Skip to main content

Advertisement

SpringerLink
Log in

Management of isolated distal deep–vein thrombosis with direct oral anticoagulants in the RIETE registry

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Abstract

Isolated distal deep–vein thrombosis (DVT, infra-popliteal DVT without pulmonary embolism) is a common presentation of venous thromboembolism (VTE), but was an exclusion criterion from the pivotal trials that validated the use of direct oral anticoagulants (DOACs) for VTE management. Using data from the international RIETE registry, we analyzed and compared trends in DOACs prescription between January 2011 and June 2019 in patients with distal vs. proximal DVT. We also assessed DOACs’ prescriptions and compared the outcomes (VTE recurrence, bleeding and death) of distal DVT patients treated with DOACs vs. those on vitamin K antagonists (VKAs). 2308 patients with distal DVT and 11,364 patients with proximal DVT were included in the current analysis. DOACs were more frequently prescribed in patients with distal than proximal DVT (25% vs. 16%, p < 0.001). DOACs use increased sharply during the observation period (P < 0.001 for trend). In 2018, 56% of patients with distal DVT received DOACs. Distal DVT patients treated with rivaroxaban or edoxaban received the dose recommended for VTE management in most (> 85%) cases. Patients treated with apixaban were older, more likely to have underlying conditions than patients treated with rivaroxaban and, in most cases (> 75%), did not receive the recommended 1-week loading dose for acute VTE management. Outcomes between distal DVT patients treated with VKAs or DOACs appeared to be similar. In patients with distal DVT, DOACs have become the most common anticoagulant regimen. Specific trials are needed to determine the optimal DOACs dose regimen for treatment of distal DVT.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

All authors had full access to all data in the study. Dr Galanaud take responsibility for the integrity of the data and the accuracy of data analysis.

References

  1. Robert-Ebadi H, Righini M (2017) Should we diagnose and treat distal deep vein thrombosis? Hematology Am Soc Hematol Educ Program 2017(1):231–236. https://doi.org/10.1182/asheducation-2017.1.231

    Article  PubMed  PubMed Central  Google Scholar 

  2. Galanaud JP, Bosson JL, Quere I (2011) Risk factors and early outcomes of patients with symptomatic distal vs. proximal deep-vein thrombosis. Curr Opin Pulm Med 17(5):387–391. https://doi.org/10.1097/MCP.0b013e328349a9e3

    Article  PubMed  Google Scholar 

  3. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N, Stevens SM, Vintch JR, Wells P, Woller SC, Moores L (2016) Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 149(2):315–352. https://doi.org/10.1016/j.chest.2015.11.026

    Article  PubMed  Google Scholar 

  4. Palareti G, Schellong S (2012) Isolated distal deep vein thrombosis: what we know and what we are doing. J Thromb Haemost 10(1):11–19. https://doi.org/10.1111/j.1538-7836.2011.04564.x

    Article  CAS  PubMed  Google Scholar 

  5. Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S (2010) Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 363(26):2499–2510. https://doi.org/10.1056/NEJMoa1007903

    Article  CAS  PubMed  Google Scholar 

  6. Buller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P (2013) Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 369(15):1406–1415. https://doi.org/10.1056/NEJMoa1306638

    Article  CAS  PubMed  Google Scholar 

  7. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI (2013) Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 369(9):799–808. https://doi.org/10.1056/NEJMoa1302507

    Article  CAS  PubMed  Google Scholar 

  8. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 361(24):2342–2352. https://doi.org/10.1056/NEJMoa0906598

    Article  CAS  PubMed  Google Scholar 

  9. van Es N, Coppens M, Schulman S, Middeldorp S, Buller HR (2014) Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 124(12):1968–1975. https://doi.org/10.1182/blood-2014-04-571232

    Article  CAS  PubMed  Google Scholar 

  10. Schellong SM, Goldhaber SZ, Weitz JI, Ageno W, Bounameaux H, Turpie AGG, Angchaisuksiri P, Haas S, Goto S, Zaghdoun A, Farjat A, Nielsen JD, Kayani G, Mantovani LG, Prandoni P, Kakkar AK (2019) Isolated distal deep vein thrombosis: perspectives from the GARFIELD-VTE registry. Thromb Haemost 19(10):1675–1685. https://doi.org/10.1055/s-0039-1693461

    Article  Google Scholar 

  11. Ageno W, Mantovani LG, Haas S, Kreutz R, Monje D, Schneider J, Bugge JP, Gebel M, Turpie AGG (2019) Patient management strategies and long-term outcomes in isolated distal deep-vein thrombosis versus proximal deep-vein thrombosis: findings from XALIA. TH Open 3(1):e85–e93

    Article  Google Scholar 

  12. Garcia R, Probeck K, Elitharp DM, Gasparis AP, Labropoulos N (2018) Diverse management of isolated calf deep venous thrombosis in a university hospital. J Vasc Surg Venous Lymphat Disord 6(2):139–145. https://doi.org/10.1016/j.jvsv.2017.08.021

    Article  PubMed  Google Scholar 

  13. Poudel SK, Park DY, Jia X, Wilks M, Pinkava V, O’Brien M, Tripp B, Song JM, McCrae KR, Khorana AA, Angelini DE (2019) Clinical outcomes of isolated distal deep vein thrombosis versus proximal venous thromboembolism in cancer patients: the cleveland clinic experience. J Thromb Haemost 18(3):651–659. https://doi.org/10.1111/jth.14700

    Article  PubMed  Google Scholar 

  14. Bungard TJ, Ritchie B, Bolt J, Semchuk WM (2018) Management of acute venous thromboembolism among a cohort of patients discharged directly from the emergency department. BMJ Open 8(10):e022064. https://doi.org/10.1136/bmjopen-2018-022064

    Article  PubMed  PubMed Central  Google Scholar 

  15. Houghton DE, Lekah A, Macedo TA, Hodge D, Saadiq RA, Little Y, Casanegra AI, McBane RD, Wysokinski WE (2019) Resolution of acute lower extremity deep vein thrombosis with rivaroxaban compared to warfarin. J Thromb Thrombolysis. https://doi.org/10.1007/s11239-019-01932-8

    Article  Google Scholar 

  16. Bikdeli B, Jimenez D, Hawkins M, Ortiz S, Prandoni P, Brenner B, Decousus H, Masoudi FA, Trujillo-Santos J, Krumholz HM, Monreal M (2018) Rationale, design and methodology of the computerized registry of patients with venous thromboembolism (RIETE). Thromb Haemost 118(1):214–224. https://doi.org/10.1160/TH17-07-0511

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kaatz S, Ahmad D, Spyropoulos A, Schulman S, S. o. C. o. Anticoagulation. (2015) Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 13(11):2119–2126. https://doi.org/10.1111/jth.13140

    Article  CAS  PubMed  Google Scholar 

  18. Lutsey PL, Walker RF, MacLehose RF, Alonso A, Adam TJ, Zakai NA (2019) Direct oral anticoagulants and warfarin for venous thromboembolism treatment: trends from 2012 to 2017. Res Pract Thromb Haemost 3(4):668–673. https://doi.org/10.1002/rth2.12222

    Article  PubMed  PubMed Central  Google Scholar 

  19. Schulman S, Singer D, Ageno W, Casella IB, Desch M, Goldhaber SZ (2017) NOACs for treatment of venous thromboembolism in clinical practice. Thromb Haemost 117(7):1317–1325. https://doi.org/10.1160/th17-01-0065

    Article  PubMed  Google Scholar 

  20. Galanaud JP, Quenet S, Rivron-Guillot K, Quere I, Sanchez Munoz-Torrero JF, Tolosa C, Monreal M (2009) Comparison of the clinical history of symptomatic isolated distal deep-vein thrombosis vs. proximal deep vein thrombosis in 11 086 patients. J Thromb Haemost. 7(12):2028–2034. https://doi.org/10.1111/j.1538-7836.2009.03629.x

    Article  CAS  PubMed  Google Scholar 

  21. Galanaud JP, Sevestre-Pietri MA, Bosson JL, Laroche JP, Righini M, Brisot D, Boge G, van Kien AK, Gattolliat O, Bettarel-Binon C, Gris JC, Genty C, Quere I (2009) Comparative study on risk factors and early outcome of symptomatic distal versus proximal deep vein thrombosis: results from the OPTIMEV study. Thromb Haemost 102(3):493–500. https://doi.org/10.1160/th09-01-0053

    Article  CAS  PubMed  Google Scholar 

  22. Kucher N, Aujesky D, Beer JH, Mazzolai L, Baldi T, Banyai M, Hayoz D, Kaeslin T, Korte W, Escher R, Husmann M, Frauchiger B, Baumgartner I, Spirk D (2016) Rivaroxaban for the treatment of venous thromboembolism. The SWIss Venous ThromboEmbolism Registry (SWIVTER). Thromb Haemost 116(3):472–479. https://doi.org/10.1160/th16-03-0209

    Article  PubMed  Google Scholar 

  23. Moustafa F, Giorgi Pierfranceschi M, Di Micco P, Bucherini E, Lorenzo A, Villalobos A, Nieto JA, Valero B, Samperiz AL, Monreal M (2017) Clinical outcomes during anticoagulant therapy in fragile patients with venous thromboembolism. Res Pract Thromb Haemost 1(2):172–179. https://doi.org/10.1002/rth2.12036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cohen AT, Gitt AK, Bauersachs R, Fronk EM, Laeis P, Mismetti P, Monreal M, Willich SN, Bramlage P, Agnelli G, C. Prefer In Vte Scientific Steering, O. The Prefer In Vte Investigators (2017) The management of acute venous thromboembolism in clinical practice. Results from the European PREFER in VTE Registry. Thromb Haemost 117(7):1326–1337. https://doi.org/10.1160/TH16-10-0793

    Article  PubMed  PubMed Central  Google Scholar 

  25. Ageno W, Mantovani LG, Haas S, Kreutz R, Monje D, Schneider J, van Eickels M, Gebel M, Zell E, Turpie AG (2016) Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study. Lancet Haematol 3(1):e12–e21. https://doi.org/10.1016/s2352-3026(15)00257-4

    Article  PubMed  Google Scholar 

  26. Trujillo-Santos J, Di Micco P, Dentali F, Douketis J, Diaz-Peromingo JA, Nunez MJ, Canas I, Mastroiacovo D, Saraiva de Sousa M, Monreal M (2017) Real-life treatment of venous thromboembolism with direct oral anticoagulants: the influence of recommended dosing and regimens. Thromb Haemost 117(2):382–389. https://doi.org/10.1160/th16-07-0494

    Article  PubMed  Google Scholar 

  27. Dawwas GK, Brown J, Dietrich E, Park H (2019) Effectiveness and safety of apixaban versus rivaroxaban for prevention of recurrent venous thromboembolism and adverse bleeding events in patients with venous thromboembolism: a retrospective population-based cohort analysis. Lancet Haematol 6(1):e20–e28. https://doi.org/10.1016/s2352-3026(18)30191-1

    Article  PubMed  Google Scholar 

  28. Aryal MR, Gosain R, Donato A, Yu H, Katel A, Bhandari Y, Dhital R, Kouides PA (2019) Systematic review and meta-analysis of the efficacy and safety of apixaban compared to rivaroxaban in acute VTE in the real world. Blood Adv 3(15):2381–2387. https://doi.org/10.1182/bloodadvances.2019000572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Palareti G (2014) How I treat isolated distal deep vein thrombosis (IDDVT). Blood 123(12):1802–1809. https://doi.org/10.1182/blood-2013-10-512616

    Article  CAS  PubMed  Google Scholar 

  30. Barco S, Corti M, Trinchero A, Picchi C, Ambaglio C, Konstantinides SV, Dentali F, Barone M (2017) Survival and recurrent venous thromboembolism in patients with first proximal or isolated distal deep vein thrombosis and no pulmonary embolism. J Thromb Haemost 15(7):1436–1442. https://doi.org/10.1111/jth.13713

    Article  CAS  PubMed  Google Scholar 

  31. Beyer-Westendorf J, Forster K, Pannach S, Ebertz F, Gelbricht V, Thieme C, Michalski F, Kohler C, Werth S, Sahin K, Tittl L, Hansel U, Weiss N (2014) Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry. Blood 124(6):955–962

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We express our gratitude to Sanofi Spain for supporting this Registry with an unrestricted educational grant. We also thank the RIETE Registry Coordinating Center, S&H Medical Science Service, for their quality control data, logistic and administrative support. Dr. Galanaud is an investigator of the CanVECTOR Network, which receives grant funding from the Canadian Institutes of Health Research (Funding Reference: CDT-142654). last but not least, we would like to express our gratitude to the patients who made the study possible.

Coordinator of the RIETE Registry: Manuel Monreal.

RIETE Steering Committee Members: Paolo Prandoni, Benjamin Brenner and Dominique Farge-Bancel.

RIETE National Coordinators: Raquel Barba (Spain), Pierpaolo Di Micco (Italy), Laurent Bertoletti (France), Sebastian Schellong (Germany), Inna Tzoran (Israel), Abilio Reis (Portugal), Marijan Bosevski (R. Macedonia), Henri Bounameaux (Switzerland), Radovan Malý (Czech Republic), Peter Verhamme (Belgium), Joseph A. Caprini (USA), Hanh My Bui (Vietnam).

RIETE Registry Coordinating Center: S & H Medical Science Service.

Members of the RIETE Group SPAIN: Adarraga MD, Agud M, Aibar J, Aibar MA, Alfonso J, Alonso J, Amado C, Arcelus JI, Baeza C, Ballaz A, Barba R, Barbagelata C, Barrón M, Barrón-Andrés B, Blanco-Molina A, Botella E, Camon AM, Cañas I, Casado I, Castro J, Criado J, de Ancos C, de Miguel J, del Toro J, Demelo-Rodríguez P, Díaz-Pedroche C, Díaz-Peromingo JA, Díez-Sierra J, Domínguez IM, Encabo M, Escribano JC, Falgá C, Farfán AI, Fernández-Capitán C, Fernández-Reyes JL, Fidalgo MA, Flores K, Font C, Font L, Francisco I, Furest I, Gabara C, Galeano-Valle F, García MA, García-Bragado F, Gavín-Sebastián O, Gil-Díaz A, Gómez-Cuervo C, Gómez-Mosquera AM, González-Martínez J, Grau E, Giménez-Suau M, Guirado L, Gutiérrez J, Hernández-Blasco L, Hernando E, Herreros M, Jara-Palomares L, Jaras MJ, Jiménez D, Joya MD, Jou I, Lecumberri R, Lima J, Lobo JL, López-Jiménez L, López-Miguel P, López-Núñez JJ, López-Reyes R, López-Sáez JB, Lorente MA, Lorenzo A, Loring M, Madridano O, Maestre A, Marchena PJ, Martín del Pozo M, Martín-Martos F, Martínez-García MA, Mella C, Mellado M, Mercado MI, Moisés J, Monreal M, Morales MV, Muñoz-Blanco A, Muñoz-Guglielmetti D, Muñoz-Rivas N, Nieto JA, Núñez A, Núñez MJ, Obispo B, Olivares MC, Orcastegui JL, Ortega-Michel C, Ortega-Recio MD, Osorio J, Otalora S, Otero R, Paredes D, Parra P, Parra V, Pedrajas JM, Pellejero G, Pesántez D, Porras JA, Portillo J, Redondo I, Reig L, Riera-Mestre A, Rivas A, Rivera F, Rodríguez-Cobo A, Rodríguez-Matute C, Rogado J, Rosa V, Rubio CM, Ruiz-Artacho P, Ruiz-Giménez N, Ruiz-Ruiz J, Ruiz-Sada P, Sahuquillo JC, Salgueiro G, Sampériz A, Sánchez-Muñoz-Torrero JF, Sancho T, Sigüenza P, Soler S, Suárez S, Suriñach JM, Torres MI, Tolosa C, Trujillo-Santos J, Uresandi F, Usandizaga E, Valle R, Vela JR, Vidal G, Villares P, Zamora C, ARGENTINA: Gutiérrez P, Vázquez FJ, BELGIUM: Vanassche T, Vandenbriele C, Verhamme P, CZECH REPUBLIC: Hirmerova J, Malý R, ECUADOR: Salgado E, FRANCE: Benzidia I, Bertoletti L, Bura-Riviere A, Crichi B, Debourdeau P, Espitia O, Farge-Bancel D, Helfer H, Mahé I, Moustafa F, Poenou G, GERMANY: Schellong S, ISRAEL: Braester A, Brenner B, Tzoran I, ITALY: Bilora F, Bortoluzzi C, Brandolin B, Ciammaichella M, Colaizzo D, Di Micco P, Grandone E, Mastroiacovo D, Maida R, Pace F, Pesavento R, Pomero F, Prandoni P, Quintavalla R, Rocci A, Romualdi R, Siniscalchi C, Tufano A, Visonà A, Vo Hong N, Zalunardo B, LATVIA: Gibietis V, Kigitovica D, Skride A, PORTUGAL: Ferreira M, Fonseca S, Martins F, Meireles J, REPUBLIC OF MACEDONIA: Bosevski M, SWITZERLAND: Bounameaux H, Mazzolai L, USA: Bikdeli B, Caprini JA, Tafur AJ, Weinberg I, Wilkins H, VIETNAM: Bui HM.

Funding

Sanofi Spain supported this Registry with an unrestricted educational grant. The funding source had no involvement in the design of the study; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the manuscript for publication.

Author information

Authors and Affiliations

  1. Division of General Internal Medicine, Sunnybrook Health Sciences Centre and University of Toronto, Toronto, ON, Canada

    Jean-Philippe Galanaud

  2. Department of Internal Medicine, Hospital General Universitario Santa Lucía. Universidad Católica de Murcia, Murcia, Spain

    Javier Trujillo-Santos

  3. Cardiovascular Medicine Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Behnood Bikdeli

  4. Yale/YNHH Center for Outcomes Research & Evaluation, New Haven, CT, USA

    Behnood Bikdeli

  5. Cardiovascular Research Foundation (CRF), New York, NY, USA

    Behnood Bikdeli

  6. Department of Internal Medicine and Emergency Room, Ospedale Buon Consiglio Fatebenefratelli, Naples, Italy

    Pierpaolo Di Micco

  7. Department of Internal Medicine, Ospedale SS. Giovanni E Paolo Di Venezia, Venice, Italy

    Cristiano Bortoluzzi

  8. Department of Vascular Medicine and Therapeutics, Hôpital Nord–CHU St-Etienne, Saint-Etienne, France

    Laurent Bertoletti

  9. Department of Internal Medicine, Hospital Clínico San Carlos, Madrid, Spain

    José María Pedrajas

  10. Department of Pneumonology, Hospital de Galdakao, Vizcaya, Spain

    Aitor Ballaz

  11. Department of Internal Medicine, Hospital Valle del Nalón, Langreo/Asturias, Spain

    Joaquín Alfonso

  12. Department of Internal Medicine, Hospital Germans Trias I Pujol, Badalona/Barcelona, Spain

    Manuel Monreal

Authors
  1. Jean-Philippe Galanaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Javier Trujillo-Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Behnood Bikdeli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pierpaolo Di Micco
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cristiano Bortoluzzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Laurent Bertoletti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. José María Pedrajas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Aitor Ballaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Joaquín Alfonso
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Manuel Monreal
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

the RIETE Investigators

Contributions

Jean-Philippe Galanaud: designed research, performed research, collected data, analyzed data and wrote the paper; Javier Trujillo-Santos, Behnood Bikdeli, Pierpaolo Di Micco, Cristiano Bortoluzzi, Laurent Bertoletti, José María Pedrajas, Aitor Ballaz, Joaquín Alfonso: performed research, collected data, analyzed data and approved manuscript; Manuel Monreal: designed research, obtained funding, performed research, collected data, analyzed data and approved manuscript.

Corresponding author

Correspondence to Jean-Philippe Galanaud.

Ethics declarations

Conflict of interest

Dr Galanaud received research grants from Bayer and Leo-Pharma and consultant fees from BMS-Pfizer, Sanofi and Servier. Dr Bertoletti reports grants, personal fees and non-financial support from ACTELION, grants, personal fees and non-financial support from BAYER, grants, personal fees and non-financial support from BMS, grants, personal fees and non-financial support from PFIZER, grants, personal fees and non-financial support from MSD, non-financial support from DAICHII-SANKYO, personal fees and non-financial support from LEO-PHARMA, during the conduct of the study; Other authors have no conflicts to disclose.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

A full list of RIETE investigators is given in the Acknowledgements section

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Material 1 (DOCX 19 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Galanaud, JP., Trujillo-Santos, J., Bikdeli, B. et al. Management of isolated distal deep–vein thrombosis with direct oral anticoagulants in the RIETE registry. J Thromb Thrombolysis 52, 532–541 (2021). https://doi.org/10.1007/s11239-020-02347-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-020-02347-6

Keywords

Search

Navigation