Prolonged enoxaparin therapy to prevent venous thromboembolism after primary hip or knee replacement. (Abstracts of Current Literature).

Comp PC, Spiro IF:, Friedman RJ, et al (The Enoxaparin Clinical Trial Group), J Bone Joint Surg Am. 2001;83: 336-343.

Venous thromboembolic complications occur rather frequently in patients after hip or knee replacement surgery. Several anticoagulants are in clinical use as prophylactic agents; however, according to the authors of this study, heparins with a low molecular weight have proven to be superior to other drugs that reduce the risk of postsurgical thromboembolism. They said that statements from a recent consensus conference suggest that prophylaxis against thromboembolism should be initiated and continued postoperatively until the patient's risk of thrombosis returns to a normal level. This study addressed the efficacy and safety of a postoperative regimen of enoxaparin, a heparin with a low molecular weight, in a large population of patients who received elective, primary total hip or knee replacement.

This prospective, parallel-group, multicenter clinical trial was conducted over a 2-year period (1994-1996), in which 57 clinical investigators enrolled 968 patients who underwent a total hip or knee replacement. The study consisted of 2 phases: the open-label phase, during which all patients received subcutaneous injections of enoxaparin (30 mg, 2 times per day) for 7 to 10 days after surgery, and the double-blind phase, during which 873 of the participants (435 received a hip replacement, 438 received a knee replacement) were randomly selected to receive either enoxaparin (40 mg) or a matching placebo once per day for 3 weeks as outpatients. The inclusion criteria for the double-blind phase were: (1) the patient received adequate enoxaparin during the open-label phase, (2) the patient did not undergo a second surgery or develop venous thrombosis or major bleeding during the first phase, and (3) the patient did not meet any of the extensive exclusion criteria.

The prevalence of venous thrombosis or symptomatic pulmonary embolism in patients during the double-blind phase was assessed by venograms, ventilation-perfusion lung scans, and pulmonary angiograms, which were interpreted by a panel of 3 vascular radiologists who were unaware of patient group assignments. Drug safety was monitored by daily inspection of patients for well-defined hemorrhagic events during the hospital stay and outpatient visits and by the data from standard biochemical and hematological tests. Upon completion of the study, the tabulated data were subjected to extensive statistical analyses.

According to the results, enoxaparin reduced the prevalence of deep venous thromboembolism in all patients with total hip replacement, but during the double-blind phase, this was true only in female patients who received a total knee replacement. Treatment with either enoxaparin or placebo did not make a difference in the prevalence of venous thrombosis in male patients who underwent knee replacement. The incidence of venous thromboembolism in the members of the hip replacement group who received enoxaparin was only 8% (18 of 224 patients), compared with an incidence of 23.2% (49 of 221 patients) in those patients with a hip replacement who received the placebo (odds ratio=3.62, 95% confidence interval=2.00, 6.55, relative risk reduction=65.5%).

There was a correlation between the site of venous thrombi and the hip replacement surgery. The prevalence of proximal venous thrombi was lower (2.7%) in patients with hip replacement who received enoxaparin compared with those patients who received the placebo (12.8%). The prevalence of proximal venous thromboemboli was not much different in the group that received a knee replacement, regardless of enoxaparin or placebo treatment. The incidence of distal venous thrombi was 5.4% in the group receiving hip replacement and 13.4% in the group receiving knee replacement. The prevalence of symptomatic pulmonary embolism among the patients after the operation was rare. Of all the patients, only 3 participants in the placebo group (1 with a hip replacement and 2 with a knee replacement) developed pulmonary embolism. Prolonged treatment of patients with enoxaparin reduced both the prevalence of readmission to hospital for venous thromboembolism (4.5% vs 15.8%) and the length of stay compared with the placebo group. With respect to drug safety, there was no significant difference between the 2 groups. The incidence of hemorrhagic events (2.4%), abnormal laboratory tests (1%), and other adverse effects (1%) in the participants were relatively rare, regardless of enoxaparin or placebo treatment.

According to the authors, the venographic data of this study indicated that extending enoxaparin therapy following hip replacement surgery for 4 weeks produced a reduction in the incidence of venous thromboembolism. This regimen provided a therapeutic benefit to the patients without affecting their safety. According to the authors, however, this study did not show a similar beneficial effect of enoxaparin in patients who underwent knee replacement surgery.

Kamran Tavakol, PT, PhD
Howard University
Washington, DC