Fondaparinux or Enoxaparin for the Initial Treatment of Symptomatic Deep Venous Thrombosis

A Randomized Trial

  1. Harry R. Büller, MD;
  2. Bruce L. Davidson, MD;
  3. Hervé Decousus, MD;
  4. Alexander Gallus, MD;
  5. Michael Gent, DSc;
  6. Franco Piovella, MD;
  7. Martin H. Prins, MD;
  8. Gary Raskob, PhD;
  9. Annelise E.M. Segers, MD;
  10. Roger Cariou, MD;
  11. Oscar Leeuwenkamp, PhD;
  12. Anthonie W.A. Lensing, MD; and
  13. The Matisse Investigators*
  1. From the Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Swedish Medical Center, University of Washington School of Medicine, Seattle, Washington; Hospital de Bellevue, University Jean Monnet, Saint-Etienne, France; Flinders Medical Centre, Bedford Park, Australia; Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada; Instituto di Clinica Medica, Policlinico San Matteo, University of Pavia, Pavia, Italy; University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; University Hospital of Maastricht, Maastricht, the Netherlands; Sanofi-Synthélabo, Paris, France; and NV Organon, Oss, the Netherlands.

    Abstract

    Background: The current standard initial therapies for deep venous thrombosis are low-molecular-weight heparin and unfractionated heparin. In a dose-ranging study of patients with symptomatic deep venous thrombosis, fondaparinux had efficacy and a safety profile similar to those of low-molecular-weight heparin (dalteparin).

    Objective: To evaluate whether fondaparinux has efficacy and safety similar to those of enoxaparin in patients with deep venous thrombosis.

    Design: Randomized, double-blind study.

    Setting: 154 centers worldwide.

    Patients: 2205 patients with acute symptomatic deep venous thrombosis.

    Intervention: Fondaparinux, 7.5 mg (5.0 mg in patients weighing <50 kg and 10.0 mg in patients weighing >100 kg) subcutaneously once daily, or enoxaparin, 1 mg/kg of body weight, subcutaneously twice daily for at least 5 days and until vitamin K antagonists induced an international normalized ratio greater than 2.0.

    Measurements: The primary efficacy outcome was the 3-month incidence of symptomatic recurrent venous thromboembolic complications. The main safety outcomes were major bleeding during initial treatment and death. An independent, blinded committee adjudicated all outcomes.

    Results: 43 (3.9%) of 1098 patients randomly assigned to fondaparinux had recurrent thromboembolic events compared with 45 (4.1%) of 1107 patients randomly assigned to enoxaparin (absolute difference, −0.15 percentage point [95% CI, −1.8 to 1.5 percentage points]). Major bleeding occurred in 1.1% of patients receiving fondaparinux and 1.2% of patients receiving enoxaparin. Mortality rates were 3.8% and 3.0%, respectively.

    Limitations: Follow-up was incomplete in 0.4% of fondaparinux-treated patients and 1.0% of enoxaparin-treated patients.

    Conclusions: Once-daily subcutaneous fondaparinux was at least as effective (not inferior) and safe as twice-daily, body weight–adjusted enoxaparin in the initial treatment of patients with symptomatic deep venous thrombosis.

    *For a list of the members of The Matisse Investigators, see the Appendix.

    Article and Author Information

    • Grant Support: By Sanofi-Synthélabo and NV Organon.

    • Potential Financial Conflicts of Interest:Employment: A.E.M. Segers (NV Organon); R. Cariou (Sanofi-Synthélabo); O. Leeuwenkamp (Organon); A.W.A. Lensing (NV Organon). Consultancies: H.R. Büller (Sanofi-Synthélabo, NV Organon); B.L. Davidson (Sanofi-Synthélabo, NV Organon, Bristol-Myers Squibb, Aventis); A. Gallus (Sanofi-Synthélabo, NV Organon); M.H. Prins (Sanofi-Synthélabo, NV Organon); G. Raskob (Sanofi-Synthélabo, NV Organon). Honoraria: H.R. Büller (Sanofi-Synthélabo, NV Organon); B.L. Davidson (Sanofi-Synthélabo, NV Organon); H. Decousus (Sanofi-Synthélabo, NV Organon); A. Gallus (Sanofi-Synthélabo, NV Organon); F. Piovella (Sanofi-Synthélabo, NV Organon); G. Raskob (Sanofi-Synthélabo, NV Organon). Stock ownership or options (other than mutual funds): R. Cariou (Sanofi-Synthélabo). Grants received: H.R. Büller (Sanofi-Synthélabo, NV Organon); H. Decousus (Sanofi-Synthélabo); G. Raskob (Sanofi-Synthélabo, NV Organon). Grants pending: H. Decousus (Sanofi-Synthélabo, NV Organon).

    • Requests for Single Reprints: Harry R. Büller, MD, Department of Vascular Medicine, Academic Medical Center, F4-211, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.

    • Current Author Addresses: Dr. Büller: Department of Vascular Medicine, Academic Medical Center, F4-211, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.

    • Dr. Davidson: 801 Broadway, Suite 915, Seattle, WA 98122.

    • Dr. Decousus: Thrombosis Research Group, University Hospital, Hôpital de Bellevue, Pavillon 5, 25 Boulevard Pasteur, 42055 St. Etienne Cedex, France.

    • Dr. Gallus: Department of Haematology, South Path, Flinders Medical Centre, Level 6, Flinders Drive, Bedford Park, South Australia, 5042 Australia.

    • Dr. Gent: Henderson Research Center, McMaster University, 711 Concession Street, Hamilton, Ontario L8V 1C3, Canada.

    • Dr. Piovella: IRCCS Policlinico San Matteo, Via le Golgi 19, 27100 Pavia, Italy.

    • Dr. Prins: Department of Epidemiology and Medical Technology Assessment, University Hospital of Maastricht, Pieter de Byeplein 1, 6212 HX Maastricht, the Netherlands.

    • Dr. Raskob: College of Public Health, University of Oklahoma Health Sciences Center, 801 Northeast 13th Street, Room 139, Oklahoma City, OK 73104.

    • Drs. Segers, Leeuwenkamp, and Lensing: NV Organon, PO Box 20, 5340 BH Oss, the Netherlands.

    • Dr. Cariou: Therapeutic Thrombosis Department, Sanofi-Synthélabo Recherche, 1 Avenue Pierre Brossolette, Chilly-Mazarin, 91385 Cedex, France.

    • Author Contributions: Conception and design: H.R. Büller, H. Decousus, A.S. Gallus, M. Gent, F. Piovella, M.H. Prins, G. Raskob, R. Cariou, O. Leeuwenkamp, A.W.A. Lensing.

    • Analysis and interpretation of the data: H.R. Büller, H. Decousus, A.S. Gallus, M. Gent, F. Piovella, M.H. Prins, G. Raskob, R. Cariou, A.E.M. Segers, O. Leeuwenkamp, A.W.A. Lensing.

    • Drafting of the article: H.R. Büller, H. Decousus, A.S. Gallus, M. Gent, F. Piovella, M.H. Prins, G. Raskob, R. Cariou, A.E.M. Segers, O. Leeuwenkamp, A.W.A. Lensing.

    • Critical revision of the article for important intellectual content: H.R. Büller, A.S. Gallus, M. Gent, F. Piovella, M.H. Prins, G. Raskob, R. Cariou, O. Leeuwenkamp, A.W.A. Lensing.

    • Final approval of the article: H.R. Büller, H. Decousus, A.S. Gallus, M. Gent, F. Piovella, M.H. Prins, G. Raskob, A.E.M. Segers, R. Cariou, O. Leeuwenkamp, A.W.A. Lensing.

    • Provision of study materials or patients: H.R. Büller, H. Decousus, A.S. Gallus, F. Piovella, M.H. Prins, A.W.A. Lensing.

    • Statistical expertise: H.R. Büller, M.H. Prins, M. Gent.

    • Obtaining of funding: H.R. Büller, M.H. Prins.

    • Administrative, technical, or logistic support: H.R. Büller, M.H. Prins, R. Cariou.

    • Collection and assembly of data: H.R. Büller, M.H. Prins.

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    1. Ann Intern Med June 1, 2004 vol. 140 no. 11 867-873
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