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      Comparison of the Non-VKA Oral Anticoagulants Apixaban, Dabigatran, and Rivaroxaban in the Extended Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis

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          Abstract

          Background

          Historically, warfarin or aspirin have been the recommended therapeutic options for the extended treatment (>3 months) of VTE. Data from Phase III randomised controlled trials (RCTs) are now available for non-VKA oral anticoagulants (NOACs) in this indication. The current systematic review and network meta-analysis (NMA) were conducted to compare the efficacy and safety of anticoagulants for the extended treatment of VTE.

          Methods

          Electronic databases (accessed July 2014 and updated April 2016) were systematically searched to identify RCTs evaluating apixaban, aspirin, dabigatran, edoxaban, rivaroxaban, and warfarin for the extended treatment of VTE. Eligible studies included adults with an objectively confirmed deep vein thrombosis, pulmonary embolism or both. A fixed-effect Bayesian NMA was conducted, and results were presented as relative risks (RRs). Sensitivity analyses examining (i) the dataset employed according to the time frame for outcome assessment (ii) the model used for the NMA were conducted.

          Results

          Eleven Phase III RCTs (examining apixaban, aspirin, dabigatran, rivaroxaban, warfarin and placebo) were included. The risk of the composite efficacy outcome (VTE and VTE-related death) was statistically significantly lower with the NOACs and warfarin INR 2.0–3.0 compared with aspirin, with no significant differences between the NOACs. Treatment with apixaban (RR 0.23, 95% CrI 0.10, 0.55) or dabigatran (RR 0.55, 95% Crl 0.43, 0.71) was associated with a statistically significantly reduced risk of ‘major or clinically relevant non-major bleed’ compared with warfarin INR 2.0–3.0. Apixaban also showed a significantly reduced risk compared with dabigatran (RR 0.42, 95% Crl 0.18, 0.97) and rivaroxaban (RR 0.23, 95% Crl 0.09, 0.59). Sensitivity analyses indicate that results were dependent on the dataset, but not on the type of NMA model employed.

          Conclusions

          Results from the NMA indicate that NOACs are an effective treatment for prevention of VTE or VTE-related death) in the extended treatment setting. However, bleeding risk differs between potential treatments, with apixaban reporting the most favourable profile compared with other NOACs, warfarin INR 2.0–3.0, and aspirin.

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          Most cited references26

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          Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis.

          New direct oral anticoagulants (NOACs) constitute a novel treatment option for acute venous thromboembolism (VTE), with practical advantages. Individual studies have demonstrated comparable efficacy to that of vitamin K antagonists (VKAs) and have suggested a more favorable safety profile . We performed a meta-analysis to determine the efficacy and safety of NOACs as compared with those of VKAs in patients with acute VTE. We searched MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews and the Clinical Trials Registry up to October 2013. Eligible studies included phase 3 trials comparing NOACs with VKAs in patients with acute VTE. Relative risks (RRs), absolute risk differences and numbers needed to treat (NNTs) to prevent one event were calculated for recurrent VTE, fatal pulmonary embolism (PE), overall mortality, major bleeding, and other bleeding complications, with random-effects models. Five studies were included, investigating four NOACs (rivaroxaban, dabigatran, apixaban, and edoxaban) in 24 455 patients with acute VTE. RRs for recurrent VTE, fatal PE and overall mortality for NOACs vs. VKAs were 0.88 (95% confidence interval [CI] 0.74-1.05), 1.02 (95% CI 0.39-5.96), and 0.97 (95% CI 0.83-1.14), respectively. The RR for major bleeding was 0.60 (95% CI 0.41-0.88). The NNT with NOACs instead of VKA to prevent one major bleed was 149. The RR and NNT for fatal bleeding were 0.36 (95% CI 0.15-0.87) and 1111. A fixed-effect network analysis did not demonstrate significant differences between individual NOACs and rivaroxaban. NOACs have comparable efficacy to that of VKAs, and are associated with a significantly lower risk of bleeding complications, although the NNT to prevent one major bleed was relatively high. © 2013 International Society on Thrombosis and Haemostasis.
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            Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study.

            The appropriate duration of oral anticoagulation after a first episode of venous thromboembolism (VTE) is uncertain and depends upon VTE recurrence rates. To estimate VTE recurrence rates and determine predictors of recurrence. Patients in Olmsted County, Minnesota, with a first lifetime deep vein thrombosis or pulmonary embolism diagnosed during the 25-year period from 1966 through 1990 (N = 1,719) were followed forward in time through their complete medical records in the community for first VTE recurrence. Four hundred four patients developed recurrent VTE during 10,198 person-years of follow-up. The overall (probable/definite) cumulative percentages of VTE recurrence at 7, 30, and 180 days and 1 and 10 years were 1.6% (0.2%), 5.2% (1.4%), 10.1% (4.1%), 12.9% (5.6%), and 30.4% (17.6%), respectively. The risk of recurrence was greatest in the first 6 to 12 months after the initial event but never fell to zero. Independent predictors of first overall VTE recurrence included increasing age and body mass index, neurologic disease with paresis, malignant neoplasm, and neurosurgery during the period from 1966 through 1980. Independent predictors of first probable/definite recurrence included diagnostic certainty of the incident event and neurologic disease in patients with hospital-acquired VTE. Recurrence risk was increased by malignant neoplasm but varied with concomitant chemotherapy, patient age and sex, and study year. Venous thromboembolism recurs frequently, especially within the first 6 to 12 months, and continues to recur for at least 10 years after the initial VTE. Patients with VTE with neurologic disease and paresis or with malignant neoplasm are at increased risk for recurrence, while VTE patients with transient or reversible risk factors are at less risk.
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              A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.

              Patients who have a first episode of venous thromboembolism in the absence of known risk factors for thrombosis (idiopathic thrombosis) are often treated with anticoagulant therapy for three months. Such patients may benefit from longer treatment, however, because they appear to have an increased risk of recurrence after anticoagulant therapy is stopped. In this double-blind study, we randomly assigned patients who had completed 3 months of anticoagulant therapy for a first episode of idiopathic venous thromboembolism to continue receiving warfarin, with the dose adjusted to achieve an international normalized ratio of 2.0 to 3.0, or to receive placebo for a further 24 months. Our goal was to determine the effects of extended anticoagulant therapy on rates of recurrent symptomatic venous thromboembolism and bleeding. A prespecified interim analysis of efficacy led to the early termination of the trial after 162 patients had been enrolled and followed for an average of 10 months. Of 83 patients assigned to continue to receive placebo, 17 had a recurrent episode of venous thromboembolism (27.4 percent per patient-year), as compared with 1 of 79 patients assigned to receive warfarin (1.3 percent per patient-year, P<0.001). Warfarin resulted in a 95 percent reduction in the risk of recurrent venous thromboembolism (95 percent confidence interval, 63 to 99 percent). Three patients assigned to the warfarin group had nonfatal major bleeding (two had gastrointestinal bleeding and one genitourinary bleeding), as compared with none of those assigned to the placebo group (3.8 vs. 0 percent per patient-year, P=0.09). Patients with a first episode of idiopathic venous thromboembolism should be treated with anticoagulant agents for longer than three months.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                3 August 2016
                2016
                : 11
                : 8
                : e0160064
                Affiliations
                [1 ]Guy’s and St Thomas’ Hospitals, King’s College, London, United Kingdom
                [2 ]BMS, Princeton, United States of America
                [3 ]Pfizer, Walton Oaks, United Kingdom
                [4 ]Abacus International, Bicester, United Kingdom
                [5 ]Pfizer, New York, United States of America
                Kurume University School of Medicine, JAPAN
                Author notes

                Competing Interests: The authors of this manuscript have the following interests: This study was funded by Bristol-Myers Squibb and Pfizer. MH and SL are employed by Bristol-Myers Squibb, RH by Pfizer Ltd, and SB and SAM by DRG Abacus. AB was employed by Pfizer Ltd when the study was conducted. ATC was a paid consultant to Bristol-Myers Squibb and Pfizer in connection with the development of this manuscript. SAM and SB are employees of DRG Abacus and were paid consultants to Bristol-Myers Squibb and Pfizer Ltd in connection with conducting this study and with the development of this manuscript. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

                • Conceived and designed the experiments: MH AB SAM SB.

                • Performed the experiments: SAM SB.

                • Analyzed the data: ATC MH AB SAM SL RH SB.

                • Contributed reagents/materials/analysis tools: ATC MH AB SAM SL RH SB.

                • Wrote the paper: ATC MH AB SAM SL RH SB.

                Article
                PONE-D-16-24166
                10.1371/journal.pone.0160064
                4972314
                27487187
                8a994733-6f29-4fcd-ae75-c2ab68ab96ab
                © 2016 Cohen 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
                : 16 June 2016
                : 11 July 2016
                Page count
                Figures: 2, Tables: 2, Pages: 13
                Funding
                This study was funded by Bristol Myers Squibb and Pfizer. Bristol Myers Squibb provided support in the form of salaries for authors MH and SL, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Pfizer provided support in the form of salaries for authors AB and RH, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. DRG Abacus provided support in the form of salaries for authors SAM and SB, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                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
                Vascular Medicine
                Thromboembolism
                Venous Thromboembolism
                Research and Analysis Methods
                Database and Informatics Methods
                Database Searching
                Research and Analysis Methods
                Research Assessment
                Systematic Reviews
                Medicine and Health Sciences
                Vascular Medicine
                Thromboembolism
                Venous Thromboembolism
                Deep Vein Thrombosis
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Meta-Analysis
                Physical Sciences
                Mathematics
                Statistics (Mathematics)
                Statistical Methods
                Meta-Analysis
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Trials
                Randomized Controlled Trials
                Medicine and Health Sciences
                Pharmacology
                Drug Research and Development
                Clinical Trials
                Randomized Controlled Trials
                Research and Analysis Methods
                Clinical Trials
                Randomized Controlled Trials
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Cardiovascular Therapy
                Anticoagulant Therapy
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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