials comparing NOACs with warfarin in patients with AF were assessed by treatment using risk ratios (RRs) and 95% confidence intervals (CIs) stratified by patient eligibility for NOAC dose reduction. Irrespective of treatments, annualized rates of stroke or systemic embolism and major bleeding were higher in patients eligible for reduced-dose NOACs than in those eligible for full-dose NOACs (2.70% vs. 1.60% and 4.35% vs. 2.87%, respectively). Effects of reduced-dose NOACs compared with warfarin in patients eligible for reduced-dose NOACs on stroke or systemic embolism [RR 0.84 (95% CI 0.69-1.03)] and on major bleeding [RR 0.70 (95% CI 0.50-0.97)] were consistent with those of full-dose NOACs relative to warfarin in those eligible for full-dose NOACs [RR 0.86 (95% CI 0.77-0.96) for stroke or systemic embolism and RR 0.87 (95% CI 0.70-1.08) for major bleeding; interaction P, 0.89 and 0.26, respectively]. In addition, NOACs were associated with reduced risks of haemorrhagic stroke, intracranial haemorrhage, fatal bleeding, and death regardless of patient eligibility for NOAC dose reduction (interaction P > 0.05 for each)., Conclusions: Patients eligible for reduced-dose NOACs were at elevated risk of thromboembolic and haemorrhagic complications when treated with anticoagulants. NOACs, when appropriately dose-adjusted, had an improved benefit-harm profile compared with warfarin. Our findings highlight the importance of prescribing reduced-dose NOACs for indicated patient populations., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

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., Competing Interests: N. Kraaijpoel has nothing to disclose. M. Di Nisio reports personal fees from Daiichi Sankyo. F.I. Mulder has nothing to disclose. N. van Es reports personal fees from Daiichi Sankyo and Pfizer. J. Beyer-Westendorf reports grants and personal fees from Bayer AG, Boehringer-Ingelheim, Daiichi Sankyo, Pfizer and Portola. M. Carrier reports grants from BMS and Leo Pharma, and personal fees from Pfizer, Bayer, Sanofi and Leo Pharma. D. Garcia reports grants and personal fees from Daiichi Sankyo, Janssen and Incyte, and personal fees from BMS and Boehringer-Ingelheim. M. Grosso, M.F. Mercuri, G. Zhang and L. Schwocho are employees of Daiichi Sankyo Inc. A.K. Kakkar reports grants and personal fees from Bayer AG, and personal fees from Boehringer-Ingelheim, Janssen Pharma, Sanofi SA and Verseon. S. Middeldorp reports grants and personal fees from GSK, BMS/Pfizer, Aspen and Daiichi Sankyo, and personal fees from Bayer, Boehringer-Ingelheim, and grants from Sanquin. C. Rojas Hernandez reports personal fees from Daiichi Sankyo. A. Santamaria reports personal fees from Bayer AG, Boehringer-Ingelheim, Pfizer, Bristol-Myers Squibb, Daiichi Sankyo, LeoPharma, Sanofi-Aventis, Rovia and SOBI. A. Segers reports grants from Daiichi Sankyo, IONIS Pharmaceuticals and Janssen Pharmaceuticals. P. Verhamme reports grants and personal fees from Bayer Healthcare, LeoPharma, Daiichi Sankyo and Boehringer-Ingelheim, and personal fees from BMS, Portola, Medscape, Medtronic and Pfizer. T.F. Wang has nothing to disclose. J.I. Weitz reports personal fees from Daiichi-Sankyo, Bayer Healthcare, BMS, Boehringer-Ingelheim, Ionis Pharmaceuticals, Janssen, Johnson and Johnson, Pfizer, Portola, Medscape and Novartis. J.I. Zwicker reports grants from Quercegen and Incyte, and personal fees from Daichii Sankyo and Parexel. H.R. Büller reports personal fees from Daiichi Sankyo, Bayer Healthcare, BMS/Pfizer, Boehringer-Ingelheim, Portola, Medscape, Eli Lilly, Sanofi Aventis and Ionis. G.E. Raskob reports personal fees from Daiichi Sankyo, Itreas, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Isis Pharmaceuticals, Janssen, Pfizer and Portola., (Georg Thieme Verlag KG Stuttgart · New York.)

Cancer patients with venous thromboembolism (VTE) have a two- to six-fold increased risk of anticoagulant-related major bleeding events compared with VTE patients without cancer. It is unknown whether major bleeding events are more severe in cancer patients than in those without cancer. Individual patient data from four randomized phase III trials that compared factor Xa inhibitors and vitamin K antagonists for the treatment of VTE were used to compare the severity of major bleeding events in patients with and without cancer. Using predefined criteria, the severity of the clinical presentation and course of major bleeding events were classified into four categories of increasing severity. A one-stage meta-analysis was used to evaluate the effect of cancer on the severity of the clinical presentation and course by estimating crude odds ratios (ORs) and ORs adjusted for age, sex and anticoagulant type with 95% confidence intervals (CIs). The study group comprised 290 patients with major bleeding, of whom 50 (17%) had cancer. The clinical presentation was judged to be severe (category 3 or 4) in 38% of patients with cancer and 44% of patients without cancer (adjusted OR, 0.90; 95% CI, 0.47-1.72). The clinical course was found to be severe in 20 and 25% of patients with and without cancer, respectively (adjusted OR, 0.75; 95% CI, 0.35-1.61). The present study suggests that the clinical presentation and course of anticoagulant-related major bleeding events are not more severe in cancer patients than in patients without cancer. This may be reassuring for physicians who treat cancer patients with anticoagulant-related bleeding., Competing Interests: Conflicts of Interest: N. K. has nothing to disclose. N. v. E. reports a personal fee from Pfizer. S. M. B. has nothing to disclose. M. P. A. B. has nothing to disclose. E. S. E. reports personal fees from CSL Behring, grants from Sanquin and grants from Baxter, outside the submitted work. A. T. C. reports grants and personal fees from Bristol-Myers Squibb and Pfizer Limited, and personal fees from Boehringer Ingelheim, Johnson & Johnson, Portola, Sanofi Aventis, XO1, Janssen and Bayer HealthCare, and grants from Daiichi Sankyo, outside the submitted work. S. M. reports grants and personal fees from GSK, BMS/Pfizer, Aspen and Daiichi Sankyo, personal fees from Bayer and Boehringer Ingelheim, and grants from Sanquin, outside the submitted work. G. E. R. reports personal fees from Daiichi Sankyo, Itreas, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Isis Pharmaceuticals, Janssen, Pfizer and Portola, outside the submitted work. H. R. B. reports grants and personal fees from Daiichi Sankyo, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Isis Pharmaceuticals, GSK, Roche, Sanofi and Thrombogenics, outside the submitted work., (Schattauer GmbH Stuttgart.)

Direct oral anticoagulants (DOACs) facilitate the outpatient treatment of venous thromboembolism (VTE). However, the pivotal trials of DOACs have not reported outcomes separately for patients managed either as outpatients or in the hospital. We performed a subgroup analysis of the Hokusai-VTE study comparing efficacy and safety of edoxaban with warfarin in 8,292 patients with acute VTE. Patients received initial therapy with open-label enoxaparin or unfractionated heparin for ≥5 days in the hospital or as an outpatient at the discretion of the treating physician. Edoxaban or warfarin was then given for 3 to 12 months. The primary efficacy outcome was the cumulative incidence of symptomatic recurrent VTE at 12 months. The principal safety outcome was the incidence of clinically relevant bleeding (composite of major or clinically relevant non-major bleeding). Of the 5,223 consecutively enrolled patients with recorded hospital status and length of stay, 1,414 patients (27.1%) were managed as outpatients and 3,809 were managed in hospital. Among the outpatients, initial presentation was symptomatic deep-vein thrombosis (DVT) in 1,183 patients (83.7%) and pulmonary embolism (PE) in 231 patients (16.3%). Among the outpatients with DVT, recurrent VTE occurred in 18 (3.0%) given edoxaban and in 21 (3.6%) given warfarin (risk difference: −0.61, 95% confidence interval [CI]: −2.6 to 1.4). The principal safety outcome in outpatients occurred in 46 edoxaban patients (7.7%) and in 48 warfarin patients (8.3%; risk difference: −0.59, 95% CI: −3.7 to 2.5). Most outpatients had symptomatic DVT at presentation. In these patients, initial heparin followed by edoxaban had similar efficacy and safety to standard therapy with heparin and warfarin., Competing Interests: Declaration of Interests: Dr. Raskob reports personal fees from Daiichi Sankyo and Itreas during the conduct of the study and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Isis Pharmaceuticals, Janssen, Pfizer and Portola outside the submitted work. Dr. Ageno reports grants, personal fees and non-financial support from Bayer, Boehringer Ingelheim, Daiichi Sankyo and Stago, and personal fees from Bristol-Myers Squibb, Pfizer and Ono, outside the submitted work. Dr. Cohen reports grants from Daiichi Sankyo Pharma Development during the conduct of the study; grants and personal fees from Bayer, Bristol-Myers Squibb and Pfizer; and personal fees from Boehringer Ingelheim, Janssen, Johnson & Johnson, Portola, Sanofi, and XO1 outside the submitted work. Dr. Chen is an employee of Daiichi Sankyo, Inc. Dr. Grosso and Dr. Lin are employees of Daiichi Sankyo Pharma Development. Dr. Mercuri is an employee of Daiichi Sankyo Pharma Development and has a patent application pending for properties of edoxaban. Dr. Segers reports grants from Daiichi Sankyo Pharma Development during the conduct of the study and grants from Isis Pharmaceuticals outside the submitted work. Dr. Verhamme reports grants and personal fees from Daiichi-Sankyo Pharma Development during the conduct of the study and grants from Leo Pharma; grants and personal fees from Boehringer Ingelheim, Sanofi and ThromboGenics; and personal fees from Bayer outside the submitted work. Dr. Wells reports personal fees from Bayer and Daiichi Sankyo and grants from Bristol-Myers Squibb and Pfizer outside the submitted work. Ms. Winters was an employee of Daiichi Sankyo, Inc. Dr. Weitz reports personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Isis Pharmaceuticals, Janssen, Pfizer and Portola outside the submitted work. Dr. Büller reports grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Isis Pharmaceuticals, Pfizer, Roche, Sanofi and Thrombogenics outside the submitted work. Dr. Medina, Dr., Brekelmans and Dr. Vanassche have nothing to disclose.

Factor Xa (fXa)-inhibitors are as effective and safer than vitamin-K-antagonists (VKA) in the treatment of venous thromboembolism (VTE). We previously classified the severity of clinical presentation and course of all major bleeding events from the EINSTEIN, AMPLIFY and HOKUSAI-VTE trials separately. The current aim was to combine these findings in order to increase precision, assess a class effect and analyse presentation and course for different types of bleeding, i. e. intracranial, gastro-intestinal, and other. We classified the clinical presentation and course of all major bleeding events using pre-defined criteria. Both classifications comprised four categories; one being the mildest, and four the most severe. Odds ratios (OR) were calculated for all events classified as category three or four between fXa-inhibitors and VKA recipients. Also, ORs were computed for different types of bleeding. Major bleeding occurred in 111 fXa-inhibitor recipients and in 187 LMWH/VKA recipients. The clinical presentation was classified as category three or four in 35 % and 48 % of the major bleeds in fXa inhibitor and VKA recipients, respectively (OR 0.59, 95 % CI 0.36-0.97). For intracranial, gastro-intestinal and other bleeding a trend towards a less severe presentation was observed for patients treated with fXa inhibitors. Clinical course was classified as severe in 22 % of the fXa inhibitor and 25 % of the VKA associated bleeds (OR 0.83, 95 % CI 0.47-1.46). In conclusion, FXa inhibitor associated major bleeding events had a significantly less severe presentation and a similar course compared to VKA. This finding was consistent for different types of bleeding.

Better understanding of risk factors for major bleeding events during anticoagulant treatment for venous thromboembolism (VTE) may help physicians when deciding on intensity and duration of treatment. The primary aim of this study was to identify risk factors for major and clinically relevant bleeding in patients receiving the oral factor Xa inhibitor edoxaban or warfarin for the treatment of acute VTE. We analysed data from 8240 patients who received ≥1 dose of study drug in the Hokusai-VTE study. Bleeding risk factors were evaluated in 4118 patients who received edoxaban and significant variables were combined in a prediction model. We used the C-statistic to estimate model discrimination and bootstrap techniques for internal validation. Major bleeding occurred in 56/4118 (1.4 %) patients given edoxaban and in 66/4122 (1.6 %) patients given warfarin. Clinically relevant bleeding occurred in 349 (8.5 %) and 423 (10.3 %), respectively. Significant risk factors for major bleeding during edoxaban treatment were female sex, concomitant antiplatelet therapy, haemoglobin ≤10 g/dl, history of arterial hypertension, and systolic blood pressure >160 mmHg. The discrimination of the model was high (C-statistic: 0.71) for major bleeding, lower for clinically relevant bleeding (C-statistic: 0.62) and when the model was applied to patients receiving warfarin (C-statistic 0.60). In conclusion, we identified five main predictors of major bleeding in patients receiving edoxaban for the treatment of acute VTE. A risk model based on these factors predicted an increased risk of bleeding with good discrimination.

Apixaban, a direct acting oral anticoagulant (DOAC), was found to be non-inferior to and safer as enoxaparin followed by warfarin for treatment of venous thromboembolism (VTE) in the AMPLIFY trial. Information is needed on how bleeding events with DOACs present and develop. In this post-hoc analysis, the clinical presentation and course of all major and clinically relevant non major (CRNM) bleeding events in the AMPLIFY trial were blindly classified by three investigators, using pre-designed classification schemes containing four categories. Odds ratios (OR) for classifying as category three or four (representing a more severe clinical presentation and course) were calculated between apixaban and enoxaparin/warfarin. In total, 63 major and 311 CRNM bleeding events were classified. Of the major bleeds, a more severe clinical presentation occurred in 28.5 % of apixaban versus 44.9 % of enoxaparin/warfarin related recipients (OR 0.49, 95 % confidence interval [CI] 0.14-1.78). A severe clinical course was observed in 14.3 % and in 12.2 %, respectively (OR 1.19, 95 %CI 0.21-6.69). Of the CRNM bleeding events, a more severe clinical presentation and extent of clinical care was found in 25 % of apixaban recipients compared to 22.7 % in the enoxaparin/warfarin group (OR 1.13, 95 %CI 0.65-1.97). The clinical presentation and course of major and CRNM bleeds were similar in apixaban and enoxaparin/warfarin treated patients. This finding should reassure physicians and patients that even in the absence of a specific reversal agent, apixaban is a convenient and safe choice for VTE.

Anticoagulation is the cornerstone of prevention and treatment of venous thromboembolism (VTE) and stroke prevention in patients with atrial fibrillation (AF). However, the mechanisms by which anticoagulants confer therapeutic benefit also increase the risk of bleeding. As such, reversal strategies are critical. Until recently, the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, apixaban, and edoxaban lacked a specific reversal agent. This report is based on findings from the Anticoagulation Education Task Force, which brought together patient groups and professionals representing different medical specialties with an interest in patient safety and expertise in AF, VTE, stroke, anticoagulation, and reversal agents, to discuss the current status of anticoagulation reversal and fundamental changes in management of bleeding associated with DOACs occasioned by the approval of idarucizumab, a specific reversal agent for dabigatran, as well as recent clinical data on specific reversal agents for factor Xa inhibitors. Recommendations are given for when there is a definite need for a reversal agent (e.g. in cases of life-threatening bleeding, bleeding into a closed space or organ, persistent bleeding despite local haemostatic measures, and need for urgent interventions and/or interventions that carry a high risk for bleeding), when reversal agents may be helpful, and when a reversal agent is generally not needed. Key stakeholders who require 24-7/around-the-clock access to these agents vary among hospitals; however, from a practical perspective the emergency department is recommended as an appropriate location for these agents. Clearly, the advent of new agents requires standardised protocols for treating bleeding on an institutional level.

Edoxaban is a once-daily direct oral anticoagulant (DOAC). The Hokusai-VTE study revealed that, after initial treatment with heparin, edoxaban was non-inferior to and safer than vitamin K antagonists (VKA) in the prevention of recurrent deep-vein thrombosis and pulmonary embolism. This is the first report on the clinical relevance and management of bleeding events with edoxaban. All major bleeding events were classified blindly by three study-independent adjudicators. Pre-defined criteria were used to classify severity of clinical presentation and, separately, the clinical course and outcome into four categories. Major bleeding occurred in 56 patients treated with edoxaban and 65 patients treated with VKA. The severest categories (3 or 4) of the clinical presentation were assigned to 46 % of the major bleeding episodes in edoxaban recipients versus 58 % of the major bleeds in VKA recipients (odds ratio [OR] 0.62, 95 % confidence interval [CI] 0.30-1.27, p = 0.19). Clinical course was classified as severe (category 3 or 4) in 23 % of the edoxaban and 29 % of the VKA associated bleeds (OR 0.73, 95 % CI 0.32-1.66, p = 0.46). In conclusion, edoxaban associated major bleeding events have a comparable clinical presentation and course to major bleeds with VKA in patients treated for venous thromboembolism in the Hokusai-VTE study. These results may assure physicians that it is safe to prescribe this medication. If a major bleeding during edoxaban treatment occurs, its clinical presentation and clinical course are not worse than in VKA-treated patients.

Background: There are few data on the relative efficacy and safety of direct oral anticoagulants, such as edoxaban, compared with vitamin K antagonists during extended therapy for venous thromboembolism. This analysis evaluates the risk-benefit of extended treatment for up to 12 months with edoxaban compared with warfarin among patients enrolled in the Hokusai-VTE study who continued therapy beyond 3 months., Methods: The Hokusai-VTE trial (NCT00986154) was a randomised, double-blind, event driven non-inferiority trial in 8292 patients comparing edoxaban with warfarin in the treatment of patients with acute venous thromboembolism. All patients were treated for at least 3 months and treatment was continued for up to 12 months. The outcomes at 12 months were documented in all patients irrespective of treatment duration. 3633 patients treated with edoxaban and 3594 treated with warfarin who completed 3 months of treatment were eligible for this analysis. The primary efficacy outcome was the incidence of adjudicated symptomatic recurrent venous thromboembolism evaluated for each of the time intervals of 3 months, greater than 3 months to 6 months, greater than 6 months to less than 12 months, and at 12 months, as well as the cumulative incidence occurring between 3 and 12 months. The principal safety outcome was the incidence of clinically relevant bleeding (composite of major or clinically relevant non-major bleeding). Both on-treatment and intention-to-treat analyses were done., Findings: In the on-treatment analysis, the incidence of recurrent venous thromboembolism at 3 months was 1·1% (0·8-1·4; 44 of 4118 patients) in the edoxaban-treated group versus 1·2% (0·9-1·6; 51 of 4122) in the warfarin-treated group; between greater than 3 months and 6 months, 0·7% (0·3-1·5; eight of 1076) versus 0·5% (0·2-1·1; five of 1084); between greater than 6 months and less than 12 months, 0·2% (0·0-0·8; two of 896) versus 0·8% (0·03-1·7; seven of 851); and at 12 months, <0·1% (0·0-0·3; one of 1661) versus 0·1% (0·0-0·4; two of 1659). In the on-treatment analysis, the cumulative incidence of recurrent venous thromboembolism between 3 and 12 months was 0·3% (95% CI 0·2-1·5; 11 of 3633 patients) in the edoxaban-treated group and 0·4% (0·2-1·7; 14 of 3594) in the warfarin-treated group (HR 0·78, 95% CI 0·36-1·72). The cumulative incidence of clinically relevant bleeding (major or non-major) between 3 and 12 months was 3·9% (95% CI 3·3-4·6; 143 of 3633 patients) in the edoxaban-treated group and 4·1% (3·5-4·8; 147 of 3594 patients) in the warfarin-treated group (HR 0·97, 95% CI 0·77-1·22); cumulative incidence of major bleeding was 0·3% (95% CI 0·2-0·5; 11 of 3633 patients) in the edoxaban-treated group and 0·7% (0·4-1·0; 24 of 3594 patients) in the warfarin-treated group (HR 0·45, 95% CI 0·22-0·92). Similar results were obtained in the intention-to-treat analysis., Interpretation: Extended treatment with edoxaban is effective and associated with less major bleeding than warfarin. Edoxaban once daily provides an attractive alternative to warfarin for patients with venous thromboembolism who require extended treatment for prevention of recurrent venous thromboembolism., Funding: Daiichi Sankyo., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The study aim was to identify predictive factors for major bleeding in patients receiving the novel oral factor Xa inhibitor rivaroxaban or enoxaparin-vitamin K antagonists (VKAs) for the treatment of acute symptomatic venous thromboembolism. We analysed data from patients included in the phase III EINSTEIN DVT and EINSTEIN PE studies. Factors associated with major bleeding events were assessed with best subset variable selection using Cox proportional hazards regression model. Three time windows were considered, i.e. the initial three weeks, after the third week onwards, and the entire duration of the anticoagulant treatment. Model discrimination was estimated using the C-statistic and validated internally by bootstrap techniques. Major bleeding occurred in 40 (1.0%) of 4130 patients receiving rivaroxaban and in 72 (1.7%) of 4116 receiving enoxaparin/VKAs, with 44% of the major bleeding events occurring in the first three weeks of treatment. Significant risk factors for major bleeding were older age, black race, low haemoglobin concentrations, active cancer, and antiplatelet or non-steroidal anti-inflammatory drug therapy. The discrimination of the model for major bleeding was high for the first three weeks (C-statistic 0.73), from the fourth week onwards (C-statistic 0.68), and the entire period of anticoagulant treatment (C-statistic 0.74). This analysis identified risk factors for major bleeding in patients receiving the novel oral anticoagulant rivaroxaban or enoxaparin/VKAs for the treatment of acute venous thromboembolism. The prognostic model based on the combination of identified risk factors may be informative to estimate the risk of major bleeding both during the initial and later phases of anticoagulation.

Background: The clinically appropriate duration of thromboprophylaxis in hospitalized patients with acute medical illnesses is unknown. In this multicenter, randomized, double-blind trial, we evaluated the efficacy and safety of oral rivaroxaban administered for an extended period, as compared with subcutaneous enoxaparin administered for a standard period, followed by placebo., Methods: We randomly assigned patients 40 years of age or older who were hospitalized for an acute medical illness to receive subcutaneous enoxaparin, 40 mg once daily, for 10±4 days and oral placebo for 35±4 days or to receive subcutaneous placebo for 10±4 days and oral rivaroxaban, 10 mg once daily, for 35±4 days. The primary efficacy outcomes were the composite of asymptomatic proximal or symptomatic venous thromboembolism up to day 10 (noninferiority test) and up to day 35 (superiority test). The principal safety outcome was the composite of major or clinically relevant nonmajor bleeding., Results: A total of 8101 patients underwent randomization. A primary efficacy outcome event occurred in 78 of 2938 patients (2.7%) receiving rivaroxaban and 82 of 2993 patients (2.7%) receiving enoxaparin at day 10 (relative risk with rivaroxaban, 0.97; 95% confidence interval [CI], 0.71 to 1.31; P=0.003 for noninferiority) and in 131 of 2967 patients (4.4%) who received rivaroxaban and 175 of 3057 patients (5.7%) who received enoxaparin followed by placebo at day 35 (relative risk, 0.77; 95% CI, 0.62 to 0.96; P=0.02). A principal safety outcome event occurred in 111 of 3997 patients (2.8%) in the rivaroxaban group and 49 of 4001 patients (1.2%) in the enoxaparin group at day 10 (P<0.001) and in 164 patients (4.1%) and 67 patients (1.7%) in the respective groups at day 35 (P<0.001)., Conclusions: In acutely ill medical patients, rivaroxaban was noninferior to enoxaparin for standard-duration thromboprophylaxis. Extended-duration rivaroxaban reduced the risk of venous thromboembolism. Rivaroxaban was associated with an increased risk of bleeding. (Funded by Bayer HealthCare Pharmaceuticals and Janssen Research and Development; MAGELLAN ClinicalTrials.gov number, NCT00571649.).

Objective: This study aimed to assess the impact of combination antithrombotic therapy on stroke and bleeding risk compared with anticoagulation therapy only in patients with atrial fibrillation (AF)., Methods: Post hoc analysis of 4,576 patients with AF (mean ± SD age, 70.1 ± 9.1 years; men, 66.5%) enrolled in the Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation (AMADEUS) trial were randomized to receive either subcutaneous idraparinux (2.5 mg weekly) (n = 2,283) or dose-adjusted vitamin K antagonists (VKAs) (international normalized ratio, 2.0-3.0) (n = 2,293). Of these patients, 848 (18.5%) received antiplatelet therapy (aspirin, clopidogrel, ticlopidine, etc) in addition to anticoagulation treatment (combination antithrombotic therapy)., Results: A total of 572 (15.3% per year) clinically relevant bleeding and 103 (2.6% per year) major bleeding events occurred. Patients receiving combination antithrombotic therapy had a 2.3- to 2.5-fold increased risk of clinically relevant bleeding events and major bleeding events, respectively, compared with those receiving anticoagulation therapy only. Multivariate analyses (hazard ratio, 95% CI) revealed that the risk of clinically relevant bleeding was significantly increased by age 65 to 74 years (1.44, 1.14-1.82) and ≥ 75 years (1.59, 1.24-2.04, P = .001) and by combination antithrombotic therapy (2.47, 2.07-2.96, P < .0001). The same held true for major bleeding events, with analogous figures for age 65 to 74 years (2.26, 1.08-4.71) and ≥ 75 years (4.19, 1.98-8.87, P = .0004) and for combination antithrombotic therapy (2.23, 1.49-3.34, P < .0001). Combination antithrombotic therapy was not associated with a decrease in ischemic stroke risk compared with anticoagulation therapy only (11 [1.4% per year] vs 22 [0.7% per year]; adjusted hazard ratio, 2.01; 95% CI, 0.94-4.30; P = .07)., Conclusions: Combination antithrombotic therapy increases the risk of clinically relevant bleeding and major bleeding in patients with AF and does not appear to reduce the risk of stroke.

Vitamin K antagonists (VKAs) are effective antithrombotic agents and advocated in guidelines for the management of cardiovascular disease. However, in the trials underlying these guidelines, many patients were excluded. We performed a case-control study in 993 patients receiving VKAs, who required hospitalization for bleeding, and contrasted them to 993 matched control patients on VKAs, who were hospitalized for an infection. We analyzed whether patients and controls would have been eligible for the clinical trials on which their indication for anticoagulation was based, and estimated the risk of hemorrhage associated with exclusion criteria as applied in those trials. Approximately one quarter (23% [95% CI: 21%-26%]) of controls had one or more exclusion criteria for the trials, supporting the use of anticoagulation for their condition. Forty percent of patients presenting with bleeding had one or more exclusion criteria (95% CI: 37%-43%). Having one exclusion criterion resulted in a 2.9-fold increased risk of bleeding (95% CI: 2.2-3.9), and this risk increased sharply when more than one exclusion criterion was present. VKAs are often prescribed to patients who would not have qualified for clinical trials, and in these patients a careful consideration should be made regarding the expected efficacy and the risk of bleeding.

Background: Pulmonary embolism (PE) is a potentially fatal disease with risks of recurrent venous thrombotic events (venous thromboembolism [VTE]) and major bleeding from anticoagulant therapy. Identifying risk factors for recurrent VTE, bleeding, and mortality may guide clinical decision making., Objective: To evaluate the incidence of recurrent VTE, hemorrhagic complications, and mortality in patients with PE, and to identify risk factors and the time course of these events., Design: We evaluated consecutive patients with PE derived from a prospective management study, who were followed for 3 months, treated with anticoagulants, and underwent objective diagnostic testing for suspected recurrent VTE or bleeding., Results: Of 673 patients with complete follow-up, 20 patients (3.0%; 95% confidence interval [CI], 1.8 to 4.6%) had recurrent VTE. Eleven of 14 patients with recurrent PE had a fatal PE (79%; 95% CI, 49 to 95%), occurring mostly in the first week after diagnosis of initial PE. In 23 patients (3.4%; 95% CI, 2.2 to 5.1%), a hemorrhagic complication occurred, 10 of which were major bleeds (1.5%; 95% CI, 0.7 to 2.7%), and 2 were fatal (0.3%; 95% CI, 0.04 to 1.1%). During the 3-month follow-up, 55 patients died (8.2%; 95% CI, 6.2 to 10.5%). Risk factors for recurrent VTE were immobilization for > 3 days and being an inpatient; having COPD or malignancies were risk factors for bleeding. Higher age, immobilization, malignancy, and being an inpatient were risk factors for mortality., Conclusions: Recurrent VTE occurred in a small percentage of patients treated for an acute PE, and the majority of recurrent PEs were fatal. Immobilization, hospitalization, age, COPD, and malignancies were risk factors for recurrent VTE, bleeding, and mortality. Close monitoring may be indicated in these patients, precluding them from out-of-hospital start of treatment.

Background: A C1173T polymorphism in intron 1 of the VKORC1 gene has been claimed to determine the interindividual variability in the response to vitamin K antagonist therapy (VKA), but it is unknown whether it also influences bleeding risk. We aimed to confirm the relationship between C1173T status and phenprocoumon or acenocoumarol use, and to examine the risk of severe bleeding for the various genotypes., Methods and Findings: We studied this in a case-control study of 110 patients who bled during VKA therapy and 220 control patients free of bleeding under the same therapy. To achieve the same target INR, CT genotype and TT genotype control patients required less phenprocoumon (CC genotype 2.9 mg/d [95% confidence interval (CI): 2.6-3.2], CT genotype 2.6 mg/d [95% CI: 2.1-3.1], TT genotype 1.4 mg/d [95 % CI: 1.1-1.7]) or acenocoumarol (CC genotype 3.2 mg/d [95% CI: 2.9-3.5], CT genotype 2.3 mg/d [95% CI: 2.1-2.5], TT genotype 1.7 mg/d [95% CI: 1.3-2.1]) than CC genotype control patients. Compared with CC genotype individuals, carriers of at least one T allele had an increased risk of bleeding in the phenprocoumon users (crude odds ratio = 2.6, 95% CI: 1.2-5.7), but not in acenocoumarol users (crude odds ratio = 1.2, 95% CI: 0.6-2.3)., Conclusion: These findings encourage taking further steps towards the evaluation of the use of VKORC1 genetic testing for bleeding prevention in individuals who receive VKA therapy.

Background: Recombinant activated factor VII (factor VIIa) is a prohemostatic agent that can be used for patients with complicated coagulation disorders. Recombinant factor VIIa is, however, increasingly used for several other indications, including patients with a preexistent normal coagulation system but who experience serious bleeding, for example, after major surgery or trauma., Data Source: We performed a systematic review of all published and unpublished clinical studies using MEDLINE (1966-2004) and all other sources available to assess the available evidence on the efficacy and safety of recombinant factor VIIa in patients with or without coagulation disorders., Study Selection: We found 483 articles related to the pharmacologic use of recombinant factor VIIa, including 28 clinical trials, 124 case series, and 176 case reports, which were all considered for this review., Data Synthesis: Recombinant factor VIIa is an effective and relatively potent prohemostatic agent in approximately 90% of patients with hemophilia and inhibiting antibodies and other types of complex coagulation disorders. The application of recombinant factor VIIa in other patients who experience severe bleeding is promising, and although sound evidence from controlled clinical trials is only scarcely available so far, forthcoming trials are likely to provide more substantiation for this use. Recombinant factor VIIa appears to be relatively safe with a 1-2% incidence of thrombotic complications based on published trials., Conclusions: More randomized controlled clinical trials are required to assess the efficacy and safety of recombinant factor VIIa for patients without a preexistent coagulation disorder and with severe bleeding. In the meantime, off-label use of recombinant factor VIIa may be considered in patients with life-threatening bleeding.

Aims Deciding to stop or continue anticoagulation for venous thromboembolism (VTE) after initial treatment is challenging, as individual risks of recurrence and bleeding are heterogeneous. The present study aimed to develop and externally validate models for predicting 5-year risks of recurrence and bleeding in patients with VTE without cancer who completed at least 3 months of initial treatment, which can be used to estimate individual absolute benefits and harms of extended anticoagulation. Methods and results Competing risk-adjusted models were derived to predict recurrent VTE and clinically relevant bleeding (non-major and major) using 14 readily available patient characteristics. The models were derived from combined individual patient data from the Bleeding Risk Study, Hokusai-VTE, PREFER-VTE, RE-MEDY, and RE-SONATE (n = 15,141, 220 recurrences, 189 bleeding events). External validity was assessed in the Danish VTE cohort, EINSTEIN-CHOICE, GARFIELD-VTE, MEGA, and Tromsø studies (n = 59 257, 2283 recurrences, 3335 bleeding events). Absolute treatment effects were estimated by combining the models with hazard ratios from trials and meta-analyses. External validation in different settings showed agreement between predicted and observed risks up to 5 years, with C-statistics ranging from 0.48–0.71 (recurrence) and 0.61–0.68 (bleeding). In the Danish VTE cohort, 5-year risks ranged from 4% to 19% for recurrent VTE and 1% –19% for bleeding. Conclusion The VTE-PREDICT risk score can be applied to estimate the effect of extended anticoagulant treatment for individual patients with VTE and to support shared decision-making. [ABSTRACT FROM AUTHOR]

Prediction models for recurrence and bleeding are infrequently used when deciding on anticoagulant treatment duration after venous thromboembolism (VTE) due to concerns about performance and validity. Our aim was to critically appraise these models by systematically summarizing data from derivation and validation studies. MEDLINE and CENTRAL were searched until November 15th, 2019. Studies on prediction models for recurrence or bleeding after at least 3 months of anticoagulation in adult patients with VTE were included. The PROBAST, ROBINS-I and RoB2 tools were used to assess risk of bias and applicability. Selection yielded 18 studies evaluating 8 models for recurrence (7 on development; 9 on validation; 1 update). Generally, models for recurrent VTE appeared to perform poorly to moderately in external validation studies (C-statistics 0.39–0.66, one 0.83). However, impact studies show that HERDOO2 and Vienna prediction model may identify patients with unprovoked VTE at low recurrence risk. Sixteen studies evaluating 14 models for anticoagulation-related bleeding were identified (7 on development; 9 on validation). Although some models seemed promising in development studies, their predictive performance was poor to moderate in external validation (C-statistics 0.52–0.71). All but 3 studies were considered at high risk of bias, mainly due to limitations in the statistical analysis. Prognostic models for recurrence and anticoagulation-related bleeding risk often have important methodological limitations and insufficient predictive accuracy. These findings do not support their use in clinical practice to weigh risks of recurrence and bleeding when deciding on continuing anticoagulation after initial treatment of VTE. • Deciding on duration of anticoagulation for venous thromboembolism is challenging. • Prediction models for recurrence and bleeding after 3 months were critically appraised. • Existing models have methodological limitations and insufficient predictive accuracy. • This questions their use to decide about continuing anticoagulation beyond 3 months. [ABSTRACT FROM AUTHOR]

Background: The role of factor XI in the pathogenesis of postoperative venous thromboembolism is uncertain. Abelacimab is a monoclonal antibody that binds to factor XI and locks it in the zymogen (inactive precursor) conformation.Methods: In this open-label, parallel-group trial, we randomly assigned 412 patients who were undergoing total knee arthroplasty to receive one of three regimens of abelacimab (30 mg, 75 mg, or 150 mg) administered postoperatively in a single intravenous dose or to receive 40 mg of enoxaparin administered subcutaneously once daily. The primary efficacy outcome was venous thromboembolism, detected by mandatory venography of the leg involved in the operation or objective confirmation of symptomatic events. The principal safety outcome was a composite of major or clinically relevant nonmajor bleeding up to 30 days after surgery.Results: Venous thromboembolism occurred in 13 of 102 patients (13%) in the 30-mg abelacimab group, 5 of 99 patients (5%) in the 75-mg abelacimab group, and 4 of 98 patients (4%) in the 150-mg abelacimab group, as compared with 22 of 101 patients (22%) in the enoxaparin group. The 30-mg abelacimab regimen was noninferior to enoxaparin, and the 75-mg and 150-mg abelacimab regimens were superior to enoxaparin (P<0.001). Bleeding occurred in 2%, 2%, and none of the patients in the 30-mg, 75-mg, and 150-mg abelacimab groups, respectively, and in none of the patients in the enoxaparin group.Conclusions: This trial showed that factor XI is important for the development of postoperative venous thromboembolism. Factor XI inhibition with a single intravenous dose of abelacimab after total knee arthroplasty was effective for the prevention of venous thromboembolism and was associated with a low risk of bleeding. (Funded by Anthos Therapeutics; ANT-005 TKA EudraCT number, 2019-003756-37.). [ABSTRACT FROM AUTHOR]

• Two classifications to assess major bleeding severity have been used in clinical trials. • Data on their interrater agreement and validity are lacking. • In this post-hoc analysis, the interrater agreement of the major bleeding severity scales was moderate to substantial. • Data incompleteness and subjective terminology may have led to discordant results. • Future studies should aim to improve methods to assess major bleeding severity. [ABSTRACT FROM AUTHOR]

We provide insight into the risk of perioperative thromboembolism and bleeding in patients who have atrial fibrillation, use anticoagulants, and undergo a surgical procedure. Ninety-four patients underwent 121 noncardiac operations during a mean follow-up of 29 months. There was a 3.6-fold increased risk for all bleeding complications within 1 month after surgery compared with the control period (95% confidence interval 1.05 to 12.0). No thromboembolic event occurred in the first month after surgery compared with 11 events in the remaining period (0.4% per month). [Copyright &y& Elsevier]