Skip to main content

Advertisement

SpringerLink
Log in

Suboptimal doses of low molecular weight heparin and acute venous thromboembolism. Data from the RIETE registry

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

The objective was to assess the use of suboptimal doses (60–149 UI kg−1 day−1) of low molecular weight heparin (LMWH) in the treatment of acute venous thromboembolism (VTE) in actual clinical practice and to evaluate the outcomes compared to standard doses (≥150 UI kg−1 day−1). Retrospective analysis of data from a multicenter registry of patients with VTE (RIETE; Registro Informatizado de Enfermedad TromboEmbólica). Patient characteristics, antithrombotic treatments, and 3-month outcomes were analyzed. We studied 12,302 patients with VTE; 10,524 patients were treated initially only with LMWH; 1,547 patients received suboptimal LMWH (mean = 122 UI kg−1 day−1), and 8,977 patients received full-dose LMWH (mean = 191 UI kg−1 day−1). The suboptimal group included significantly more patients with recent major bleeding, weight more than 100 kg, raised creatinine, or deep vein thrombosis. No significant differences in mortality rate (7.7 vs 7.8%), VTE recurrence (2.7 vs 2.3%), or fatal hemorrhage (0.6 vs 0.6%) occurred between the suboptimal and the standard group. Major bleeding episodes occurred more frequently in the patients with pulmonary embolism treated with suboptimal LMWH (4.5 vs 2.4%; p = 0.02). In the multivariate analysis, after adjusting for bleeding risk factors, major hemorrhage was not associated with the heparin dose. Suboptimal doses of LMWH are used in actual clinical practice in a reduced group of patients at an outcome rate not very different to that of standard doses. Bleeding episodes depend more on the patient’s characteristics than on the LMWH dose. Randomized trials should be performed to corroborate these results.

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

References

  1. Büller HR, Agnelli G, Hull RD, Hyers TH, Prins MH, Raskob GE (2004) Antithrombotic therapy for venous thromboembolic disease. The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126: 401S–428S

    Article  PubMed  Google Scholar 

  2. Hirsh J, Raschke R (2004) Heparin and low-molecular-weight heparin. The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126:188S–203S

    Article  PubMed  CAS  Google Scholar 

  3. Frydman AM, Bara L, Le Roux Y, Woler M, Chauliac F, Samama MM (1988) The antithrombotic activity and pharmacokinetics of enoxaparin, a low molecular weight heparin, in humans given single subcutaneous doses of 20 to 80 mg. J Clin Pharmacol 28:609–618

    PubMed  CAS  Google Scholar 

  4. Matzsch T, Bergqvist D, Hedner OR, Ostergaard P (1987) Effects of an enzymatically depolymerised heparin ace compared with conventional heparin in healthy volunteers. Thromb Haemost 57:97–101

    PubMed  CAS  Google Scholar 

  5. Quinlan DJ, McQuillan TO, Eikelboom JW (2004) Low-molecular-weight heparin compared with intravenous unfractionated heparin for treatment of pulmonary embolism: a goal-analysis of randomized controlled trials. Ann Intern Med 140:175–183

    PubMed  CAS  Google Scholar 

  6. Bratt G, Tornebohm AND, Widlund L, Lockner D (1986) Low molecular weight heparine (KABI 2165, Fragmin): pharmacokinetics after intravenous and subcutaneous administration in human volunteers. Thromb Res 42:613–620

    Article  PubMed  CAS  Google Scholar 

  7. Brophy DF, Martin EJ, Best AM, Gehr TW, Carr ME (2004) Antifactor Xa activity correlates to thrombin generation cheats, platelet contactile forced and clot elastic modulus following former alive enoxaparin exposure in patients with and without renal dysfunction. Thromb Haemost 2:1299–1304

    Article  CAS  Google Scholar 

  8. Bianchini P, Bergonzini GL, Parma B, Osima B (1995) Relationship between captures antifactor Xa activity and the antithrombotic activity of heparins of molecular different mass. Haemostasis 25:288–298

    PubMed  CAS  Google Scholar 

  9. Gosselin RC, King JH, Janatpour KA, Dager WE, Larkin EC, Owings JT (2004) Variability of captures anti-Xa activities with different lots of enoxaparin. Ann Pharmacother 38:563–568

    Article  PubMed  CAS  Google Scholar 

  10. Greaves M (2002) Limitations of the laboratory monitoring of heparin therapy. Thromb Haemost 87:163–164

    PubMed  CAS  Google Scholar 

  11. González-Fajardo JA, Arreba AND, Castrodeza J, Pérez JL, Fernández L, Agundez I, Mateo AM, Career S, Gutiérrez V, Cowboy C (1999) Venographic comparison of subcutaneous low-molecular weight heparin with oral anticoagulant therapy in the long-term treatment of deep venous thrombosis. J Vasc Surg 30:283–292

    Article  PubMed  Google Scholar 

  12. Pini M, Aiello S, Manotti C, Pattacini C, Quintavalla R, Poli T, Tagliaferri TO, Dettori AG (1994) Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis. Thromb Haemost 72:191–197

    PubMed  CAS  Google Scholar 

  13. Marchetti M, Pistorio TO, Barone M, Serafini S, Barosi G (2001) Low-molecular-weight Heparin versus warfarin for secondary prophylaxis of venous thromboembolism. A cost-effectiviness analysis. Am J Med 111:159–160

    Article  Google Scholar 

  14. Veiga F, Scribe TO, Maluenda MP, López Rubio M, Margalet I, Lezana TO, Galician J, Riverside JM (2000) Low molecular weight heparin (enoxaparin) versus oral anticoagulant therapy (acenocoumarol) in the long-term treatment of deep venous thrombosis in the elderly: a randomized trial. Thromb Haemost 84:559–564

    PubMed  CAS  Google Scholar 

  15. Arcelus JL, Monreal M, Caprini JA, Suarez C, González-Fajardo JA, for the RIETE investigators (2003) The management and outcome of acute venous thromboembolism: a prospective registry including 4,011 patients. J Vasc Surg 38:916–922

    Article  PubMed  Google Scholar 

  16. Monreal M, Súarez C, González-Fajardo JA, Barba R, Uresandi F, Valle R, Rondón P, and the RIETE Investigators (2004) Management of patients with acute venous thromboembolism: findings from the RIETE Registry. Pathophysiol Haemost Thromb 33:330–334

    Article  Google Scholar 

  17. Nieto JA, Diaz de Tuesta A, Marchena J, Tiberio G, Todoli JA, Samperiz AL y Monreal M (2005) Clinical outcome of patients with venous thromboembolism and recent major bleeding: findings from a prospective registry (RIETE). J Thromb Haemost 3:703–709

    Article  PubMed  CAS  Google Scholar 

  18. Monreal M, Kakkar AK, Caprini JA, Barba R, Uresandi F, Valle R, Suárez C, Otero R, the RIETE Investigators (2004) The outcome after treatment of venous thromboembolism is different in surgical and acutely ill medical patients. Findings from the RIETE Registry. J Thromb Haemost 2:1–7

    Article  Google Scholar 

  19. Wicki J, Perrier A, Perneger TV, Bounameaux H, Junod AF (2000) Predicting adverse outcome in patients with acute pulmonary embolism: a risk score. Thromb Haemost 84:548–552

    PubMed  CAS  Google Scholar 

  20. Heit JA, Silverstein MD, Mohr DN, Petterson TM, Lohse CM, O’Fallon WM, Melton LJ (2001) The epidemiology of venous thromboembolism in the community. Thromb Haemost 86:452–463

    PubMed  CAS  Google Scholar 

  21. Prandoni P, Lensing AWA, Piccioli A, Bernardi E, Simioni P, Girolani B, Marchiori A, Sabbion P, Prins MH, Noventa F, Girolami A (2002) Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 100:3484–3488

    Article  PubMed  CAS  Google Scholar 

  22. Douketis JD, Foster GA, Crowther MA, Prins MH, Ginsberg JS (2000) Clinical risks factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch Intern Med 160:3431–3436

    Article  PubMed  CAS  Google Scholar 

  23. Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Eichinger S (2004) The risk of recurrent venous thromboembolism in men and women. N Engl J Med 350:2558–2563

    Article  PubMed  CAS  Google Scholar 

  24. Jimenez D, Diaz G, Marin E, Vidal R, Sueiro A, Yusen RD (2006) The risk of recurrent venous thromboembolism in patients with unprovoked symptomatic deep vein thrombosis and asymptomatic pulmonary embolism. Thromb Haemost 95:562–566

    PubMed  CAS  Google Scholar 

  25. Decousus H, Leizorovicz A, Parent F, Page Y, Tardy B, Girard P, Laporte S, Faivre R, Charbonnier B, Barral FG, HUet Y, Simonneau G (1998) A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med 338:409–415

    Article  PubMed  CAS  Google Scholar 

  26. Hansson PO, Sorbo J, Eriksson H (2000) Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med 160:769–774

    Article  PubMed  CAS  Google Scholar 

  27. Santamaría MG, Agnelli G, Taliani MR, Prandoni P, Moia M, Bazzan M, Guazzaloca G, Agneno W, Bertoldi A, Silingardi M, Tomasi C, Ambrosio GB (2005) Thrombophilic abnormalities and recurrence of venous thromboembolism in patients treated with standardized anticoagulant treatment. Thromb Res 116:301–306

    Article  PubMed  CAS  Google Scholar 

  28. Wells PS, Forgie MA, Simms M, Greene A, Touchie D, Lewis G, Anderson J, Rodger MA (2003) The outpatient bleeding risk index. Validation of a tool for predicting bleeding rates in patients treated for deep venous thrombosis and pulmonary embolism. Arch Intern Med 163:917–920

    Article  PubMed  Google Scholar 

  29. White RH, Beyth RJ, Zhou H, Romano PS (1999) Major bleeding after hospitalization for deep vein thrombosis. Am J Med 107:414–424

    Article  PubMed  CAS  Google Scholar 

  30. Kuijer PMM, Hutten BA, Prins MH, Büller HR (1999) Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 159:457–460

    Article  PubMed  CAS  Google Scholar 

  31. Landefeld CS, Cook EF, Flatley M, Weisberg M, Goldman L (1987) Identification and preliminary validation of predictors of major bleeding in hospitalized patients starting anticoagulant therapy. Am J Med 82:703–713

    Article  PubMed  CAS  Google Scholar 

  32. Hull R, Raskob GE, Rosemblom D, Panju AA, Brill-Edwards P, Ginsberg JS, Hirsh J, Martín GJ, Green D (1990) Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med 322:1260–1264

    Article  PubMed  CAS  Google Scholar 

  33. Eriksson H, Lundstrom T, Wahlander K, Clason SB, Schulman S, THRIVE III Investigators (2005) Prognostic factors for recurrence of venous thromboembolism or bleeding during long term secondary prevention of VTE with ximelagatran. Thromb Haemost 94:522–527

    PubMed  CAS  Google Scholar 

  34. Hull RD, Raskob GE, Rosemblom D, Lemaire J, Pineo GF, Baylis B, Ginsberg JS, Panju AA, Brill-Edwards P, Brant R (1992) Optimal therapeutic level of heparin therapy in patients with venous thrombosis. Arch Intern Med 152:1589–1595

    Article  PubMed  CAS  Google Scholar 

  35. Siegbahn A, Y-Hassan S, Boberg J, Bylund H, Neerstrand HS, Ostergaard P, Hedner U (1989) Subcutaneous treatment of deep venous thrombosis with low molecular weight heparin. A dose finding study with LMWH-Novo. Thromb Res 55:767–768

    Article  PubMed  CAS  Google Scholar 

  36. Bratt G, Tornebohm E, Widlund L, Lockner D (1986) Low molecular heparin (KABI 2165, Fragmin): pharmacokinetics after intravenous and subcutaneous administration in human volunteers. Thromb Res 42:613–620

    Article  PubMed  CAS  Google Scholar 

  37. Samama MM, Gerotziafas GT (2000) Comparative pharmacokinetics of LMWHs. Semin Thromb Hemost 26:31–38

    Article  PubMed  CAS  Google Scholar 

  38. Siragusa S, Cosmi B, Piovella F, Hirsh J, Ginsberg JS (1996) Low-molecular-weight heparins and unfractionated heparin in the treatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med 100:269–277

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We express our gratitude to Sanofi-Aventis for supporting this registry with an unrestricted educational grant and the Registry Coordinating Center, S & H Medical Science Service, for their logistic and administrative support. We thank Ms. Uta M. Klepzig for the assistance in the preparation of the manuscript. The project has been partially supported by Red Respira from the Instituto Carlos III (RedRespira-ISCiii-RTIC-03/11).

Conflict of interest statement

None was declared.

Author information

Authors and Affiliations

  1. Servicio de Medicina Interna, Hospital Virgen de la Luz, 16002, Cuenca, Spain

    Ma. Jesús Bruscas, José Antonio Nieto & Monserrat Perez-Pinar

  2. Internal Medicine, Hospital Provincial Reina Sofía, Cordova, Spain

    Luciano López-Jiménez

  3. Internal Medicine, Hospital Universitario La Paz, Madrid, Spain

    Carmen Fernández-Capitán

  4. Hematology, Hospital Arnau de Vilanova, Valencia, Spain

    Francisca López-Chuliá

  5. Hematology, Hospital de Navarra, Navarra, Spain

    Ma. Teresa Orue-Lecue

Authors
  1. Ma. Jesús Bruscas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. José Antonio Nieto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Monserrat Perez-Pinar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luciano López-Jiménez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carmen Fernández-Capitán
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Francisca López-Chuliá
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ma. Teresa Orue-Lecue
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the RIETE Investigators

Corresponding author

Correspondence to José Antonio Nieto.

Additional information

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

Appendix

Appendix

Members of the RIETE Group

Spain: Arcelus JI., Barba R., Blanco A., Barrón M., Bugés J., Cabezudo MA., Casado I., Conget F., De las Heras G., Falgá C., Fernández-Capitán C., Font L., Gallego P., García-Bragado F., González CR, Grau E., Guijarro R., Guil M., Gutiérrez J., Hernández L., Jiménez D., Laserna E., Lecumberri R., Lobo JL., López F., López L., López I., Maestre A., Martín JJ., Monreal M., Naufall MD., Nieto JA., Orue MT, Otero R., Pedrajas JM., Portillo J., Rabuñal R., Raguer E., Raventos A., Román P., Romero C., Rosa V., Sampériz AL., Sánchez R., Sánchez JF., Soler S., Tiberio G., Tirado R., Tolosa C., Trujillo J., Uresandi F., Valle R., Vasco B and Llobet X. (Medical Department, Sanofi -Aventis).

France: Mismetti P., Rivron-Guillot K.

Italy: Di Micco P., Tiraferri E.

Argentina: Bottaro F.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bruscas, M.J., Nieto, J.A., Perez-Pinar, M. et al. Suboptimal doses of low molecular weight heparin and acute venous thromboembolism. Data from the RIETE registry. Ann Hematol 86, 519–526 (2007). https://doi.org/10.1007/s00277-007-0282-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-007-0282-x

Keywords

Search

Navigation