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6 February 2001 | Volume 134 Issue 3 | Pages 191-202
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.
Author and Article Information
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.
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. ARTICLE
Subcutaneous Enoxaparin Once or Twice Daily Compared with Intravenous Unfractionated Heparin for Treatment of Venous Thromboembolic Disease
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