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

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% Cl, -3.04% to 3.49%) for once-daily enoxaparin and -1.2% (Cl, -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.