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Source: Merli G, et al. Ann Intern Med. 2001;134:191-202.
Deep vein thrombosis (DVT) remains a major cause of morbidity and mortality. Typically, patients with diagnosed DVT are treated with 5-10 days of unfractionated heparin intravenously, as initial treatment and warfarin is added within the first few days. Recently, low molecular-weight heparins (LMWH) have been introduced and have been used successfully for both prevention and treatment of DVT.1,2 Randomized trials and meta-analysis have shown subcutaneously administered LMWH to have antithrombotic efficacy equal to 3-6 or greater than7-9 that of continuously administered unfractionated heparin in the initial treatment of DVT, and equal to that of unfractionated heparin in the treatment of pulmonary embolism (PE).10,11 However, many of these trials were small, did not biochemically monitor LMWH activity, and used intermediate end points, such as venographic, plethysmographic, or scintigraphic end points rather than clinical end points such as recurrent DVT or PE.
The study conducted by the Enoxaparin Clinical Trial Group (and supported by Aventis) was designed to determine whether enoxaparin administered subcutaneously once or twice per day is as effective as continuously infused unfractionated heparin in the treatment of patients with acute, symptomatic venous thromboembolic disease. Patients with acute DVT (n = 900), including 287 (32%) with pulmonary embolus, from 74 hospitals in 16 countries were randomized to receive 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 (warfarin) was started in all patients within 72 hours of randomization.
Equivalent efficacy was seen in the heparin group and both enoxaparin groups. Recurrent DVTs occurred in 12 of 290 patients receiving unfractionated heparin (4.1%), 13 of 298 patients receiving once daily enoxaparin (4.4%), and nine of 312 patients receiving twice daily enoxaparin (2.9%). Compared with unfractionated heparin, the treatment difference was 0.2% (95% CI, 3.04-3.49%) for once-daily enoxaparin and -1.2% (95% CI, 14.2-1.7%) for twice-daily enoxaparin. Adverse events were comparable in the three groups. Major hemorrhage occurred in six of 290 patients (2.1%) in the unfractionated heparin group, five of 298 patients (1.7%) in the once-daily enoxaparin group, and four of 312 patients (1.3%) in the twice-daily enoxaparin group.
Subgroup analysis on the basis of age, sex, weight, medical history (prior PE, presence of cancer, etc.), and location of DVT did not reveal any significant differences in either efficacy or occurrence of adverse events in any particular subgroup. Thus, Merli and colleagues concluded that 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.
Comment by William B. Ershler, MD
The introduction of LMWHs to hospital and community pharmacies has been a major advance in the past decade. Physicians have been quick to use these agents because they offer the advantage of ease of treatment and reduced length of hospital stay (and, thereby, costs). Furthermore, there has been a sense that adverse events were fewer, and the incidence of treatment-associated thrombocytopenia was reduced.12 Yet, there is also a feeling of uncertainty because laboratory monitoring is not readily available.
Thus, the current study offers reassurance for those of us who have already adopted this approach for the management of acute DVT. Furthermore, it demonstrated that once-daily injection of a larger dose of enoxaparin was equivalent to the twice-daily dose. The rationale for trying the once-daily dose was based upon pharmacokinetic studies that were specific for this particular LMWH, and should not be applied to other LMWHs, some of which already were shown to be effective at once-daily dosing. With regard to enoxaparin, however, a careful review of the data presented in this paper suggest that for the particularly high-risk patients (eg, those with cancer, prior PE, or obesity), there was a trend, albeit, not significant, that would suggest that twice-daily dosing was more efficacious than the single dosing. Perhaps, in a larger study, these trends would reach a level of significance.
This was a carefully performed, multi-center clinical investigation with outstanding design, cautious interpretation, and a clear presentation of results. Clinical trials designed to establish comparable efficacy with an agent already known to be efficacious in a great majority of patients are complicated, require large sample sizes, and clearly stated, statistical objectives. This report is an excellent example of the way it should be done, and is recommended in that light for those developing skills in clinical trial methodology.
Dr. Ershler is Director, Institute for Advanced Studies in Aging, Washington, DC.