Low-molecular-weight heparin or warfarin for deep vein thrombosis
ACP J Club. 1994 May-June;120:70. doi:10.7326/ACPJC-1994-120-3-070
Hull R, Raskob G, Pineo G, et al. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. N Engl J Med. 1993 Nov 4;329:1370-6.
To compare the effectiveness and safety of subcutaneous low-molecular-weight (LMW) heparin with oral warfarin sodium for the prevention of venous thrombosis after hip or knee replacement.
Randomized, double-blind trial with a mean follow-up of 9.4 days after surgery.
4 centers in Canada and the United States.
1436 patients (mean age 64 y, 59% women) scheduled for total hip or knee arthroplasty. Exclusion criteria were active bleeding; contraindication to anticoagulants; a history of pulmonary embolism or deep vein thrombosis (DVT); heparin-associated thrombocytopenia; allergy to heparin, bisulfites, fish, or radiopaque contrast medium; deficiency of antithrombin III, protein C, or protein S; pregnancy; malignant hypertension, hepatic failure, or renal failure; or treatment with warfarin sodium, LMW heparin, or heparinoids within the past 7 days.
721 patients were allocated to receive warfarin sodium, 10 mg postoperatively followed by a daily dose adjusted to maintain an international normalized ratio (INR) of 2.0 to 3.0, and a daily placebo injection. 715 patients were allocated to receive LMW heparin, 75 international factor Xa inhibitory units per kilogram of body weight subcutaneously, and a daily placebo capsule. Treatment in both groups continued for 14 days after surgery or until hospital discharge.
Main outcome measures
Venogram-proven DVT, major bleeding, and wound hematoma.
231 of 617 patients (37.4%) in the warfarin group compared with 185 of 590 patients (31.4%) in the LMW heparin group developed DVT (absolute difference 6.0%, 95% CI 0.8% to 11.4%). 9 of 721 patients (1.2%) in the warfarin group compared with 20 of 715 patients (2.8%) in the LMW heparin group had major bleeding (absolute difference 1.6%, CI 0.1% to 3.0%). 29 patients (4.0%) in the warfarin group compared with 51 patients (7.1%) in the LMW heparin group had wound hematomas (absolute difference 3.1%, CI 0.8% to 5.4%).
The incidence of deep vein thrombosis was reduced with subcutaneous low-molecular-weight heparin compared with oral warfarin sodium in patients with hip or knee replacement, but the rate of bleeding complications was increased.
Sources of funding: Heart and Stroke Foundation of Alberta and Novo Nordisk.
For article reprint: Dr. R. Hull, Department of Medicine, University of Calgary, 3330 Hospital Drive Northwest, Calgary, Alberta T2N 4N1, Canada. FAX 403-283-4740.
The incidence of DVT may be as high as 50% in patients having total hip arthroplasty and even higher after major knee surgery. Accordingly, there is considerable interest in prophylaxis for DVT in patients having these procedures. Based on a review of randomized trials, low-dose treatment with warfarin (INR, 2.0 to 3.0) was recommended as the most effective anticoagulant regimen for prophylaxis by the American College of Chest Physicians' Third Consensus Conference on Antithrombotic Therapy (1).
The study by Hull and colleagues suggests that treatment with a LMW heparin (Logiparin; Novo Nordisk Pharmaceuticals Inc.), administered as a single daily subcutaneous injection, may be slightly more effective than low-dose warfarin but is associated with a slightly higher incidence of bleeding. Logiparin and other LMW heparins have a high degree of bioavailability and a long half-life. A slightly greater benefit may also occur using LMW heparin compared with warfarin in patients having knee surgery. Overall, Logiparin reduced the incidence of proximal DVT by 1.5% and of distal thrombosis by 4.5%, albeit with a 1.6% increase in risk for major bleeding episodes.
The review by Anderson and colleagues concluded that LMW heparins were potentially more cost-effective than unfractionated heparins (administered subcutaneously twice daily) based on an analysis of the cost of managing patients with DVT and bleeding complications. In their meta-analysis comparing the 2 types of heparin, a 7% reduction occurred in the incidence of proximal DVT using LMW heparin but no difference occurred in the incidence of distal DVT or in the rates of major or minor bleeding. Anderson and colleagues suggest that if LMW heparin costs 2.6 times as much as standard unfractionated heparin (administered subcutaneously twice daily), the increased cost is offset by the decreased number of patients who require treatment for proximal DVT. Applying the costs calculated by Anderson and colleagues for managing DVT and major bleeding complications to the study by Hull and colleagues, it is unlikely that LMW heparin is more cost-effective than low-dose warfarin because the cost of the increase in major bleeding complications with Logiparin would diminish the benefit of a decrease in the number of patients requiring treatment for DVT. Further, Anderson and colleagues suggest that LMW heparins are cost-effective based on an increased price of only 2.6 times that of unfractionated heparin. Enoxaparin (Lovenox, Rhône-Poulenc), the first LMW heparin to be approved in the United States for prophylaxis of DVT after hip replacement, was introduced at an average wholesale price of $23/d (2). This is considerably more than the cost of subcutaneous heparin twice daily in most U.S. hospitals or the cost of low-dose warfarin. Thus, treatment with LMW heparins appears to offer greater protection from DVT after total hip or knee arthroplasty than does subcutaneous administration of unfractionated heparin, and may be equivalent to the preferred regimen of low-dose warfarin prophylaxis, but at a greater cost.
Paul Eisenberg, MD
Washington University School of Medicine St. Louis, Missouri, USA