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


CONCLUSIONS
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.
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.
Caroline
C
Sindet-Pedersen
Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Jannik Langtved
JL
Pallisgaard
Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark.
Jonas Bjerring
JB
Olesen
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.
Gunnar Hilmar
GH
Gislason
Department of Pharmacy, Section for Social and Clinical Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Lourdes Cantarero
LC
Arevalo
D000284:Administration, Oral; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008875:Middle Aged; D054556:Venous Thromboembolism; D014859:Warfarin / Q000494:pharmacology / Q000627:therapeutic use*
D000925:Anticoagulants; D014859:Warfarin
Bleeding; New oral anticoagulants; Recurrent venous thromboembolism; Venous thromboembolism; Vitamin K antagonists