Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, Weisslinger N. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients.
Overall Study Question
To determine the baseline frequency of venous thromboembolism acutely ill medical patients as well as to determine whether anticoagulation with enoxaparin was effective in reducing the risk of deep vein thrombosis (DVT) and pulmonary embolsim (PE).
Are the Results of the Study Valid?
Was assignment of patients randomized?
Yes, Patients were randomized to either placebo, 20mg enoxaparin once daily, or 40 mg enoxaparin once daily for 6-14 days during hospitalization.
Were all patients who entered the trial properly accounted for and attributed at its conclusion?
All patients were accounted for, although 21.4% of patients randomized were not evaluated (with respect to the primary outcome variable) due to death, patient refusal to submit to venography, unevaluable venogram, etc. Intention to treat analysis did not include these patients. Such exclusions were evenly balanced between the three groups. 97.4% of patients randomized were included in the safety analysis.
Were patients, their clinicians, and study personnel ‘blind’ to treatment?
Yes. The study employed a double-blind design.
Were the groups similar at the start of the trial?
Yes. The baseline characteristics between the groups were similar.
Aside from the experimental intervention, were the groups treated equally?
Overall, are the results of the study valid?
What were the Results?
How large was the treatment effect?
Venous thromboembolism (detected by leg venography) by day 14 of hospitalization: enoxaparin 40: 5.5% (16/291) (p<0.0001 vs. placebo) enoxaparin 20: 15% (43/287); placebo: 14.9% (43/288). NNT to prevent one asymptomatic DVT (within 15 days of hospitalization) with enoxaparin 40 for 6-14 days vs. placebo = 11. The reduction was significant for both distal or proximal DVT in the 40 mg group vs. placebo. Only 6 of the DVT were symptomatic (spread through the 3 groups). Secondary outcome (DVT reported by patients from discharge to day 110): enoxaparin 40: 7.0% (19/272) (p<0.001) enoxaparin 20: 17.5% (46/263); placebo: 17.1% (45/263). NNT to prevent one symptomatic DVT (during 110 days after hospitalization) with enoxaparin 40 for 6-14 days vs. placebo = 10. Only 4 pulmonary emboli occurred early, 6 occurred late (4 were fatal), thus between group comparisons were not possible. No statistically significant decrease in mortality at 110 days in 40 mg group vs. placebo. There were no significant differences between groups during treatment with respect to thrombocytopenia or major or minor hemorrhage. There were more local injection site reactions in the enoxaparin 40 group than placebo (5 vs. 0; p=0.0).
How precise was the estimate of the treatment effect?
The relative risk of DVT within 14 days (enoxaparin 40 vs. placebo) was 0.37 (97.6% CI 0.22-0.63).
Will the Results Help Me in Caring for My Patients?
Can the results be applied to my patient care?
The benefits of enoxaparin 40 mg therapy may be worth the costs, since other (less expensive) methods of thromboprophylaxis (e.g. unadjusted unfractionated heparin) have not been consistently shown to to be effective in this population. The incidence of hemorrhage (major or minor) did not differ significantly between the groups and other adverse effects (e.g.. thrombocytopenia) was non-significantly less common in the enoxaparin 40 mg group than in the placebo arm.
Were all clinically important outcomes considered?
Yes. The outcomes measured were relevant and the reporting of outcomes complete.
Are the likely treatment benefits worth the potential harms and costs?
Yes. The benefits of enoxaparin 40 mg may be worth the costs, since other (less expensive) methods of thromboprophylaxis (e.g.. unadjusted unfractionated heparin) have not been consistently shown to to be effective in this population. The incidence of hemorrhage (major or minor) and other adverse events (e.g. thrombocytopenia) did not differ significantly between the groups.
This study is the first large trial to systematically characterize the incidence of proximal and distal DVT among general medical patients. Previous studies have been smaller in size and used less sensitive methods of detection (e.g.. ultrasonography). Although the incidence of asymptomatic DVT was reduced by enoxaparin 40mg in this trial compared to placebo, the occurrence of symptomatic DVT, pulmonary embolism, or post-phlebitic syndrome was too infrequent to conclude that the therapy resulted in an obvious clinical benefit.
A much larger trial would be required to establish this. The trend toward a reduction in mortality in this trial, combined with the aggregate data of numerous other DVT prevention trials probably supports the use of the “surrogate” endpoint of venographically detected DVT since the consequences of untreated DVT may be very severe and irreversible. Despite these limitations, this study lends reasonable support to the need to identify patients at risk for DVT in general medicine units and treat them with effective doses of antithrombotic therapy. The evidence to date most strongly supports the administration of enoxaparin 40 mg subcutaneously daily for this indication.
Future studies should compare enoxaparin 40 mg daily (or another low molecular weight heparin in comparable doses) to unfractionated heparin in this patient population using the same methodology, since the latter heparin preparation is still widely used despite the lack of reliable data to support its efficacy in preventing DVT in these patients.