Safety and efficacy of direct oral anticoagulants compared to warfarin for extended treatment of venous thromboembolism -a systematic review and meta-analysis

Caroline Sindet-Pedersen; Jannik Langtved Pallisgaard; Jonas Bjerring Olesen; Gunnar Hilmar Gislason; Lourdes Cantarero Arevalo

doi:10.1016/j.thromres.2015.07.022

Safety and efficacy of direct oral anticoagulants compared to warfarin for extended treatment of venous thromboembolism -a systematic review and meta-analysis

Thromb Res. 2015 Oct;136(4):732-8. doi: 10.1016/j.thromres.2015.07.022. Epub 2015 Jul 29.

Authors

Caroline Sindet-Pedersen¹, Jannik Langtved Pallisgaard², Jonas Bjerring Olesen³, Gunnar Hilmar Gislason⁴, Lourdes Cantarero Arevalo⁵

Affiliations

¹ Department of Pharmacy, Section for Social and Clinical Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark. Electronic address: carolinesindet@gmail.com.
² Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
³ Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark.
⁴ Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; The National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark; The Danish Heart Foundation, Copenhagen, Denmark.
⁵ Department of Pharmacy, Section for Social and Clinical Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.

PMID: 26277682
DOI: 10.1016/j.thromres.2015.07.022

Abstract

Objective: To examine and compare the safety and efficacy of extended treatment with dabigatran, apixaban, rivaroxaban and warfarin in patients with unprovoked venous thromboembolism.

Methods: PubMed and Embase were searched for randomized clinical trials reporting on the use of direct oral anticoagulants (DOACs) and warfarin for the extended treatment of VTE. Meta-analysis was performed on studies reporting similar study design and comparator.

Results: A total of 729 articles were identified and 5 studies covering 6 randomized clinical trials met the eligibility criteria and were included in the study. 5 studies were included in the meta-analysis. Results from the meta-analysis showed that the extended use of DOACs and warfarin significantly decreased the risk of recurrent VTE with 83 % when compared placebo. Warfarin (RR: 0.03, CI: 0.00-0.49) and dabigatran (RR: 0.08, CI: 0.03-0.27) showed the largest relative risk reduction followed by apixaban 2.5mg (RR: 0.19, CI: 0.11-0.33), rivaroxaban (RR:0.19, CI: 0.09-0.40) and apixaban 5mg (RR: 0.20, CI: 0.11-0.34). No significant increased risk of major bleeding was observed with the extended use of any DOACs and warfarin compared to placebo (1.15, CI: 0.40-3.31), but an overall increased risk of non-major clinically relevant bleeding (NMCRB) was observed (RR: 2.12, CI: 1.55-2.90). Apixaban 2.5mg and warfarin was not individually associated with an increased risk of NMCRB. Furthermore, it was found from a study not included in the meta-analysis that dabigatran was non-inferior to VKA for the prevention of recurrent VTE (HR: 1.44, CI: 0.78-2.64, p=0.01 for noninferiority) and decreased the risk of NMCRB compared to VKA (RR: 0.58, CI: 0.43-0.77).

Conclusion: Extended treatment with both warfarin and DOACs are effective in preventing recurrent VTE and does not increase the risk of major bleeding, but increases the risk of NMCRB.

Keywords: Bleeding; New oral anticoagulants; Recurrent venous thromboembolism; Venous thromboembolism; Vitamin K antagonists.

Publication types

Meta-Analysis
Review
Systematic Review

MeSH terms

Administration, Oral
Anticoagulants / pharmacology
Anticoagulants / therapeutic use*
Humans
Middle Aged
Venous Thromboembolism
Warfarin / pharmacology
Warfarin / therapeutic use*

Substances

Anticoagulants
Warfarin