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 references 26

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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.

Laura Dekkers, P Martijn den Reijer, P. F. Klok … (2013)

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.

T Petterson, L. Joseph Melton, D Mohr … (2000)

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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Use of indirect and mixed treatment comparisons for technology assessment.

Nicola Cooper, Alex Sutton, Philip Ades … (2007)

Indirect and mixed treatment comparison (MTC) approaches to synthesis are logical extensions of more established meta-analysis methods. They have great potential for estimating the comparative effectiveness of multiple treatments using an evidence base of trials that individually do not compare all treatment options. Connected networks of evidence can be synthesized simultaneously to provide estimates of the comparative effectiveness of all included treatments and a ranking of their effectiveness with associated probability statements. The potential of the use of indirect and MTC methods in technology assessment is considerable, and would allow for a more consistent assessment than simpler alternative approaches. Although such models can be viewed as a logical and coherent extension of standard pair-wise meta-analysis, their increased complexity raises some unique issues with far-reaching implications concerning how we use data in technology assessment, while simultaneously raising searching questions about standard pair-wise meta-analysis. This article reviews pair-wise meta-analysis and indirect and MTC approaches to synthesis, clearly outlining the assumptions involved in each approach. It also raises the issues that the National Institute for Health and Clinical Excellence (NICE) needed to consider in updating their 2004 Guide to the Methods of Technology Appraisal, if such methods are to be used in their technology appraisals.

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Author and article information

Contributors

Yoshihiro Fukumoto: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 3 August 2016

Publication date Collection: 2016

Volume: 11

Issue: 8

Electronic Location Identifier: 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.

* E-mail: sbatson@ 123456teamdrg.com

Article

Publisher ID: PONE-D-16-24166

DOI: 10.1371/journal.pone.0160064

PMC ID: 4972314

PubMed ID: 27487187

SO-VID: 8a994733-6f29-4fcd-ae75-c2ab68ab96ab

License:

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

Date received : 16 June 2016

Date accepted : 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.

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Data Availability All relevant data are within the paper and its Supporting Information files.

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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Conclusions

Related collections

PLOS Climate

Most cited references 26

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.

Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study.

Use of indirect and mixed treatment comparisons for technology assessment.

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