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Meta-Analysis
. 2023 Apr 14;4(4):CD010956.
doi: 10.1002/14651858.CD010956.pub3.

Oral direct thrombin inhibitors or oral factor Xa inhibitors versus conventional anticoagulants for the treatment of deep vein thrombosis

Xiaoqin Wang #  1 , Yanfang Ma #  2 , Xu Hui  3   4 , Meixuan Li  3   4 , Jing Li  3   4 , Jinhui Tian  3   4 , Qi Wang  5 , Peijing Yan  6 , Jianfeng Li  7 , Ping Xie  7 , Kehu Yang  3   4 , Liang Yao  5
Affiliations
Meta-Analysis

Oral direct thrombin inhibitors or oral factor Xa inhibitors versus conventional anticoagulants for the treatment of deep vein thrombosis

Xiaoqin Wang et al. Cochrane Database Syst Rev. .

Abstract

Background: Deep vein thrombosis (DVT) is a condition in which a clot forms in the deep veins, most commonly of the leg. It occurs in approximately one in 1000 people. If left untreated, the clot can travel up to the lungs and cause a potentially life-threatening pulmonary embolism (PE). Previously, a DVT was treated with the anticoagulants heparin and vitamin K antagonists. However, two forms of direct oral anticoagulants (DOACs) have been developed: oral direct thrombin inhibitors (DTIs) and oral factor Xa inhibitors, which have characteristics that may be favourable compared to conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or dose adjustment and few known drug interactions. DOACs are now commonly being used for treating DVT: recent guidelines recommended DOACs over conventional anticoagulants for both DVT and PE treatment. This Cochrane Review was first published in 2015. It was the first systematic review to measure the effectiveness and safety of these drugs in the treatment of DVT. This is an update of the 2015 review. OBJECTIVES: To assess the effectiveness and safety of oral DTIs and oral factor Xa inhibitors versus conventional anticoagulants for the long-term treatment of DVT.

Search methods: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 1 March 2022.

Selection criteria: We included randomised controlled trials (RCTs) in which people with a DVT, confirmed by standard imaging techniques, were allocated to receive an oral DTI or an oral factor Xa inhibitor compared with conventional anticoagulation or compared with each other for the treatment of DVT. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were recurrent venous thromboembolism (VTE), recurrent DVT and PE. Secondary outcomes included all-cause mortality, major bleeding, post-thrombotic syndrome (PTS) and quality of life (QoL). We used GRADE to assess the certainty of evidence for each outcome.

Main results: We identified 10 new studies with 2950 participants for this update. In total, we included 21 RCTs involving 30,895 participants. Three studies investigated oral DTIs (two dabigatran and one ximelagatran), 17 investigated oral factor Xa inhibitors (eight rivaroxaban, five apixaban and four edoxaban) and one three-arm trial investigated both a DTI (dabigatran) and factor Xa inhibitor (rivaroxaban). Overall, the studies were of good methodological quality. Meta-analysis comparing DTIs to conventional anticoagulation showed no clear difference in the rate of recurrent VTE (odds ratio (OR) 1.17, 95% confidence interval (CI) 0.83 to 1.65; 3 studies, 5994 participants; moderate-certainty evidence), recurrent DVT (OR 1.11, 95% CI 0.74 to 1.66; 3 studies, 5994 participants; moderate-certainty evidence), fatal PE (OR 1.32, 95% CI 0.29 to 6.02; 3 studies, 5994 participants; moderate-certainty evidence), non-fatal PE (OR 1.29, 95% CI 0.64 to 2.59; 3 studies, 5994 participants; moderate-certainty evidence) or all-cause mortality (OR 0.66, 95% CI 0.41 to 1.08; 1 study, 2489 participants; moderate-certainty evidence). DTIs reduced the rate of major bleeding (OR 0.58, 95% CI 0.38 to 0.89; 3 studies, 5994 participants; high-certainty evidence). For oral factor Xa inhibitors compared with conventional anticoagulation, meta-analysis demonstrated no clear difference in recurrent VTE (OR 0.85, 95% CI 0.71 to 1.01; 13 studies, 17,505 participants; moderate-certainty evidence), recurrent DVT (OR 0.70, 95% CI 0.49 to 1.01; 9 studies, 16,439 participants; moderate-certainty evidence), fatal PE (OR 1.18, 95% CI 0.69 to 2.02; 6 studies, 15,082 participants; moderate-certainty evidence), non-fatal PE (OR 0.93, 95% CI 0.68 to 1.27; 7 studies, 15,166 participants; moderate-certainty evidence) or all-cause mortality (OR 0.87, 95% CI 0.67 to 1.14; 9 studies, 10,770 participants; moderate-certainty evidence). Meta-analysis showed a reduced rate of major bleeding with oral factor Xa inhibitors compared with conventional anticoagulation (OR 0.63, 95% CI 0.45 to 0.89; 17 studies, 18,066 participants; high-certainty evidence). AUTHORS' CONCLUSIONS: The current review suggests that DOACs may be superior to conventional therapy in terms of safety (major bleeding), and are probably equivalent in terms of efficacy. There is probably little or no difference between DOACs and conventional anticoagulation in the prevention of recurrent VTE, recurrent DVT, pulmonary embolism and all-cause mortality. DOACs reduced the rate of major bleeding compared to conventional anticoagulation. The certainty of evidence was moderate or high.

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Conflict of interest statement

XW: none known. YM: none known. XH: none known. ML: none known. JL: none known. JT: none known. QW: none known. PY: none known. JFL: none known. PX: none known. KY: none known. LY: none known.

Figures

1
1
Study flow diagram
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
4
4
Funnel plot of oral factor Xa inhibitors versus conventional anticoagulants for recurrent VTE
5
5
Funnel plot of oral factor Xa inhibitors versus conventional anticoagulants for major bleeding
1.1
1.1. Analysis
Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 1: Recurrent venous thromboembolism
1.2
1.2. Analysis
Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 2: Recurrent deep vein thrombosis
1.3
1.3. Analysis
Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 3: Fatal pulmonary embolism
1.4
1.4. Analysis
Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 4: Non‐fatal pulmonary embolism
1.5
1.5. Analysis
Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 5: All‐cause mortality
1.6
1.6. Analysis
Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 6: Major bleeding
1.7
1.7. Analysis
Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 7: Health‐related quality of life: SF‐36 physical component
1.8
1.8. Analysis
Comparison 1: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation, Outcome 8: Health‐related quality of life: SF‐36 psychological component
2.1
2.1. Analysis
Comparison 2: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation (sensitivity analysis excluding ximelagatran), Outcome 1: Recurrent venous thromboembolism
2.2
2.2. Analysis
Comparison 2: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation (sensitivity analysis excluding ximelagatran), Outcome 2: Recurrent deep vein thrombosis
2.3
2.3. Analysis
Comparison 2: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation (sensitivity analysis excluding ximelagatran), Outcome 3: Fatal pulmonary embolism
2.4
2.4. Analysis
Comparison 2: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation (sensitivity analysis excluding ximelagatran), Outcome 4: Non‐fatal pulmonary embolism
2.5
2.5. Analysis
Comparison 2: Oral direct thrombin inhibitors (DTIs) versus conventional anticoagulation (sensitivity analysis excluding ximelagatran), Outcome 5: Major bleeding
3.1
3.1. Analysis
Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 1: Recurrent venous thromboembolism
3.2
3.2. Analysis
Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 2: Recurrent deep vein thrombosis
3.3
3.3. Analysis
Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 3: Fatal pulmonary embolism
3.4
3.4. Analysis
Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 4: Non‐fatal pulmonary embolism
3.5
3.5. Analysis
Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 5: All‐cause mortality
3.6
3.6. Analysis
Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 6: Major bleeding
3.7
3.7. Analysis
Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 7: Post‐thrombotic syndrome
3.8
3.8. Analysis
Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 8: Health‐related quality of life: SF‐36 physical component
3.9
3.9. Analysis
Comparison 3: Oral factor Xa inhibitors versus conventional anticoagulation, Outcome 9: Health‐related quality of life: SF‐36 psychological component
4.1
4.1. Analysis
Comparison 4: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis of participants with versus without active cancer, Outcome 1: Recurrent VTE
4.2
4.2. Analysis
Comparison 4: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis of participants with versus without active cancer, Outcome 2: Major bleeding
5.1
5.1. Analysis
Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 1: Recurrent venous thromboembolism
5.2
5.2. Analysis
Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 2: Recurrent deep vein thrombosis
5.3
5.3. Analysis
Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 3: Fatal pulmonary embolism
5.4
5.4. Analysis
Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 4: Non‐fatal pulmonary embolism
5.5
5.5. Analysis
Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 5: All‐cause mortality
5.6
5.6. Analysis
Comparison 5: Oral factor Xa inhibitors versus conventional anticoagulation: subgroup analysis by different oral factor Xa inhibitors, Outcome 6: Major bleeding
6.1
6.1. Analysis
Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 1: Recurrent venous thromboembolism
6.2
6.2. Analysis
Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 2: Recurrent deep vein thrombosis
6.3
6.3. Analysis
Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 3: Fatal pulmonary embolism
6.4
6.4. Analysis
Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 4: Non‐fatal pulmonary embolism
6.5
6.5. Analysis
Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 5: All‐cause mortality
6.6
6.6. Analysis
Comparison 6: Oral factor Xa inhibitors versus conventional anticoagulation (sensitivity analysis excluding high risk of bias studies), Outcome 6: Major bleeding
7.1
7.1. Analysis
Comparison 7: Oral direct thrombin inhibitor (DTI) versus oral factor Xa inhibitor, Outcome 1: Health‐related quality of life: SF‐36 physical component
7.2
7.2. Analysis
Comparison 7: Oral direct thrombin inhibitor (DTI) versus oral factor Xa inhibitor, Outcome 2: Health‐related quality of life: SF‐36 psychological component
See this image and copyright information in PMC

Update of

Comment in

References

References to studies included in this review

AMPLIFY 2013 {published data only}
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Caravaggio 2020 {published data only}
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de Athayde 2019 {published data only}
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EINSTEIN‐DVT 2010 {published data only}
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EINSTEIN‐DVT dose 2008 {published data only}
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EINSTEIN‐PE 2012 {published data only}
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eTRIS 2016 {published data only}
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Farhan 2019 {published data only}
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Hokusai‐VTE 2013 {published data only}
    1. Bistervels I, Bavalia R, Boersma W, Meijer K, Verhamme P, Ten Cate-Hoek AJ, et al. Hokusai Post-DVT Study: a follow-up study on long-term outcomes of deep vein thrombosis in patients treated with edoxaban vs warfarin. Research and Practice in Thrombosis and Haemostasis 2020;4(Suppl 1):PB2207.
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Hokusai VTE Cancer 2018 {published data only}
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J‐EINSTEIN DVT and PE 2015 {published data only}
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Mokadem 2021 {published data only}
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ODIXa‐DVT 2007 {published data only}
    1. Agnelli G, Gallus A, Goldhaber SZ, Haas S, Huisman MV, Hull RD, et al. Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAT 59-7939 in patients with acute symptomatic deep-vein thrombosis) study. Circulation 2007;116:180-7. - PubMed
Ohmori 2019 {published data only}
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PRAIS 2019 {published data only}
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RE‐COVER 2009 {published data only}
    1. Goldhaber SZ, Schellong S, Kakkar A, Eriksson H, Feuring M, Kreuzer J, et al. Treatment of acute pulmonary embolism with dabigatran versus warfarin. A pooled analysis of data from RE-COVER and RE-COVER II. Thrombosis and Haemostasis 2016;116(4):714-21. - PubMed
    1. NCT00291330. Efficacy and safety of dabigatran compared to warfarin for 6 month treatment of acute symptomatic venous thromboembolism (RE-COVER I). clinicaltrials.gov/ct/show/NCT00291330 (first received 14 February 2006).
    1. Schulman S, Eriksson H, Goldhaber S, Kakkar AK, Kearon C, Kvamme AM, et al. Dabigatran or warfarin for extended maintenance therapy of venous thromboembolism. Journal of Thrombosis and Haemostasis 2011;9(Suppl 2):731-2.
    1. Schulman S, Eriksson H, Goldhaber SZ, Kakkar A, Kearon C, Mismetti P, et al. Safety of dabigatran vs. warfarin for acute venous thromboembolism: pooled analyses of RE-COVER and RE-COVER II. Journal of Thrombosis and Haemostasis 2013;11:225-6.
    1. Schulman S, Eriksson H, Goldhaber SZ, Kakkar A, Kearon C, Schellong SM, et al. Influence of age on the efficacy and safety of dabigatran versus warfarin for the treatment of acute venous thromboembolism: a pooled analysis of RE-COVER and RE-COVER II. Blood 2013;122:2375.
RE‐COVER II 2014 {published data only}
    1. Goldhaber SZ, Schellong S, Kakkar A, Eriksson H, Feuring M, Kreuzer J, et al. Treatment of acute pulmonary embolism with dabigatran versus warfarin. A pooled analysis of data from RE-COVER and RE-COVER II. Thrombosis and Haemostasis 2016;116(4):714-21. - PubMed
    1. NCT00680186. Phase III study testing efficacy & safety of oral dabigatran etexilate vs warfarin for 6 m treatment for acute symp venous thromboembolism (VTE) (RE-COVER II). clinicaltrials.gov/ct2/show/NCT00680186 (first received 20 May 2008).
    1. Schulman S, Eriksson H, Goldhaber SZ, Kakkar A, Kearon C, Mismetti P, et al. Safety of dabigatran vs. warfarin for acute venous thromboembolism: pooled analyses of RE-COVER and RE-COVER II. Journal of Thrombosis and Haemostasis 2013;11:225-6.
    1. Schulman S, Eriksson H, Goldhaber SZ, Kakkar A, Kearon C, Schellong SM, et al. Influence of age on the efficacy and safety of dabigatran versus warfarin for the treatment of acute venous thromboembolism: a pooled analysis of RE-COVER and RE-COVER II. Blood 2013;122:2375.
    1. Schulman S, Eriksson H, Goldhaber SZ, Kakkar A, Kearon C, Schellong SM, et al. Influence of concomitant NSAID or ASA on the efficacy and safety of dabigatran versus warfarin for the treatment of acute venous thromboembolism: a pooled analysis from RE-COVER and RECOVER II. Blood 2013;122(21):212.
Sukovatykh 2017 {published data only}
    1. Sukovatykh BS, Sereditskiĭ AV, Muradian VF, Belikov LN, Gerasimova OF. Results of administering oral anticoagulants for treatment of patients with venous thromboembolic complications. Angiologiia i sosudistaia khirurgiia [Angiology and Vascular Surgery] 2017;23(2):82. - PubMed
THRIVE 2005 {published data only}
    1. Fiessinger JN, Huisman MV, Davidson BL, Bounameaux H, Francis CW, Eriksson H, et al. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomised trial. JAMA 2005;293(6):681-9. - PubMed
    1. Francis CW, Ginsberg JS, Berkowitz SD, Bounameaux H, Davidson BL, Eriksson H, et al. Efficacy and safety of the oral direct thrombin inhibitor ximelagatran compared with current therapy for acute, symptomatic deep vein thrombosis, with or without pulmonary embolus: the THRIVE treatment study. Blood 2003;102(11):Abstract 7.
    1. Harenberg J, Ingrid J, Tivadar F. Treatment of venous thromboembolism with the oral thrombin inhibitor, ximelagatran. Israel Medical Association Journal 2002;4(11):1003-5. - PubMed
    1. Harenberg J, Joerg I, Weiss C. Incidence of recurrent venous thromboembolism of patients after termination of treatment with ximelagatran. European Journal of Clinical Pharmacology 2006;62(3):173-7. - PubMed
    1. Harenberg J, Jorg I, Weiss C, Harenberg J, Jorg I, Weiss C. Observations of alanine aminotransferase and aspartate aminotransferase in THRIVE studies treated orally with ximelagatran. International Journal of Toxicology 2006;25(3):165-9. - PubMed

References to studies excluded from this review

ADAM VTE trial 2020 {published data only}
    1. McBane RD 2nd, Loprinzi CL, Ashrani A, Perez-Botero J, Ferre RA, Henkin S, et al. Apixaban and dalteparin in active malignancy associated venous thromboembolism. The ADAM VTE trial. Thrombosis and Haemostasis 2017;117(10):1952-61. - PubMed
    1. McBane RD 2nd, Wysokinski WE, Le-Rademacher JG, Zemla T, Ashrani A, Tafur A, et al. Apixaban and dalteparin in active malignancy-associated venous thromboembolism: The ADAM VTE trial. Thrombosis and Haemostasis 2020;18(2):411-21. - PubMed
    1. NCT02585713. Apixaban or dalteparin in reducing blood clots in patients with cancer related venous thromboembolism. clinicaltrials.gov/ct2/show/NCT02585713 (first received 23 October 2015).
AMPLIFY Extended Study 2013 {published data only}
    1. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Apixaban for extended treatment of venous thromboembolism. New England Journal of Medicine 2013;368(8):699-708. - PubMed
    1. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson MR, et al. Two doses of apixaban for the extended treatment of venous thromboembolism. Blood 2012;120:LBA-1.
    1. Liu X, Thompson J, Phatak H, Mardekian J, Porcari AR, Johnson MR. Apixaban reduces hospitalization in patients with venous thromboembolism: an analysis of the AMPLIFY-EXT trial. Blood 2013;122(21):3638. [DOI: 10.1182/blood.V122.21.3638.3638] - DOI - PubMed
Borsi 2021 {published data only}
    1. Borsi SH, Raji H, Dargahi MM, Nokhostin F, Kargaran A. Rivaroxaban versus enoxaparin for treatment of patients with nonhematologic cancer with venous thromboembolism: a randomized clinical trial. Tehran University Medical Journal 2021;79(4):281-9.
CASTA DIVA Trial 2022 {published data only}
    1. NCT02746185. Cancer associated thrombosis, a pilot treatment study using rivaroxaban (CASTA-DIVA). clinicaltrials.gov/ct2/show/NCT02746185 (first received 21 April 2016).
    1. Planquette B, Bertoletti L, Charles-Nelson A, Laporte S, Grange C, Mahé I, et al. Rivaroxaban vs dalteparin in cancer-associated thromboembolism: a randomized trial. Chest 2022;161(3):781-90. - PubMed
COBRRA 2017 {published data only}
    1. Castellucci LA, Hogg K, Chiang P, Wu CM, Templier GL, Gal GL, et al. Comparison of bleeding risk between rivaroxaban and apixaban: a pilot feasibility study. Blood 2017;130:1108.
CONKO‐011 study 2015 {published data only}
    1. EUCTR2015-001478-16-DE. The role of rivaroxaban in the treatment of tumor patients with thrombosis. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2015-001478-16-DE (first received 9 September 2015).
    1. NCT02583191. Rivaroxaban in the treatment of venous thromboembolism (VTE) in cancer patients. clinicaltrials.gov/ct2/show/NCT02583191 (first received 22 October 2015).
    1. Riess H, Sinn M, Kreher S. CONKO-011: evaluation of patient satisfaction with the treatment of acute venous thromboembolism with rivaroxaban or low molecular weight heparin in cancer patients. A randomized phase III study. Deutsche Medizinische Wochenschrift 2015;140(Suppl 1):S22. - PubMed
    1. Riess H, Sinn M, Lohneis A, Hellmann M, Striefler J, Südhoff T, et al. Improved patient-reported treatment satisfaction with rivaroxaban as compared to low molecular weight heparins for cancer patients with acute venous thromboembolism – results from the CONKO-011 trial. Research and Practice in Thrombosis and Haemostasis 2021;5(Suppl 2):LPB0041.
    1. Sinn M, Juhling A, Hellmann M, Omar M, Sudhoff T, Stahl M, et al. Patient-reported treatment satisfaction with Rivaroxaban in cancer patients with acute venous thromboembolism - results from the CONKO-011 trial. Oncology Research and Treatment 2021;44(Suppl 2):276-7.
DIVERSITY 2021 {published data only}
    1. Albisetti M, Biss B, Bomgaars L, Brandão LR, Brueckmann M, Chalmers E, et al. Design and rationale for the DIVERSITY study: an open-label, randomized study of dabigatran etexilate for pediatric venous thromboembolism. Research and Practice in Thrombosis and Haemostasis 2018;2(2):347-56. - PMC - PubMed
    1. Albisetti M, Brandão L, Bomgaars L, Chalmers E, Luciani M, Mitchell L, et al. Efficacy and safety of dabigatran etexilate for treatment of venous thromboembolism in paediatric patients - results of the DIVERSITY trial. ISTH Academy 2019:OC 57.3.
    1. Albisetti M, Tartakovsky I, Halton J, Bomgaars L, Chalmers E, Mitchell L, et al. Efficacy and safety of dabigatran in the treatment and secondary prevention of venous thromboembolism in children with central line or implantable device–related thrombosis. Research and Practice in Thrombosis and Haemostasis 2021;5(Suppl 2):OC 69.2.
    1. Brandão L, Tartakovsky I, Halton J, Bomgaars L, Chalmers E, Mitchell L, et al. Efficacy and safety of dabigatran in the treatment and secondary prevention of venous thromboembolism in children with cerebral venous and sinus thrombosis. Research and Practice in Thrombosis and Haemostasis 2021;5(Suppl 2):PB0787.
    1. EUCTR2013-002114-12. Open label study comparing efficacy and safety of dabigatran etexilate to standard of care in paediatric patients with VTE. trialsearch.who.int/?TrialID=EUCTR2013%E2%80%90002114%E2%80%9012%E2%80%9... (first received 18 Feburary 2014).
EINSTEIN‐CHOICE 2017 {published data only}
    1. Prandoni P, Lensing AW, Prins MH, Gebel M, Pap AF, Homering M, et al. Benefits and risks of extended treatment of venous thromboembolism with rivaroxaban or with aspirin. Thrombosis Research 2018;168:121-9. - PubMed
    1. Weitz JI, Lensing AW, Prins MH, Bauersachs R, Beyer-Westendorf J, Bounameaux H, et al. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. New England Journal of Medicine 2017;376(13):1211-22. - PubMed
EINSTEIN‐Jr 2020 {published data only}
    1. Lensing AW, Male C, Young G, Kubitza D, Kenet G, Massicotte MP, et al. Rivaroxaban versus standard anticoagulation for acute venous thromboembolism in childhood. Design of the EINSTEIN-Jr phase III study. Thrombosis Journal 2018;16:34. - PMC - PubMed
    1. Male C, Lensing AW, Palumbo JS, Kumar R, Nurmeev I, Hege K, et al. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial. Lancet Haematology 2020;7(1):e18-e27. - PubMed
    1. NCT01684423. Oral rivaroxaban in children with venous thrombosis (EINSTEIN Junior). clinicaltrials.gov/show/NCT01684423 (first received 13 September 2012).
    1. NCT02234843. EINSTEIN Junior: oral rivaroxaban in children with venous thrombosis. clinicaltrials.gov/ct2/show/NCT02234843 (first received 9 September 2014).
    1. NCT02309411. EINSTEIN Junior phase II: oral rivaroxaban in young children with venous thrombosis (EINSTEIN Jr). hclinicaltrials.gov/ct2/show/NCT02309411 (first received 5 December 2014).
Peacock 2018 {published data only}
    1. NCT02584660. A study of rivaroxaban for early discharge of low risk pulmonary embolism from the emergency department. clinicaltrials.gov/ct2/show/NCT02584660 (first received 22 October 2015).
    1. Peacock FW, Coleman CI, Diercks DB, Francis S, Kabrhel C, Keay C, et al. Emergency department discharge of pulmonary embolus patients. Academic Emergency Medicine 2018;25(9):995-1003. - PMC - PubMed
    1. Peacock W, Diercks D, Francis S, Kabrhel C, Keay C, Kline J, et al. Multicenter trial of rivaroxaban for early discharge of pulmonary embolism from the emergency department. Annals of Emergency Medicine 2017;70(4):S29-S30.
PRIORITY 2022 {published data only}
    1. Kim JH, Yoo C, Seo S, Jeong JH, Ryoo BY, Kim KP, et al. A phase II study to compare the safety and efficacy of direct oral anticoagulants versus subcutaneous dalteparin for cancer-associated venous thromboembolism in patients with advanced upper gastrointestinal, hepatobiliary and pancreatic cancer: PRIORITY. Cancers 2022;14(3):559. - PMC - PubMed
    1. NCT03139487. A randomized phase II open label study to compare the safety and efficacy of subcutaneous dalteparin versus direct oral anticoagulants for cancer-associated venous thromboembolism. clinicaltrials.gov/ct2/show/NCT03139487 (first received 4 May 2017).
REMEDY 2013 {published data only}
    1. Liem TK, DeLoughery TG. Randomised controlled trial: extended-duration dabigatran is non-inferior to warfarin and more effective than placebo for symptomatic VTE. Evidence Based Medicine 2014;19(1):29. - PubMed
    1. Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra A, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. New England Journal of Medicine 2013;368:709-18. - PubMed
RE‐SONATE 2013 {published data only}
    1. Schulman S, Baanstra D, Eriksson H, Goldhaber S, Kakkar A, Kearon C, et al. Dabigatran vs. placebo for extended maintenance therapy of venous thromboembolism. Journal of Thrombosis and Haemostasis 2011;9(Suppl 2):22.
    1. Schulman S, Baanstra D, Eriksson H, Goldhaber SZ, Kakkar A, Kearon C, et al. Benefit of extended maintenance therapy for venous thromboembolism with dabigatran etexilate is maintained over 1 year of post-treatment follow-up. Blood 2012;120(21):Abstract 332.
    1. Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. New England Journal of Medicine 2013;368(8):709-18. - PubMed
SELECT‐D 2018 {published data only}
    1. EUCTR2012-005589-37-GB. Anticoagulation therapy in selected cancer patients at risk of recurrence of venous thromboembolism. trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2012-005589-37-GB (first received 18 February 2013).
    1. Young A, Dunn J, Chapman O, Grumett J, Marshall A, Phillips J, et al. SELECT-D: anticoagulation therapy in selected cancer patients at risk of recurrence of venous thromboembolism. Journal of Clinical Oncology 2014;32(Suppl 15):TPS9661-TPS9661. - PubMed
    1. Young A, Marshall A, Thirlwall J, Hill C, Hale D, Dunn J, et al. Anticoagulation therapy in selected cancer patients at risk of recurrence of venous thromboembolism: results of the select-D™ pilot trial. Blood 2017;130:625.
    1. Young A, Phillips J, Hancocks H, Hill C, Joshi N, Marshall A, et al. Anticoagulation therapy in selected cancer patients at risk of recurrence of venous thromboembolism (OC-11). Thrombosis Research 2016;140(Suppl 1):S172-3. - PubMed
    1. Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). Journal of Clinical Oncology 2018;36(20):2017-23. - PubMed
THRIVE I 2003 {published data only}
    1. Eriksson H, Wåhlander K, Gustafsson D, Welin LT, Frison L, Schulman S, et al. A randomized, controlled, dose-guiding study of the oral direct thrombin inhibitor ximelagatran compared with standard therapy for the treatment of acute deep vein thrombosis: THRIVE I. Journal of Thrombosis and Haemostasis 2003;1:41-7. - PubMed
THRIVE III 2003 {published data only}
    1. Eriksson H, Lundstrom T, Wahlander K, Clason SB, Schulman S. Prognostic factors for recurrence of venous thromboembolism (VTE) or bleeding during long-term secondary prevention of VTE with ximelagatran. Thrombosis and Haemostasis 2005;94(3):522-7. - PubMed
    1. Eriksson H, Wahlander K, Lundstrom T, Billing CS, Schulman S. Extended secondary prevention with the oral direct thrombin inhibitor ximelagatran for 18 months after 6 months of anticoagulation in patients with venous thromboembolism: a randomized, placebo-controlled trial. Blood 2002;100(Suppl):81a.
    1. Schulman S, Lundstrom T, Walander K, Billing CS, Eriksson H. Ximelagatran for the secondary prevention of venous thromboembolism: a complementary follow-up analysis of the THRIVE III study. Thrombosis and Haemostasis 2005;94(4):820-4. - PubMed
    1. Schulman S, Wahlander K, Lundstrom T, Clason SB, Eriksson H, THRIVE III Investigators. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. New England Journal of Medicine 2003;349(18):1713-21. - PubMed

References to studies awaiting assessment

NCT01780987 {published data only}
    1. NCT01780987. A study to evaluate safety and efficacy of apixaban in Japanese acute deep vein thrombosis (DVT) and pulmonary embolism (PE) patients. clinicaltrials.gov/show/NCT01780987 (first received 31 January 2013).

References to ongoing studies

EudraCT 2014‐002606‐20 {published data only}
    1. 2014-002606-20. A randomized, open-label, active controlled, safety and descriptive efficacy study in pediatric subjects requiring anticoagulation for the treatment of a venous thromboembolic event. clinicaltrialsregister.eu/ctr-search/trial/2014-002606-20/3rd (first received 8 June 2015).
NCT01516840 {published data only}
    1. NCT01516840. Venous thromboembolism (VTE) treatment study in Japanese deep vein thrombosis (DVT) patients. clinicaltrials.gov/show/NCT01516840 (first received 25 January 2012).
NCT02464969 {published data only}
    1. NCT02464969. Apixaban for the acute treatment of venous thromboembolism in children. clinicaltrials.gov/ct2/show/NCT02464969 (first received 8 June 2015).
NCT02664155 {published data only}
    1. NCT02664155. Venous thromboembolism in renally impaired patients and direct oral anticoagulants. clinicaltrials.gov/ct2/show/NCT02664155 (first received 26 January 2016).
NCT02744092 {published data only}
    1. NCT02744092. Direct oral anticoagulants (DOACs) versus LMWH +/- warfarin for VTE in cancer. clinicaltrials.gov/ct2/show/NCT02744092 (first received 20 April 2016).
NCT02798471 {published data only}
    1. NCT02798471. Hokusai Study in pediatric patients with confirmed venous thromboembolism (VTE). clinicaltrials.gov/ct2/show/NCT02798471 (first received 14 June 2016).
NCT02829957 {published data only}
    1. NCT02829957. Rivaroxaban vs. apixaban for heavy menstrual bleeding (RAMBLE). clinicaltrials.gov/ct2/show/study/NCT02829957 (first received 12 July 2016).
NCT03129555 {published data only}
    1. NCT03129555. The Danish non-vitamin K antagonist oral anticoagulation study in patients with venous thromboembolism (DANNOAC-VTE). clinicaltrials.gov/ct2/show/NCT03129555 (first received 26 April 2017).
NCT03266783 {published data only}
    1. NCT03266783. Comparison of bleeding risk between rivaroxaban and apixaban for the treatment of acute venous thromboembolism (COBRRA). clinicaltrials.gov/ct2/show/NCT03266783 (first received 30 August 2017).
NCT04066764 {published data only}
    1. NCT04066764. Rivaroxaban and vitamin K antagonists for the anticoagulation for the implantation of vena cava filters (EPICT). clinicaltrials.gov/ct2/show/NCT04066764 (first received 26 August 2019).
NCT05171049 {published data only}
    1. NCT05171049. A study comparing abelacimab to apixaban in the treatment of cancer-associated VTE (ASTER). clinicaltrials.gov/ct2/show/NCT05171049 (first received 28 December 2021).

Additional references

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Cannon 2017
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References to other published versions of this review

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