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Thromb Haemost 2017; 117(02): 382-389
DOI: 10.1160/TH16-07-0494
Stroke, Systemic or Venous Thromboembolism
Schattauer GmbH

Real-life treatment of venous thromboembolism with direct oral anticoagulants: The influence of recommended dosing and regimens

Javier Trujillo-Santos
1   Department of Internal Medicine, Hospital General Universitario Santa Lucía, Murcia, Spain
,
Pierpaolo Di Micco
2   Department of Internal Medicine and Emergency Room, Ospedale Buon Consiglio Fatebenefratelli, Naples, Italy
,
Francesco Dentali
3   Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy
,
James Douketis
4   Department of Medicine, St. Joseph’s Healthcare, McMaster University, Hamilton, Ontario, Canada
,
José Antonio Díaz-Peromingo
5   Department of Internal Medicine, Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain
,
Manuel Jesús Núñez
6   Department of Internal Medicine, Complejo Hospitalario de Pontevedra, Pontevedra, Spain
,
Inmaculada Cañas
7   Department of Internal Medicine, Hospital General de Granollers, Barcelona, Spain
,
Daniela Mastroiacovo
8   Department of Angiology, Ospedale SS. Filippo e Nicola, Avezzano, Italy
,
Marta Saraiva De Sousa
9   Department of Internal Medicine, Centro Hospitalar Gaia/Espinho, EPE. Vila Nova de Gaia, Portugal
,
Manuel Monreal
10   Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol de Badalona, Universidad Católica de Murcia, Murcia, Spain
,
RIETE Investigators › Author Affiliations Financial support: Sanofi Spain supported this Registry with an unrestricted educational grant. Support by Bayer Pharma AG was limited to the part of RIETE outside Spain, which accounts for a 23.06 % of the total patients included in the RIETE Registry.
Further Information

Publication History

Received:04 July 2016

Accepted after major revision:06 October 2016

Publication Date:
01 December 2017 (online)

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Summary

In patients with venous thromboembolism (VTE), the influence on outcome of using direct oral anticoagulants (DOACs) at non-recommended doses or regimens (once vs twice daily) has not been investigated yet. We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) registry to compare the outcomes in patients with VTE receiving DOACs according to the recommendations of the product label versus in those receiving non-recommended doses and/or regimens. The major outcomes were the rate of VTE recurrences, major bleeding and death during the course of therapy. As of March 2016, 1635 VTE patients had received DOACs for initial therapy and 1725 for long-term therapy. For initial therapy, 287 of 1591 patients (18 %) on rivaroxaban and 22 of 44 (50 %) on apixaban did not receive the recommended therapy. For long-term therapy, 217 of 1611 patients (14 %) on rivaroxaban, 29 of 81 (36 %) on apixaban and 15 of 33 (46 %) on dabigatran did not receive the recommended therapy. During the course of therapy with DOACs, eight patients developed VTE recurrences, 14 had major bleeding and 13 died. Patients receiving DOACs at non-recommended doses and/or regimens experienced a higher rate of VTE recurrences (adjusted HR: 10.5; 95 %CI: 1.28–85.9) and a similar rate of major bleeding (adjusted HR: 1.04; 95 %CI: 0.36–3.03) or death (adjusted HR: 1.41; 95 %CI: 0.46–4.29) than those receiving the recommended doses and regimens. In our cohort, a non-negligible proportion of VTE patients received non-recommended doses and/or regimens of DOACs. This use may be associated with worse outcomes.

Keywords

clinical studies - pulmonary embolism - deep-vein thrombosis

* A full list of RIETE investigators is given in the Appendix.


 

  • References

  • 1 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic therapy for VTE disease. Chest guideline and expert panel report Chest 2016; 149: 315-352.
    CrossrefPubMedGoogle Scholar
  • 2 Schulman S, Kearon C, Kakkar AK. et al. , for the RE-COVER Study. N Engl J Med 2009; 361: 2342-2352.
    CrossrefPubMedGoogle Scholar
  • 3 EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thrombo-embolism. N Engl J Med 2010; 363: 2499-2510.
    CrossrefPubMedGoogle Scholar
  • 4 EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287-1297.
    CrossrefPubMedGoogle Scholar
  • 5 Agnelli G, Buller HR, Cohen A. et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369: 799-808.
    CrossrefPubMedGoogle Scholar
  • 6 Hokusai-VTE Investigators, Büller HR, Décousus H. et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369: 1406-1415.
    CrossrefPubMedGoogle Scholar
  • 7 Gómez-Outes A, Lecumberri R, Suárez-Gea ML. et al. Case fatality rates of recurrent thromboembolism and bleeding in patients receiving direct oral anticoagulants for the initial and extended treatment of venous thromboembolism: A systematic review. J Cardiovasc Pharmacol Ther 2015; 20: 490-500.
    CrossrefPubMedGoogle Scholar
  • 8 Yao X, Shah ND, Sangaralingham LR, Gersh BJ. Effectiveness and safety of reduced dose non-vitamin K antagonist oral anticoagulants in patients without severe renal impairment. Value Health 2016; 19: A2.
    PubMedGoogle Scholar
  • 9 Barra ME, Fanikos J, Connors JM. et al. Evaluation of dose-reduced direct oral anticoagulant therapy. Am J Med. https://doi.org/10.2016/j.amjmed.2016.05.041 2016
    CrossrefPubMedGoogle Scholar
  • 10 Muriel A, Jiménez D, Aujesky D. et al. Survival effects of inferior vena cava filter in patients with acute symptomatic venous thromboembolism and a significant bleeding risk. J Am Coll Cardiol 2014; 63: 1675-1683.
    CrossrefPubMedGoogle Scholar
  • 11 Ruíz-Giménez N, Suárez C, González R. et al. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008; 100: 26-31.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 12 Farge-Bancel D, Trujillo-Santos J, Debourdeau P. et al. Fatal events in cancer patients receiving anticoagulant therapy for venous thromboembolism. Medicine 2015; 94: e1235.
    CrossrefPubMedGoogle Scholar
  • 13 Jiménez D, de Miguel-Díez J, Guijarro R. et al. Trends in the management and outcomes of acute pulmonary embolism: Analysis from the RIETE Registry. J Am Coll Cardiol 2016; 67: 162-170.
    CrossrefPubMedGoogle Scholar
  • 14 Sánchez Muñoz-Torrero JF, Bounameaux H, Pedrajas JM. et al. Effects of age on the risk of dying from pulmonary embolism or bleeding during treatment of deep vein thrombosis. J Vasc Surg 2011; 54: 26S-32S.
    PubMedGoogle Scholar
  • 15 Martin DO, Austin H. Exact estimates for a rate ratio. Epidemiology 1996; 07: 29-33.
    CrossrefPubMedGoogle Scholar
  • 16 Burnett AE, Mahan CE, Vazquez SR. et al. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis 2016; 41: 206-232.
    CrossrefPubMedGoogle Scholar
  • 17 Burnett AE, Mahan CE, Vazquez SR. et al. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis 2016; 41: 206-232.
    CrossrefPubMedGoogle Scholar
  • 18 Van der Hulle T, Kooiman J, den Exter PL. et al. 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. J Thromb Haemost 2014; 12: 320-328.
    CrossrefPubMedGoogle Scholar