Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2015 Dec 4;2015(12):CD010957.
doi: 10.1002/14651858.CD010957.pub2.

Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of pulmonary embolism

Lindsay Robertson  1 , Patrick Kesteven, James E McCaslin
Affiliations
Review

Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of pulmonary embolism

Lindsay Robertson et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: Pulmonary embolism is a potentially life-threatening condition in which a clot can travel from the deep veins, most commonly in the leg, up to the lungs. Previously, a pulmonary embolism was treated with the anticoagulants heparin and vitamin K antagonists. Recently, however, two forms of direct oral anticoagulants (DOACs) have been developed: oral direct thrombin inhibitors (DTI) and oral factor Xa inhibitors. The new drugs have characteristics that may be favourable over conventional treatment, including oral administration, a predictable effect, lack of frequent monitoring or re-dosing and few known drug interactions. To date, no Cochrane review has measured the effectiveness and safety of these drugs in the long-term treatment (minimum duration of three months) of pulmonary embolism.

Objectives: To assess the effectiveness of oral DTIs and oral factor Xa inhibitors for the long-term treatment of pulmonary embolism.

Search methods: The Cochrane Vascular Trials Search Co-ordinator searched the Specialised Register (last searched January 2015) and the Cochrane Register of Studies (last searched January 2015). Clinical trials databases were also searched for details of ongoing or unpublished studies. We searched the reference lists of relevant articles retrieved by electronic searches for additional citations.

Selection criteria: We included randomised controlled trials in which patients with a pulmonary embolism confirmed by standard imaging techniques were allocated to receive an oral DTI or an oral factor Xa inhibitor for the long-term (minimum duration three months) treatment of pulmonary embolism.

Data collection and analysis: Two review authors (LR, JM) independently extracted the data and assessed the risk of bias in the trials. Any disagreements were resolved by discussion with the third author (PK). We used meta-analyses when we considered heterogeneity low. The two primary outcomes were recurrent venous thromboembolism and pulmonary embolism. Other outcomes included all-cause mortality and major bleeding. We calculated all outcomes using an odds ratio (OR) with a 95% confidence interval (CI).

Main results: We included five randomised controlled trials with a total of 7897 participants. Two studies tested oral DTIs (dabigatran) and three studies tested oral factor Xa inhibitors (one rivaroxaban, one edoxaban and one apixaban).Analysis showed no difference in the effectiveness of oral DTIs and standard anticoagulation in preventing recurrent pulmonary embolism (OR 1.02, 95% CI 0.50 to 2.04; two studies; 1602 participants; high quality evidence), recurrent venous thromboembolism (OR 0.93, 95% CI 0.52 to 1.66; two studies; 1602 participants; high quality evidence), deep vein thrombosis (DVT) (OR 0.79, 95% CI 0.29 to 2.13; two studies; 1602 participants; high quality evidence) and major bleeding (OR 0.50, 95% CI 0.15 to 1.68; two studies; 1527 participants; high quality evidence).For oral factor Xa inhibitors, when we combined the three included studies together in meta-analyses, there was significant heterogeneity for recurrent pulmonary embolism (OR 1.08, 95% CI 0.46 to 2.56; two studies; 4509 participants; I(2) = 58%; moderate quality evidence). The oral factor Xa inhibitors were no more or less effective in the prevention of recurrent venous thromboembolism (OR 0.85, 95% CI 0.63 to 1.15; three studies; 6295 participants; high quality evidence), DVT (OR 0.72, 95% CI 0.39 to 1.32; two studies; 4509 participants; high quality evidence), all-cause mortality (OR 1.16, 95% CI 0.79 to 1.70; one study; 4817 participants; moderate quality evidence) or major bleeding (OR 0.97, 95% CI 0.59 to 1.62; two studies; 4507 participants; high quality evidence). None of the studies measured quality of life.

Authors' conclusions: Moderate to high quality evidence suggests that there are no differences between DOACs and standard anticoagulation for the long-term treatment of pulmonary embolism, for the outcomes recurrent pulmonary embolism, recurrent venous thromboembolism, DVT, all-cause mortality and major bleeding.

PubMed Disclaimer

Conflict of interest statement

LR: none known. PK: I have received consultancy fees for attendance at advisory boards of Boehringer‐Ingelheim, Bayer and Daiitchi‐Sankyo and payment from Bayer for lectures at the 2013 anticoagulation master class. My institution was paid travel/accommodation/meeting expenses by Boehringer‐Ingelheim for my attendance at the 2013 ISTH meeting and staff and NHS costs by Boehringer‐Ingelheim and Daiitchi‐Sankyo for involvement in phase III trials of novel anticoagulants in venous thrombosis. Since Summer 2014 I have declined all invitations to advisory boards, or lectures on behalf of the pharmaceutical industry. JM: I received travel, course fees, accommodation and meals from Medtronic as part of the Medtronic University program. This is an educational program, and includes registration and attendance at the European Vascular Course 2012. No financial remuneration was received by myself, other than costs of travel, accommodation, course fees and meals. I received sponsorship to attend the Vascular Society annual meeting 2012 and 2014 in the form of registration fees and accommodation/travel costs. I received sponsorship to attend a stenting master class, the Verve clinical meeting in 2013, and a technology forum in Phoenix, Arizona from Gore Medical. This was in the form of travel, accommodation and meals. No other financial remuneration was received. I received sponsorship to attend the LINC 2015 meeting in Leipzig, Germany from Abbott Medical in the form of registration, accommodation, travel and meals. I am a co‐founder of UKETS, a trainee initiative, which receives funding through sponsorship from endovascular technology and simulation companies. The majority of this is non‐financial (i.e. the companies supply trainers on the courses or allow use of their simulators), although some direct financial input is received from Vascutek and Mentice and is used to run events. No profit is derived from this initiative. Medtronic, Gore Medical, Abbott Medical, Vascutek and Mentice do not manufacture any pharmaceuticals, including anticoagulants.

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.
1.1
1.1. Analysis
Comparison 1 Oral DTI versus standard anticoagulation, Outcome 1 Recurrent pulmonary embolism.
1.2
1.2. Analysis
Comparison 1 Oral DTI versus standard anticoagulation, Outcome 2 Recurrent venous thromboembolism.
1.3
1.3. Analysis
Comparison 1 Oral DTI versus standard anticoagulation, Outcome 3 Deep vein thrombosis.
1.4
1.4. Analysis
Comparison 1 Oral DTI versus standard anticoagulation, Outcome 4 Major bleeding.
2.1
2.1. Analysis
Comparison 2 Oral factor Xa versus standard anticoagulation, Outcome 1 Recurrent pulmonary embolism.
2.2
2.2. Analysis
Comparison 2 Oral factor Xa versus standard anticoagulation, Outcome 2 Recurrent venous thromboembolism.
2.3
2.3. Analysis
Comparison 2 Oral factor Xa versus standard anticoagulation, Outcome 3 Deep vein thrombosis.
2.4
2.4. Analysis
Comparison 2 Oral factor Xa versus standard anticoagulation, Outcome 4 All‐cause mortality.
2.5
2.5. Analysis
Comparison 2 Oral factor Xa versus standard anticoagulation, Outcome 5 Major bleeding.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

References to studies included in this review

AMPLIFY Study {published data only}
    1. Agnelli G. Apixaban was noninferior to enoxaparin plus warfarin in patients with acute venous thromboembolism. Annals of Internal Medicine 2013;159(8):JC2. - PubMed
    1. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Oral apixaban for the treatment of acute venous thromboembolism. New England Journal of Medicine 2013;369(9):799‐808. - PubMed
    1. Agnelli GB, Masiukiewicz UP. Apixaban for the treatment of symptomatic deep‐vein thrombosis and pulmonary embolism: a randomized, double‐blind trial (AMPLIFY). Journal of Thrombosis and Haemostasis 2013;11(Suppl):18.
    1. NCT00633893. Efficacy and safety study of apixaban for the treatment of deep vein thrombosis or pulmonary embolism. http://clinicaltrials.gov/ct2/show/NCT00633893?term=ajax&rank=5 2009.
EINSTEIN‐PE {published data only}
    1. Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. New England Journal of Medicine 2012;366:1287‐97. - PubMed
    1. NCT00439777. Oral direct factor Xa inhibitor rivaroxaban In patients with acute symptomatic pulmonary embolism with or without symptomatic deep‐vein thrombosis: Einstein‐PE evaluation. https://clinicaltrials.gov/ct2/show/NCT00439777 (accessed June 2015) 2008.
    1. Prins M, Bamber L, Cano S, Wang M, Lensing AWA, Bauersachs R. Patient‐reported treatment satisfaction with oral rivaroxaban versus standard therapy in the treatment of acute symptomatic pulmonary embolism. Blood 2012;120(21):Abstract 1163.
    1. Prins MH, Lensing AW, Bauersachs R, Bellen B, Bounameaux H, Brighton TA, et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN‐DVT and PE randomized studies. Thrombosis Journal 2013;11(1):21. - PMC - PubMed
    1. Prins MHE. Incidence of recurrent venous thromboembolism in patients following completion of the EINSTEIN DVT and EINSTEIN PE studies. Journal of Thrombosis and Haemostasis 2013;11(Suppl):257.
Hokusai‐VTE Study {published data only}
    1. Raskob G, Buller H, Prins M, Segers A, Shi M, Schwocho L, et al. Edoxaban for the long‐term treatment of venous thromboembolism: rationale and design of the Hokusai‐venous thromboembolism study ‐ methodological implications for clinical trials. Journal of Thrombosis and Haemostasis 2013;11(7):1287‐94. - PubMed
    1. Raskob GE, Buller H, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, et al. Edoxaban for long‐term treatment of venous thromboembolism in cancer patients. Blood 2013;122(21):211.
    1. The Hokusai‐VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. New England Journal of Medicine 2013;369(15):1406‐15. - PubMed
RE‐COVER {published data only}
    1. NCT00291330. Efficacy and safety of dabigatran compared to warfarin for 6 month treatment of acute symptomatic venous thromboembolism (RE‐COVER I). http://clinicaltrials.gov/ct/show/NCT00291330 (accessed June 2015) 2007.
    1. Schulman S, Baanstra D, Eriksson H, Goldhaber S, Kakkar A, Kearon C. 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, Eriksson H, Feuring M, Hantel S. Efficacy of dabigatran versus warfarin in patients with acute venous thromboembolism and thrombophilia: a pooled analysis of RE‐COVER and RE‐COVER II. Circulation. 2014; Vol. 130:A18594.
    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. - PubMed
RE‐COVER II {published data only}
    1. Schulman S. A randomized trial of dabigatran versus warfarin in the treatment of acute venous thromboembolism (RE‐COVER II). Blood 2011;118(21):95‐6.
    1. Schulman S, Eriksson H, Feuring M, Hantel S. Efficacy of dabigatran versus warfarin in patients with acute venous thromboembolism and thrombophilia: a pooled analysis of RE‐COVER and RE‐COVER II. Circulation. 2014; Vol. 130:A18594.
    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. - PubMed
    1. Schulman S, Eriksson H, Goldhaber SZ, Kakkar A, Kearon C, Mismetti P, et al. Treatment of acute pulmonary embolism with dabigatran or warfarin: a pooled analysis of efficacy data from RE‐COVER and RE‐COVER II. European Society of Cardiology Conference, Barcelona, Spain. 2014:Abstract: P5509.
    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.

References to studies excluded from this review

Ageno 2014 {published data only}
    1. Ageno W, Mantovani LG, Haas S, Kreutz R, Haupt V, et al. XALIA: Rationale and design of a non‐interventional study of rivaroxaban compared with standard therapy for initial and long‐term anticoagulation in deep vein thrombosis. Thrombosis Journal 2014;12(1):16. - PMC - PubMed
AMPLIFY Extended Study {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(21):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):Abstract 3638. - PubMed
Botticelli DVT Study {published data only}
    1. Barrett YC, Wang J, Knabb R, Mohan P. Apixaban decreases coagulation activity in patients with acute deep‐vein thrombosis. Thrombosis and Haemostasis 2011;105:181‐9. - PubMed
    1. Botticelli IWC, Buller H, Deitchman D, Prins M, Segers A. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose‐ranging study. Journal of Thrombosis and Haemostasis 2008;6(8):1313‐8. - PubMed
    1. Buller HR. A dose finding study of the oral direct factor Xa inhibitor apixaban in the treatment of patients with acute symptomatic deep vein thrombosis ‐ The Botticelli Investigators. XXIst Congress of the International Society on Thrombosis and Haemostasis; 2007 Jul 6‐12; Geneva. 2007.
    1. NCT00252005. Oral direct factor Xa‐inhibitor apixaban in patients with acute symptomatic deep‐vein thrombosis ‐ the Botticelli DVT study. http://clinicaltrials.gov/ct/show/NCT00252005?order=1 2007.
Einstein‐DVT Dose Study {published data only}
    1. Buller H, Darius H. EINSTEIN DVT: Oral rivaroxaban versus standard therapy in the initial treatment of symptomatic deep vein thrombosis and long‐term prevention of recurrent venous thromboembolism. http://www.escardio.org/congresses/esc‐2010/congress‐reports/Pages/708‐4... 2010.
    1. Buller HR, Agnelli G. Once‐ or twice‐daily rivaroxaban for the treatment of proximal deep vein thrombosis: similar efficacy and safety to standard therapy in dose‐ranging studies. Blood 2006;108(11 Pt 1):172‐3.
    1. Buller HR, Lensing AW, Prins MH, Agnelli G, Cohen A, Gallus AS, et al. A dose‐ranging study evaluating once‐daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein‐DVT dose‐ranging study. Blood 2008;112(6):2242‐7. - PubMed
    1. NCT00395772. Once‐daily oral direct factor Xa inhibitor BAY 59‐7939 in patients with acute symptomatic deep‐vein thrombosis. The Einstein‐DVT dose‐finding study. http://clinicaltrials.gov/ct2/show/NCT00395772?term=einstein‐dvt&rank=2 2006.
Einstein DVT Study {published data only}
    1. Bamber L, Wang MY, Prins MH, Ciniglio C, et al. Patient‐reported treatment satisfaction with oral rivaroxaban versus standard therapy in the treatment of acute symptomatic deep‐vein thrombosis. Thrombosis and Haemostasis 2013;110(4):732‐41. - PubMed
    1. Buller HR. Oral rivaroxaban for the acute and continued treatment of symptomatic venous thromboembolism. The Einstein‐DVT and Einstein‐Extension study. Blood 2010;116(21):Abstract 187.
    1. Prandoni P. Treatment of patients with acute deep vein thrombosis and/or pulmonary embolism: efficacy and safety of non‐VKA oral anticoagulants in selected populations. Thrombosis Research 2014;134(2):227‐33. - PubMed
EINSTEIN Extension Study {published data only}
    1. NCT00439725. Once ‐ daily oral direct factor Xa inhibitor rivaroxaban In the long‐term prevention of recurrent symptomatic venous thromboembolism in patients with symptomatic deep‐vein thrombosis or pulmonary embolism. The Einstein‐Extension study. http://clinicaltrials.gov/ct2/show/NCT00439725?term=NCT00439725&rank=1 2008.
ODIXa‐DVT Study {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 BAY 59‐7939 in patients with acute symptomatic deep‐vein thrombosis) study. Circulation 2007;116(2):180‐7. - PubMed
    1. Anon. Oral direct factor Xa inhibitor BAY 59‐7939 in patients with acute symptomatic proximal deep vein thrombosis. ‐ ODIXa‐DVT study. http://trialfinder.bayerscheringpharma.de/html/pdf/11223_Study_Synopsis_... 2008. - PubMed
Piazza 2014 {published data only}
    1. NCT01662908. A randomized, open‐label, parallel‐group, multi‐center study for the evaluation of efficacy and safety of edoxaban monotherapy versus low molecular weight (LMW) heparin/warfarin in subjects with symptomatic deep‐vein thrombosis (eTRIS). http://www.clinicaltrials.gov/ct2/show/NCT01662908?term=edoxaban&rank=4 (accessed 3 February 2015).
    1. Piazza G, Mani V, Grosso M, Mercuri M, Lanz H, Schussler S, et al. A randomized, open‐label, multicenter study of the efficacy and safety of edoxaban monotherapy versus low‐molecular weight heparin/warfarin in patients with symptomatic deep vein thrombosis‐edoxaban thrombus reduction imaging study (eTRIS). Circulation 2014;130:A12074.
REMEDY {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 D, et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. New England Journal of Medicine 2013;368(8):709‐18. - PubMed
RE‐SONATE {published data only}
    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
THRIVE {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 randomized trial. JAMA 2005;293(6):681‐9. - PubMed
    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
THRIVE I {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, 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(1):41‐7. - PubMed
    1. Eriksson H, Wahlander K, Lundstrom T, Billing Clason S, 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;100:81a.
    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. Huisman MV, The THRIVETSI. Efficacy and safety of the oral direct thrombin inhibitor ximelagatran compared with current standard therapy for acute symptomatic deep vein thrombosis, with or without pulmonary embolism: a randomized, double‐blind, multinational study. Journal of Thrombosis & Haemostasis 2003;1(Suppl 1):Abstract OC003.
THRIVE III {published data only}
    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
    1. Schulman S, Wahlander K, Lundstrom T, Clason SB, Eriksson H, THRIVE III I. 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 ongoing studies

ChiCTR‐TRC‐14005223 {published data only}
    1. ChiCTR‐TRC‐14005223. Efficacy and safety of rivaroxaban or warfarin on venous thromboembolic disease: a randomized controlled trial. http://www.chictr.org/en/proj/show.aspx?proj=10248 (accessed 1 February 2015).
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. http://clinicaltrials.gov/show/NCT01780987 (accessed 1 March 2014).
NCT01895777   {published data only}
    1. NCT01895777. Open label study comparing efficacy and safety of dabigatran etexilate to standard of care in paediatric patients with venous thromboembolism (VTE). http://clinicaltrials.gov/show/NCT01895777 (accessed 1 March 2014).
NCT02234843 {published data only}
    1. NCT02234843. EINSTEIN Junior phase III: oral rivaroxaban in children with venous thrombosis (EINSTEIN Jr). https://clinicaltrials.gov/ct2/show/NCT02234843 (accessed 1 February 2015).
NCT02309411 {published data only}
    1. NCT02309411. EINSTEIN Junior phase II: oral rivaroxaban in young children with venous thrombosis (EINSTEIN Jr). https://clinicaltrials.gov/ct2/show/NCT02309411 (accessed 1 February 2015).

Additional references

Ageno 2012
    1. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G, American College of Chest Physicians. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest 2012;141(Suppl 2):e44S‐88S. - PMC - PubMed
Agnelli 2007
    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 BAY 59‐7939 in patients with acute symptomatic deep‐vein thrombosis) study. Circulation 2007;116(2):180‐7. - PubMed
Agnelli 2013
    1. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Oral apixaban for the treatment of acute venous thromboembolism. New England Journal of Medicine 2013;369(9):799‐808. - PubMed
Anderson 2009
    1. Anderson DR, Barnes DC. Computerized tomographic pulmonary angiography versus ventilation perfusion lung scanning for the diagnosis of pulmonary embolism. Current Opinion in Pulmonary Medicine 2009;15(5):425‐9. - PubMed
Antoniazzi 2103
    1. Antoniazzi S, Berdai D, Conti V, Robinson P, Radice S, Clementi E, et al. Risk of major bleeding with dabigatran versus active controls: a systematic review and meta‐analysis. Congres de Physiologie de Pharmacolgoie et de Therapeutique; 2013 April 22‐24. 2013.
Atkins 2004
    1. Atkins D, Best D, Briss PA, Eccles M, Falck‐Ytter Y, Flottorp S, et al. GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004;328(7454):1490‐4. - PMC - PubMed
Baetz 2008
    1. Baetz BE, Spinler SA. Dabigatran etexilate: an oral direct thrombin inhibitor for prophylaxis and treatment of thromboembolic diseases. Pharmacotherapy 2008;28(11):1354‐73. - PubMed
Botticelli Investigators
    1. Botticelli Investigators, Writing Committee, Buller H, Deitchman D, Prins M, Segers A. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose‐ranging study. Journal of Thrombosis and Haemostasis 2008;6(8):1313‐8. - PubMed
Boudes 2006
    1. Boudes PF. The challenges of new drugs benefits and risks analysis: lessons from the ximelagatran FDA Cardiovascular Advisory Committee. Contemporary Clinical Trials 2006;27(5):432‐40. - PubMed
Boutitie 2011
    1. Boutitie F, Pinede L, Schulman S, Agnelli G, Raskob G, Julian J, et al. Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants' data from seven trials. BMJ 2011;342:d3036. - PMC - PubMed
Castellucci 2013
    1. Castellucci LA, Cameron C, Gal G, Rodger MA, Coyle D, Wells PS, et al. Efficacy and safety outcomes of oral anticoagulants and antiplatelet drugs in the secondary prevention of venous thromboembolism: systematic review and network meta‐analysis. BMJ 2013;347:f5133. - PMC - PubMed
Connolly 2009
    1. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. New England Journal of Medicine 2009;361(12):1139‐51. - PubMed
Deeks 2011
    1. Deeks JJ, Higgins JPT, Altman DG (editors). Chapter 9: Analysing data and undertaking meta‐analyses. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
Eikelboom 2010
    1. Eikelboom JW, Weitz JI. Update on antithrombotic therapy: new anticoagulants. Circulation 2010;121(13):1523‐32. - PubMed
EINSTEIN Investigators
    1. EINSTEIN Investigators, Bauersachs R, Berkowitzm SD, Brenner B, Buller HR, Decousus H, et al. Oral rivaroxaban for symptomatic venous thromboembolism. New England Journal of Medicine 2010;363(26):2499‐510. - PubMed
Eriksson 2003
    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(1):41‐7. - PubMed
Eriksson 2007
    1. Eriksson BI, Dahl OE, Rosenecher N, Kurtha AA, Dijk CN, Frostick SP, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE‐MODEL randomized trial. Journal of Thrombosis and Haemostasis 2007;5(11):2178‐85. - PubMed
Eriksson 2009
    1. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clinical Pharmacokinetics 2009;48(1):1‐22. - PubMed
Fox 2012
    1. Fox BD, Kahn SR, Langleben D, Eisenberg MJ, Shimony A. Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta‐analysis of randomised controlled trials. BMJ 2012;345:e7498. - PMC - PubMed
Gomez‐Outes 2014
    1. Gomez‐Outes A, Terleira‐Fernandez AI, Lecumberri R, Suarez‐Gea ML, Vargas‐Castrillon E. Direct oral anticoagulants in the treatment of acute venous thromboembolism: a systematic review and meta‐analysis. Thrombosis Research 2014;134(4):774‐82. - PubMed
Higgins 2011
    1. Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
Hirschl 2014
    1. Hirschl M, Kundi M. New oral anticoagulants in the treatment of acute venous thromboembolism ‐ a systematic review with indirect comparisons. [Review]. Vasa 2014;43(5):353‐64. - PubMed
Huerta 2007
    1. Huerta C, Johansson S, Wallander MA, Garcia Rodriguez LA. Risk factors and short‐term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Archives of Internal Medicine 2007;167(9):935‐43. - PubMed
Kam 2005
    1. Kam PC, Kaur N, Thong CL. Direct thrombin inhibitors: pharmacology and clinical relevance. Anaesthesia 2005;60(6):565‐74. - PubMed
Kang 2014
    1. Kang N, Sobieraj DM. Indirect treatment comparison of new oral anticoagulants for the treatment of acute venous thromboembolism. Thrombosis Research 2014;133:1145‐51. - PubMed
Kearon 2012
    1. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e419S‐94S. - PMC - PubMed
Laurence 2012
    1. Laurence IJ, Redman SL, Corrigan AJ, Graham RN. V/Q SPECT imaging of acute pulmonary embolus ‐ a practical perspective. Clinical Radiology 2012;67(10):941‐8. - PubMed
Lee 2011
    1. Lee CJ, Ansell JE. Direct thrombin inhibitors. British Journal of Clinical Pharmacology 2011;72(4):581‐92. - PMC - PubMed
NICE 2012a
    1. National Institute for Health and Care Excellence. Venous thromboembolic diseases: the management of thromboembolic diseases and the role of thrombophilia testing, 2012. guidance.nice.org.uk/CG144 (accessed 11 January 2014).
NICE 2012b
    1. National Institute of Health and Care Excellence. Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism, 2012. guidance.nice.org.uk/TA261 (accessed 11 January 2014).
NICE 2013
    1. National Institute for Health and Care Excellence. Pulmonary embolism likely based on two‐level Wells score, 2013. http://pathways.nice.org.uk/pathways/venous‐thromboembolism/pulmonary‐em... (accessed 11 January 2013).
NICE 2014
    1. National Institute for Health Care and Excellence. Dabigatran etexilate for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism. NICE technology appraisal guidance [TA327] December 2014.
Oldgren 2011
    1. Oldgren J, Budaj A, Granger CB, Khder Y, Roberts J, Siegbahn A, et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double‐blind, phase II trial. European Heart Journal 2011;32(22):2781‐9. - PubMed
Palladino 2013
    1. Palladino M, Merli G, Thomson L. Evaluation of the oral direct factor Xa inhibitor ‐ betrixaban. Expert Opinion on Investigational Drugs 2013;22(11):1465‐72. - PubMed
Qaseem 2007
    1. Qaseem A, Snow V, Barry PE, Hornbake R, Rodnick JE, Tobolic T, et al. Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians. Annals of Internal Medicine 2007;146(6):454‐8. - PubMed
RevMan 2014 [Computer program]
    1. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Riedel 2004
    1. Riedel M. Diagnosing pulmonary embolism. Postgraduate Medicine Journal 2004;80(944):309‐19. - PMC - PubMed
Robertson 2015
    1. Robertson L, Kesteven P. Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis. Cochrane Database of Systematic Reviews 2015, Issue 6. [DOI: 10.1002/14651858.CD010956.pub2] - DOI - PubMed
Sardar 2014
    1. Sardar P, Chatterjee S, Mukherjee D. Efficacy and safety or new oral anticoagulants for extended treatment of venous thromboembolism: systematic review and meta‐analyses of randomised controlled trials. Drugs 2013;73:1171‐82. - PubMed
Schulman 2005
    1. Schulman S, Kearon C, and the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non‐surgical patients. Journal of Thrombosis and Haemostasis 2005;3(4):692‐4. - PubMed
Schulman 2011
    1. Schulman S, Kakkar AK, Schellong SM, Goldhaber SZ, Henry E, Mismetti P, et al. A randomized trial of dabigatran versus warfarin in the treatment of acute venous thromboembolism (RE‐COVER II). Blood 2011;118:Abstract 205.
SIGN 2010
    1. Scottish Intercollegiate Guidelines Network. Prevention and management of venous thromboembolism: a national clinical guideline, 2010. www.sign.ac.uk/pdf/sign122.pdf (accessed 11 January 2014).
Spyropoulos 2012
    1. Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery. Blood 2012;120(15):2954‐62. - PubMed
Sterne 2011
    1. Sterne JAC, Egger M, Moher D. Chapter 10: Addressing reporting biases. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
Van de Werf 2012
    1. Werf F, Brueckmann M, Connolly SJ, Friedman J, Granger CB, Hartter S, et al. A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: the randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE‐ALIGN). American Heart Journal 2012;163(6):931‐7. - PubMed
van der Huille 2014
    1. Huille T, Exter PL, Dekkers OM, Klok FA. Effectiveness and safety of novel anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta‐analysis. Journal of Thrombosis and Haemostasis 2014;12:320‐8. - PubMed
Weitz 2003
    1. Weitz JI. A novel approach to thrombin inhibition. Thrombosis Research 2003;109(Suppl 1):S17‐22. - PubMed
Wells 2000
    1. Wells PS, Anderson DR, Rodger M, Ginsberg JS, Kearon C, Gent M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D‐dimer. Thrombosis and Haemostasis 2000;83(3):416‐20. - PubMed

References to other published versions of this review

Robertson 2014b
    1. Robertson L, Kesteven P. Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of pulmonary embolism. Cochrane Database of Systematic Reviews 2014, Issue 2. [DOI: 10.1002/14651858.CD010957] - DOI - PMC - PubMed

MeSH terms