Skip to main content
Log in

Venous thromboembolism prophylaxis in medically ill patients: a mixed treatment comparison meta-analysis

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

Abstract

The American College of Chest Physicians guidelines recommend unfractionated heparin (UFH), low molecular weight heparins (LMWHs) or fondaparinux for prevention of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), in medically-ill patients. Direct oral anticoagulants (DOACs) have been evaluated relative to enoxaparin for VTE prophylaxis though head-to-head comparisons of these agents are lacking. Therefore, we conducted a mixed treatment comparisons meta-analysis to evaluate the safety and efficacy of established treatments and DOACs for VTE prophylaxis in medically-ill patients. A comprehensive literature search was conducted to identify randomized trials evaluating UFH, LMWHs or DOACS for the prevention of VTE in medically ill patients. Articles were retrieved and cross-referenced for additional trials, evaluated and entered into ADDIS (version 1.16.6) to generate direct and indirect treatment comparisons for VTE, DVT, PE, death from any cause, and bleeding. Ten articles were included and eight anticoagulants were evaluated in a treatment network representing data on 28,382 patients. We found each treatment had similar efficacy in preventing VTE, DVT, PE, death from any cause and each had similar risk of minor and major bleeding. Overall, placebo was associated with more VTE and DVT events compared to LMWHs and DOACs. We found that UFH, LMWHs and DOACs are comparable in preventing VTE, DVT, PE, and death from any cause and in association with minor and major bleeding. Anticoagulant selection for VTE prophylaxis in medically-ill patients should be individualized by patient characteristics, risks and preferences along with specific pharmacokinetic and pharmacodynamic considerations.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Heit JA, Spencer FA, White RH (2016) The epidemiology of venous thromboembolism. J Thromb Thrombolysis. doi:10.1007/s11239-015-1311-6

    PubMed  PubMed Central  Google Scholar 

  2. Kahn SR, Lim W, Dunn AS et al (2012) Prevention of VTE in nonsurgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest 141(2 Suppl):e195S–e226S

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cohen AT, Spiro TE, Büller HR et al (2013) Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 368(6):513–523

    Article  CAS  PubMed  Google Scholar 

  4. Goldhaber SZ, Leizorovicz A, Kakkar AK et al (2011) Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 365(23):2167–2177

    Article  CAS  PubMed  Google Scholar 

  5. Jadad AR, Moore RA, Carroll D et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17(1):1–12

    Article  CAS  PubMed  Google Scholar 

  6. Lu G, Ades AE (2004) Combination of direct and indirect evidence in mixed treatment comparisons. Stat Med 23(20):3105–3124

    Article  CAS  PubMed  Google Scholar 

  7. Lu G, Ades AE (2006) Assessing evidence inconsistency in mixed treatment comparisons. J Am Stat Assoc 101(474):447–459

    Article  CAS  Google Scholar 

  8. Woods BS, Hawkins N, Scott DA (2010) Network meta-analysis on the log-hazard scale, combining count and hazard ratio statistics accounting for multi-arm trials: a tutorial. BMC Med Res Methodol 10:54

    Article  PubMed  PubMed Central  Google Scholar 

  9. van Valkenhoef G, Tervonen T, Zwinkels T, de Brock B, Hillege H (2012) ADDIS: a decision support system for evidence-based medicine. Decis Support Syst 55:459–475

    Article  Google Scholar 

  10. Lumley T (2002) Network meta-analysis for indirect treatment comparisons. Stat Med 21(16):2313–2324

    Article  PubMed  Google Scholar 

  11. Caldwell DM, Ades AE, Higgins JP (2005) Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ 331:897–900

    Article  PubMed  PubMed Central  Google Scholar 

  12. Salanti G, Higgins JP, Ades AE, Ioannidis JP (2008) Evaluation of networks of randomized trials. Stat Methods Med Res 17(3):279–301

    Article  PubMed  Google Scholar 

  13. Dias S, Welton NJ, Caldwell DM, Ades AE (2010) Checking consistency in mixed treatment comparison meta-analysis. Stat Med 29(7–8):932–944

    Article  CAS  PubMed  Google Scholar 

  14. Cohen AT, Davidson BL, Gallus AS et al (2006) Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 332(7537):325–329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fraisse F, Holzapfel L, Couland JM et al (2000) Nadroparin in the prevention of deep vein thrombosis in acute decompensated COPD. The Association of Non-University Affiliated Intensive Care Specialist Physicians of France. Am J Respir Crit Care Med 161(4 Pt 1):1109–1114

    Article  CAS  PubMed  Google Scholar 

  16. Lechler E, Schramm W, Flosbach CW (1996) The venous thrombotic risk in non-surgical patients: epidemiological data and efficacy/safety profile of a low-molecular-weight heparin (enoxaparin). The Prime Study Group. Haemostasis 26(Suppl 2):49–56

    CAS  PubMed  Google Scholar 

  17. Leizorovicz A, Cohen AT, Turpie AG et al (2004) Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 110(7):874–879

    Article  CAS  PubMed  Google Scholar 

  18. Mahé I, Bergmann JF, D’azémar P, Vaissie JJ, Caulin C (2005) Lack of effect of a low-molecular-weight heparin (nadroparin) on mortality in bedridden medical in-patients: a prospective randomised double-blind study. Eur J Clin Pharmacol 61(5–6):347–351

    Article  PubMed  Google Scholar 

  19. Samama MM, Cohen AT, Darmon JY et al (1999) A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 341(11):793–800

    Article  CAS  PubMed  Google Scholar 

  20. Harenberg J, Roebruck P, Heene DL (1996) Subcutaneous low-molecular-weight heparin versus standard heparin and the prevention of thromboembolism in medical inpatients. The Heparin Study in Internal Medicine Group. Haemostasis 26(3):127–139

    CAS  PubMed  Google Scholar 

  21. Riess H, Haas S, Tebbe U et al (2010) A randomized, double blind study of certoparin versus unfractionated heparin to prevent venous thromboembolic events in acutely ill, nonsurgical patients. J Thromb Haemost 8:1209–1215

    Article  CAS  PubMed  Google Scholar 

  22. Hull RD, Schellong SM, Tapson VF, Monreal M, Samama M, Nicol P et al (2010) Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med 153:8–18. doi:10.7326/0003-4819-153-1-201007060-00004

    Article  PubMed  Google Scholar 

  23. Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM (2016) Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med 375(6):534–544

    Article  CAS  PubMed  Google Scholar 

  24. Salanti G, Kavvoura FK, Ioannidis JP (2008) Exploring the geometry of treatment networks. Ann Intern Med 148(7):544–553

    Article  PubMed  Google Scholar 

  25. Liew AYL, Piran S, Eikelboom JW et al (2017) Extended-duration versus short-duration pharmacological thromboprophylaxis in acutely ill hospitalized medical patients: a systematic review and meta-analysis of randomized controlled trails. J Thromb Thrombolysis 43:291–301

    Article  CAS  PubMed  Google Scholar 

  26. Dooley C, Kaur R, Sobieraj DM (2014) Comparison of the efficacy and safety of low molecular weight heparins for venous thromboembolism prophylaxis in medically ill patients. Curr Med Res Opin 30(3):367–380. doi:10.1185/03007995.2013.837818

    Article  CAS  PubMed  Google Scholar 

  27. Albertsen IE, Larsen TB, Rasmussen LH, Overvad TF, Lip GYH (2012) Prevention of venous thromboembolism with new oral anticoagulants versus standard pharmacological treatment in acute medically ill patients: a systematic review and meta-analysis. Drugs 72(13):1755–1764

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

All authors contributed equally to this manuscript. The authors thank Abdulrahman Alwhaibi, PharmD his assistance with technical aspects of this project.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Abir O. Kanaan.

Ethics declarations

Conflict of interest

The authors have indicated that they have no conflicts of interest regarding the content of this article.

Ethical approval

This article does not contain any studies with human participants or animals performed by any authors.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 492 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Al Yami, M.S., Silva, M.A., Donovan, J.L. et al. Venous thromboembolism prophylaxis in medically ill patients: a mixed treatment comparison meta-analysis. J Thromb Thrombolysis 45, 36–47 (2018). https://doi.org/10.1007/s11239-017-1562-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-017-1562-5

Keywords

Navigation