Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease

Ann Intern Med. 2001 Feb 6;134(3):191-202. doi: 10.7326/0003-4819-134-3-200102060-00009.


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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Cutaneous
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Anticoagulants / administration & dosage*
  • Anticoagulants / adverse effects
  • Drug Administration Schedule
  • Enoxaparin / administration & dosage*
  • Enoxaparin / adverse effects
  • Female
  • Follow-Up Studies
  • Hemorrhage / chemically induced
  • Heparin, Low-Molecular-Weight / administration & dosage*
  • Heparin, Low-Molecular-Weight / adverse effects
  • Humans
  • Infusions, Intravenous
  • Male
  • Middle Aged
  • Pulmonary Embolism / complications
  • Pulmonary Embolism / drug therapy*
  • Recurrence
  • Risk Factors
  • Single-Blind Method
  • Thrombocytopenia / chemically induced
  • Treatment Outcome
  • Venous Thrombosis / complications
  • Venous Thrombosis / drug therapy*


  • Anticoagulants
  • Enoxaparin
  • Heparin, Low-Molecular-Weight