Enoxaparin vs. Heparin for Thromboembolic Disease
Enoxaparin vs. Heparin for Thromboembolic Disease
Abstract & Commentary
Source: Merli G, et al. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med 2001;134:191-202.
The purpose of this international, multicenter, randomized, controlled trial was to determine whether subcutaneous enoxaparin administered once or twice daily is as effective as continuously infused unfractionated heparin in acute, symptomatic venous thromboembolic disease. A total of 900 patients with symptomatic, lower extremity deep venous thrombosis (DVT), including 287 (32%) with confirmed pulmonary embolism (PE), were randomly assigned to one of the three treatment groups. Patients assigned to enoxaparin received a weight-adjusted subcutaneous dose: either 1.0 mg/kg of body weight twice daily or 1.5 mg/kg once daily. Patients assigned to the non-blinded unfractionated heparin group received a bolus and infusion based on approved institution-specific nomograms. Both enoxaparin and heparin treatments were continued for at least five days, and warfarin was started within 72 hours and continued for at least three months. The primary clinical end points were recurrent DVT or PE within three months of randomization. Patients with symptoms of recurrent DVT underwent confirmatory testing with venography, ultrasonography, or both. Patients with suspected PE underwent lung perfusion scanning, pulmonary angiography, or both.
Equivalent efficacy was seen among all three groups. Venous thromboembolism occurred in 4.1% of the heparin group, 4.4% of the once daily enoxaparin group, and 2.9% of the twice daily enoxaparin group. Compared with unfractionated heparin, the treatment difference was 0.2% (95% CI, -3.04% to 3.49%) for once daily enoxaparin and -1.2% (95% CI, -4.2% to 1.7%) for twice daily enoxaparin. The three treatment groups did not differ significantly in safety profile, including all hemorrhagic complications, transfusion requirements, deaths, or thrombocytopenia.
Commentary by Stephanie B. Abbuhl, MD, FACEP
The low-molecular-weight heparins (LMWHs) have revolutionized the treatment of venous thromboembolism by simplifying dosing and administration. Despite their high cost, the savings to a health care system for outpatient treatment of DVT can be substantial.1 This unblinded study, which was sponsored by Aventis Pharmaceuticals, concluded that subcutaneous enoxaparin once or twice daily is as effective and safe as dose-adjusted, continuously infused unfractionated heparin for the prevention of recurrent symptomatic venous thromboembolic disease. The power of the study was 0.9 to detect a 10% difference between enoxaparin and heparin. These results add to the mounting evidence favoring LMWHs (and specifically, enoxaparin) for the treatment of thromboembolic disease.
It should be noted that since various LMWHs differ in their pharmacokinetic profiles, study results that apply to one cannot be generalized to another. Enoxaparin was used in this trial and, along with tinzaparin, is one of two FDA-approved LMWHs for the treatment of DVT with or without PE. It is reassuring to see more evidence of the efficacy and safety of enoxaparin for the treatment of patients who have not only DVT, but PE as well. At baseline, 32% of the patients in this study had PE; 95% had DVT. Additional data supporting the equivalent efficacy for the once daily enoxaparin dose also are useful because this regimen can further simplify drug administration and encourage potential outpatient treatment.
Despite the optimism generated by a study like this, it is important to remember that the LMWHs are not perfect. It is still uncertain if a weight-adjusted dosing regimen without laboratory monitoring should be used in patients who are obese, are pregnant, or have renal insufficiency; in our institution, these patients have anti-factor Xa levels checked. Another concern is whether protamine is an effective antidote for LMWHs. Reversal of anticoagulation with an LMWH is limited to molecules larger than 400 Da, and many LMWH chains are smaller than this. Finally, the LMWHs still are associated with a risk of thrombocytopenia (although lower than that associated with heparin), and should not be given to patients with a history of heparin-induced thrombocytopenia.
References
1. O’Brien B, et al. Economic evaluation of outpatient treatment with low-molecular-weight heparin for proximal vein thrombosis. Arch Intern Med 1999;159:2298-2304.
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