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      Extended anticoagulation for the secondary prevention of venous thromboembolic events: An updated network meta-analysis

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          Abstract

          Background

          Extended treatment is preconized in a significant proportion of patients with unprovoked venous thromboembolism (VTE). However, limited direct/indirect comparisons are available to appropriately weight the benefit/risk ratio of the diverse treatments available. We aimed to compare the rate of symptomatic recurrent VTE and major bleeding (MB), the net clinical benefit (VTE+MB) and death on vitamin-K antagonist (VKA), direct oral anticoagulants (DOAC) and antiplatelet drugs for extended anticoagulation.

          Methods

          A systematic literature search through September 2018 identified randomized trials studying these pharmacologic therapies for extended anticoagulation following VTE. Treatment effects were calculated using network meta-analysis with frequentist fixed-effects model.

          Results

          18 trials (18,221 patients) were included in the analysis. All treatments reduced the risk of recurrence compared to placebo/observation. Nonetheless, VKA (RR 0.22; 95%CI 0.13–0.39) and DOAC (RRs ranging from 0.25–0.32; 95%CI ranging from 0.13–0.52) were more effective than aspirin, whereas low-dose VKA was less effective than standard-dose VKA (RR 2.47; 95%CI 1.34–4.55). The efficacy of DOAC was globally comparable to standard-adjusted dose VKA. Low- (RR 3.13; 95%CI 1.37–7.16) and standard-dose (RR 3.23; 95%CI 1.16–8.99) VKA also increased the risk of MB, which was not the case for any DOAC. Low-dose VKA and low-dose DOAC had similar effects on MB compared to standard-doses. Although there was a trend for reduced MB and enhanced net clinical benefit for DOAC compared to VKA, this was not statistically significant. The specific anticoagulant therapies had no significant effects on deaths.

          Conclusion

          Standard-dose VKA and low/standard-dose DOAC share similar effects on VTE recurrence and MB, whereas aspirin and low-dose VKA were associated with lower benefit/risk ratio.

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          Most cited references30

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          2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism.

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            Pulmonary embolism and deep vein thrombosis.

            Pulmonary embolism is the third most common cause of death from cardiovascular disease after heart attack and stroke. Sequelae occurring after venous thromboembolism include chronic thromboembolic pulmonary hypertension and post-thrombotic syndrome. Venous thromboembolism and atherothrombosis share common risk factors and the common pathophysiological characteristics of inflammation, hypercoagulability, and endothelial injury. Clinical probability assessment helps to identify patients with low clinical probability for whom the diagnosis of venous thromboembolism can be excluded solely with a negative result from a plasma D-dimer test. The diagnosis is usually confirmed with compression ultrasound showing deep vein thrombosis or with chest CT showing pulmonary embolism. Most patients with venous thromboembolism will respond to anticoagulation, which is the foundation of treatment. Patients with pulmonary embolism should undergo risk stratification to establish whether they will benefit from the addition of advanced treatment, such as thrombolysis or embolectomy. Several novel oral anticoagulant drugs are in development. These drugs, which could replace vitamin K antagonists and heparins in many patients, are prescribed in fixed doses and do not need any coagulation monitoring in the laboratory. Although rigorous clinical trials have reported the effectiveness and safety of pharmacological prevention with low, fixed doses of anticoagulant drugs, prophylaxis remains underused in patients admitted to hospital at moderate risk and high risk for venous thromboembolism. In this Seminar, we discuss pulmonary embolism and deep vein thrombosis of the legs. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study

              Objective To determine the real world risk of gastrointestinal bleeding associated with the use of the novel oral anticoagulants dabigatran and rivaroxaban compared with warfarin. Design Retrospective, propensity matched cohort study. Setting: Optum Labs Data Warehouse, a large database including administrative claims data on privately insured and Medicare Advantage enrollees. Participants New users of dabigatran, rivaroxaban, and warfarin from 1 November 2010 to 30 September 2013. Main outcome measures Incidence rates (events/100 patient years) and propensity score matched Cox proportional hazards models were used to estimate rates of total gastrointestinal bleeds, upper gastrointestinal bleeds, and lower gastrointestinal bleeds for the novel oral anticoagulants compared with warfarin in patients with and without atrial fibrillation. Heterogeneity of treatment effect related to age was examined using a marginal effects model. Results The incidence of gastrointestinal bleeding associated with dabigatran was 2.29 (95% confidence interval 1.88 to 2.79) per 100 patient years and that associated with warfarin was 2.87 (2.41 to 3.41) per 100 patient years in patients with atrial fibrillation. In non-atrial fibrillation patients, the incidence of gastrointestinal bleeding was 4.10 (2.47 to 6.80) per 100 patient years with dabigatran and 3.71 (2.16 to 6.40) per 100 patient years with warfarin. With rivaroxaban, 2.84 (2.30 to 3.52) gastrointestinal bleeding events per 100 patient years occurred in atrial fibrillation patients (warfarin 3.06 (2.49 to 3.77)/100 patient years) and 1.66 (1.23 to 2.24) per 100 patient years in non-atrial fibrillation patients (warfarin 1.57 (1.25 to 1.99)/100 patient years). In propensity score matched models, the risk of gastrointestinal bleeding with novel oral anticoagulants was similar to that with warfarin in atrial fibrillation patients (dabigatran v warfarin, hazard ratio 0.79 (0.61 to 1.03); rivaroxaban v warfarin, 0.93 (0.69 to 1.25)) and in non-AF patients (dabigatran v warfarin, hazard ratio 1.14 (0.54 to 2.39); rivaroxaban v warfarin, 0.89 (0.60 to 1.32)). The risk of gastrointestinal bleeding increased after age 65, such that by age 76 the risk exceeded that with warfarin among atrial fibrillation patients taking dabigatran (hazard ratio 2.49 (1.61 to 3.83)) and patients with and without atrial fibrillation taking rivaroxaban (2.91 (1.65 to 4.81) and 4.58 (2.40 to 8.72), respectively). Conclusions: The risk of gastrointestinal bleeding related to novel oral anticoagulants was similar to that for warfarin. Caution should be used when prescribing novel oral anticoagulants to older people, particularly those over 75 years of age.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: MethodologyRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                1 April 2019
                2019
                : 14
                : 4
                : e0214134
                Affiliations
                [1 ] Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Ville de Québec, Canada
                [2 ] Service de Médecine Vasculaire et Thérapeutique, CHU de St-Etienne, Saint-Etienne, France
                [3 ] Université Jean-Monnet, UMR 1059, SAINBIOSE, St-Etienne, France
                [4 ] INSERM CIC 1408, St-Etienne, France
                [5 ] Groupe d’Etude Multidisciplinaire des Maladies Thrombotiques (GEMMAT), Hospices Civils de Lyon, Lyon, France
                [6 ] Univ Lyon, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, CNRS, Villeurbanne, France
                [7 ] Service de Pharmacologie et de toxicologie, Hospices Civils de Lyon, Lyon, France
                [8 ] Département de Médecine Interne et Vasculaire, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite, France
                University of York, UNITED KINGDOM
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-7535-9972
                Article
                PONE-D-18-26953
                10.1371/journal.pone.0214134
                6443183
                30933993
                aef1a28b-e2b5-4846-9d18-ee0d1f26bd43
                © 2019 Mai et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 14 September 2018
                : 7 March 2019
                Page count
                Figures: 4, Tables: 4, Pages: 19
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Medicine and Health Sciences
                Vascular Medicine
                Thromboembolism
                Venous Thromboembolism
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Metaanalysis
                Physical Sciences
                Mathematics
                Statistics
                Statistical Methods
                Metaanalysis
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Hemorrhage
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Hemorrhage
                Medicine and Health Sciences
                Vascular Medicine
                Hemorrhage
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Cardiovascular Therapy
                Anticoagulant Therapy
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Computer and Information Sciences
                Network Analysis
                Medicine and Health Sciences
                Oncology
                Cancer Treatment
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Anticoagulants
                Custom metadata
                All relevant data are within the manuscript and its Supporting Information files.

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