Subcutaneous Enoxaparin Once or Twice Daily Compared with Intravenous Unfractionated Heparin for Treatment of Venous Thromboembolic Disease

  1. Geno Merli, MD;
  2. Theodore E. Spiro, MD;
  3. Carl-Gustav Olsson, MD, PhD;
  4. Ulrich Abildgaard, MD, PhD;
  5. Bruce L. Davidson, MD, MPH;
  6. Amiram Eldor, MD;
  7. Darlene Elias, MD;
  8. Andrew Grigg, MBBS;
  9. Dominique Musset, MD;
  10. George M. Rodgers, MD, PhD;
  11. Arthur A. Trowbridge, MD;
  12. Roger D. Yusen, MD;
  13. Krystyna Zawilska, MD; and
  14. for the Enoxaparin Clinical Trial Group*
  1. From Thomas Jefferson University, Philadelphia, Pennsylvania; Aventis Pharma SA, Antony, and Hôpital Antoine Béclère, Clamart, France; Aker Hospital, Oslo, Norway; Virginia Mason Medical Center, Seattle, Washington; Institute of Hematology, Tel Aviv, Israel; Scripps Clinic and Research Foundation, La Jolla, California; Royal Melbourne Hospital, Victoria, Australia; University Hospital of Lund, Lund, Sweden; University of Utah Medical Center, Salt Lake City, Utah; Texas A&M University, Temple, Texas; Washington University School of Medicine, Saint Louis, Missouri; and Academy of Medicine, Poznan, Poland.

    Abstract

    Background: Low-molecular-weight heparins administered subcutaneously once or twice daily have been reported to be as safe and efficacious as intravenous unfractionated heparin in the treatment of acute venous thromboembolic disease.

    Objective: To determine whether subcutaneous enoxaparin administered once or twice daily is as effective as continuously infused unfractionated heparin in acute symptomatic venous thromboembolic disease.

    Design: Randomized, controlled, partially blinded equivalence trial.

    Setting: 74 hospitals in 16 countries.

    Patients: 900 patients with symptomatic lower-extremity deep venous thrombosis, including 287 (32%) with confirmed pulmonary embolism.

    Interventions: Initial therapy with dose-adjusted intravenous unfractionated heparin compared with subcutaneous enoxaparin at fixed dosages of 1.0 mg/kg of body weight twice daily or 1.5 mg/kg once daily. Long-term oral anticoagulation was started in all patients within 72 hours of randomization.

    Measurements: Clinical end points assessed during a 3-month follow-up period.

    Results: Equivalent efficacy was seen in the heparin group and both enoxaparin groups. Symptomatic venous thromboembolism recurred in 12 of 290 patients receiving unfractionated heparin (4.1%), 13 of 298 patients receiving once-daily enoxaparin (4.4%), and 9 of 312 patients receiving twice-daily enoxaparin (2.9%). Compared with unfractionated heparin, the treatment difference was 0.2% (95% CI, −3.04% to 3.49%) for once-daily enoxaparin and −1.2% (CI, −4.2% to 1.7%) for twice-daily enoxaparin. Incidence of major hemorrhage did not differ among the three treatment groups. Major hemorrhage occurred in 6 of 290 patients (2.1%) in the unfractionated heparin group, 5 of 298 patients (1.7%) in the once-daily enoxaparin group, and 4 of 312 patients (1.3%) in the twice-daily enoxaparin group.

    Conclusions: Subcutaneous enoxaparin once or twice daily is as effective and safe as dose-adjusted, continuously infused unfractionated heparin in the prevention of recurrent symptomatic venous thromboembolic disease.

    *For members of the Enoxaparin Clinical Trial Group and other study participants, see Appendix.

    Article and Author Information

    • Grant Support: By Aventis Pharmaceuticals, Inc., Bridgewater, New Jersey, and Aventis Pharma SA, Antony, France (formerly known as Rhône-Poulenc Rorer Pharmaceuticals, Inc., Collegeville, Pennsylvania, and Rhône-Poulenc Rorer SA, Antony, France).

    • Requests for Single Reprints: Theodore E. Spiro, MD, Aventis Pharma SA, Cardiovascular Therapeutic Area, 20 Avenue Raymond Aron, 92165 Antony Cedex, France; e-mail, theodore.spiro{at}aventis.com.

    • Current Author Addresses: Dr. Merli: Division of Internal Medicine, Thomas Jefferson University, 3rd Floor, 211 South Ninth Street, Philadelphia, PA 19107.

    • Dr. Spiro: Cardiovascular Therapeutic Area, Aventis Pharma SA, 20 Avenue Raymond Aron, 92165 Antony Cedex, France.

    • Dr. Olsson: Medical Department, University Hospital of Lund, S 22185 Lund, Sweden.

    • Dr. Abildgaard: Medical Department, Aker Hospital, 0514 Oslo, Norway.

    • Dr. Davidson: Pulmonary and Critical Care, Virginia Mason Medical Center, C7-PUL, 1100 Ninth Avenue, Seattle, WA 98101.

    • Dr. Eldor: Institute of Hematology, Tel-Aviv Souraski Medical Center, Tel Aviv 63409, Israel.

    • Dr. Elias: Chest and Critical Care Medicine, Scripps Clinic and Research Foundation, 10666 North Torrey Pines Road, Mailstop 207 W, La Jolla, CA 92037.

    • Dr. Grigg: Department of Haematology, Royal Melbourne Hospital, Grattan Street, Victoria 3052, Australia.

    • Dr. Musset: Hôpital Antoine Béclère. 157 rue de la Porte de Trivaux, 92140 Clamart, France.

    • Dr. Rodgers: Hematology-Oncology Division, University of Utah Medical Center, 50 North Medical Drive, Salt Lake City, UT 84132.

    • Dr. Trowbridge: Division of Hematology/Oncology, Scott and White Clinic, Texas A&M University, College of Medicine, 2401 South 31st Street, Temple, TX 76508.

    • Dr. Yusen: Divisions of Pulmonary and Critical Care Medicine and General Medical Sciences, Washington University School of Medicine, Campus Box 8052, Barnes-Jewish Hospital, 660 South Euclid Avenue, Saint Louis, MO 63110-1093.

    • Dr. Zawilska: Department of Haematology, Academy of Medicine, Ul. Szkolna 8/12, 61-833 Poznan, Poland.

    • Author Contributions: Conception and design: G. Merli, T.E. Spiro, C.-G. Olsson, U. Abildgaard, B.L. Davidson, A.A. Trowbridge.

    • Analysis and interpretation of the data: G. Merli, T.E. Spiro, C.-G. Olsson, U. Abildgaard, B.L. Davidson, A. Eldor, D. Elias, A. Grigg, D. Musset, G.M. Rodgers, R.D. Yusen.

    • Drafting of the article: G. Merli, T.E. Spiro, C.-G. Olsson, U. Abildgaard, B.L. Davidson, A. Eldor, D. Elias, G.M. Rodgers, A.A. Trowbridge, R.D. Yusen.

    • Critical revision of the article for important intellectual content: G. Merli, T.E. Spiro, C.-G. Olsson, U. Abildgaard, B.L. Davidson, A. Eldor, D. Elias, A. Grigg, D. Musset, G.M. Rodgers, A.A. Trowbridge, R.D. Yusen, K. Zawilska.

    • Final approval of the article: G. Merli, T.E. Spiro, C.-G. Olsson, B.L. Davidson, A. Eldor, A. Grigg, A.A. Trowbridge, R.D. Yusen, K. Zawilska.

    • Provision of study materials or patients: T.E. Spiro, C.-G. Olsson, U. Abildgaard, B.L. Davidson, A. Eldor, D. Elias, A. Grigg, D. Musset, G.M. Rodgers, A.A. Trowbridge, R.D. Yusen, K. Zawilska.

    • Statistical expertise: T.E. Spiro, B.L. Davidson, R.D. Yusen.

    • Obtaining of funding: T.E. Spiro.

    • Administrative, technical, or logistic support: T.E. Spiro.

    • Collection and assembly of data: T.E. Spiro, B.L. Davidson, A.A. Trowbridge, R.D. Yusen.

    Summary for Patients

    • Summaries for Patients:Comparison of Two Forms of the Anticlotting Drug Heparin for Treatment of Blood Clots in the Legs Ann Intern Med February 6, 2001 134:S76
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    1. Ann Intern Med February 6, 2001 vol. 134 no. 3 191-202
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