BACKGROUND: Several studies have shown that initial treatment with subcutaneous low-molecular-weight heparin is as effective as intravenous unfractionated heparin in preventing the sequelae of VTE. This randomized controlled trial addressed this issue with a large population that included patients with pulmonary embolus (PE).
POPULATION STUDIED: A total of 900 patients from 74 hospitals in 16 countries were enrolled. Subjects were adults with venogram- or ultrasound-proven lower extremity deep venous thrombosis, symptomatic PE with high-probability ventilation-perfusion (V/Q) scan, or a positive angiogram with radiologic evidence of a lower extremity VTE. Exclusion criteria included previous administration of heparin or warfarin for more than 24 hours, risk for hemorrhage, and allergies to the medications or to pork products. The average age was 61 years; 55% were men. Twenty-four percent had had a previous VTE; 16% had cancer; and 32% had a concurrent PE. The study population seems to be similar to that of a family physician., although more information about referral pattern and local diagnostic and therapeutic protocols would be valuable.
STUDY DESIGN AND VALIDITY: This was a randomized unblinded trial. Subjects received 1 of 3 antithrombotic regimens: heparin bolus and continuous infusion to achieve a target activated partial thromboplastin time of 55 to 80 seconds, enoxaparin 1 mg per kg twice daily, or enoxaparin 1.5 mg per kg once daily. These regimens were continued for at least 5 days. Warfarin was started within the first 3 days and was continued for at least 3 months, adjusted to maintain an international normalized ratio between 2.0 and 3.0. All subjects received baseline V/Q scans or angiograms. Although the clinicians were not masked to treatment status, all imaging studies and outcomes were reviewed by committees masked to treatment status. The maker of enoxaparin sponsored and performed the study.
OUTCOMES MEASURED: The major outcomes were recurrence or worsening of VTE or PE, major hemorrhage (ie, >2.0 g/L hemoglobin drop, requiring transfusion of 2 or more units, bleeding requiring intervention, or death), thrombocytopenia, or other side effects. Cost and patient satisfaction were not addressed.
RESULTS: The groups were similar at baseline. There was no significant difference in recurrence or worsening of VTE among patients in the unfractionated heparin group (4.1%), enoxaparin daily group (4.4%), and enoxaparin twice-daily group (2.9%). New PE was rare in all 3 groups (4/900). Regardless of treatment, patients with cancer or symptomatic PE at baseline were at higher risk of subsequent VTE (odds ratio [OR]=3.7; 95% confidence interval [CI], 1.3-11; OR=3.4; 95% CI, 1.55-7.3), respectively. These findings were unchanged when analysis was restricted to subjects for whom all data were available. Similarly, there was no significant difference among the groups in the incidence of major hemorrhage (2.1%, 1.7%, 1.3%, respectively), death (3.1%, 3.7%, 2.2%, respectively), or thrombocytopenia. Adherence to enoxaparin in both groups was better than for unfractionated heparin group (83.6% and 85.3% vs 75.9%, respectively).
This study provides additional evidence that low-molecular-weight heparin is a safe and effective alternative to intravenous unfractionated heparin for initial treatment of acute DVT. For patients for whom outpatient treatment is feasible, enoxaparin is less expensive and is easier to administer than intravenous heparin. These results do not imply that treatment of PE in the outpatient setting is appropriate; likewise, the finding of good results with once-daily dosing is promising but requires confirmation with more rigorous methods. Clinicians should look for studies that address the value of initial overnight hospitalization for VTEs, the impact of the out-of-pocket expense of enoxaparin, and the effectiveness of this intervention in nonclinical trial settings.