Correspondence
Low-Molecular-Weight Heparin vs. Warfarin for Prophylaxis against Deep-Vein Thrombosis
N Engl J Med 1994; 330:862-863March 24, 1994
- Article
To the Editor:
Hull and colleagues (Nov. 4 issue)1 compared postoperative warfarin therapy with a once-daily postoperative regimen of the low-molecular-weight heparin Logiparin for the prevention of postoperative venous thrombosis in patients undergoing major orthopedic surgery. They found a small but significant reduction in thrombosis in the low-molecular-weight-heparin group at the cost of a small but significant increase in bleeding. The event rate in the low-molecular-weight-heparin group was higher than that reported in other studies that used a twice-daily postoperative dosing regimen and mandatory venography to assess thrombosis2-5. The observed differences in the incidence of postoperative thrombosis between the study by Hull and associates and the other reports could be due to chance or to differences in dosage regimens among the various studies. Thus, Hull and associates evaluated a once-daily preparation of low-molecular-weight heparin given postoperatively without studying a twice-daily regimen. In all the other studies in which low-molecular-weight-heparin treatment was started postoperatively, a twice-daily regimen was included as one of the comparison groups. In three studies, a twice-daily regimen was compared with a once-daily regimen; in all three there was a lower incidence of thrombosis with the twice-daily regimen, which was statistically significant in two studies. Although the once-daily regimen is more convenient, this fact should not override the concern for efficacy. The results of the two studies involving enoxaprin, comparing a once-daily with a twice-daily dosage regimen, led the Food and Drug Administration to approve the twice-daily regimen for the prevention of venous thrombosis after elective hip or knee surgery3,4.
5 ReferencesJack Hirsh, M.D.
Hamilton Civic Hospitals Research Centre, Hamilton, ON L8V 1C3, Canada1
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;329:1370-1376
Full Text | Web of Science | Medline2
Heit J ,Kessler C ,Mammen E , et al. Efficacy and safety of RD heparin (a LMWH) versus warfarin for prevention of deep-vein thrombosis after hip or knee replacement. Blood 1991;79:Suppl:187A-187A abstract.3
Spiro TE, Enoxaparin Clinical Trials Group
Web of Science4
Colwell CW Jr ,Spiro TE ,Trowbridge AA , et al. Use of enoxaparin, a low-molecular-weight heparin, and unfractionated heparin for the prevention of deep venous thrombosis after elective hip replacement: a clinical trial comparing the efficacy and safety. J Bone Joint Surg Am 1994;76:3-14
Web of Science | Medline5
Leclerc JR ,Geerts WH ,Desjardins L , et al. Prevention of deep vein thrombosis after major knee surgery -- a randomized, double-blind trial comparing a low molecular weight heparin fragment (enoxaparin) to placebo. Thromb Haemost 1992;67:417-423
Web of Science | Medline
To the Editor:
The paper by Hull et al. addresses several of the issues confounding the thromboembolism literature to date -- i.e., stratification of patients, adequate numbers, randomization, and variation between centers. However, there are two important issues that were not addressed. First, what are the implications of deep-vein thrombosis as detected by routine screening after total joint surgery? With rates of deep-vein thrombosis of approximately 37 percent but a rate of nonfatal pulmonary embolism of only 0.2 percent, deep-vein thrombosis would not seem to be an accurate marker of the patient at risk for pulmonary embolism after total joint surgery, unlike medical patients with cancer and congestive heart failure. If deep-vein thrombosis after total joint replacement is not a sensitive marker, then it should not in itself be considered a trigger for the initiation of therapeutic levels of anticoagulation, with the inherent risks to the postoperative patient.
Second, the two pulmonary emboli in their study and several “asymptomatic” deep-vein thromboses developed several weeks into the postoperative period. This would imply that the risk of pulmonary embolism continues after discharge and that patients should be given some form of prolonged prophylaxis. Because we have made similar findings, we currently continue our prophylactic treatment for eight weeks postoperatively and would be interested to learn what the authors recommend.
Paul A. Lotke, M.D.
Malcolm L. Ecker, M.D.
Hospital of the University of Pennsylvania, Philadelphia, PA 19104Author/Editor Response
The authors reply:
To the Editor: We agree with Dr. Hirsh's comments that the differences in thrombosis rates between our study and other similar studies could have been due to chance or to differences in dosing regimens. As our study showed, there was a striking variability in thrombosis rates between centers, making it hazardous to compare rates across studies.
In the two abstracts comparing once-daily and twice-daily dosing,1,2 venography was performed only on the leg that was operated on and thus could have underestimated thrombosis rates by at least 20 percent. Furthermore, different doses of low-molecular-weight heparin were compared in the once-daily and twice-daily protocols (90 units per kilogram of body weight per day and 50 units per kilogram twice a day in the trial using enoxaparin; 4000 units per day and 3000 units twice a day in the trial using ardeparin)2. The effectiveness of low-molecular-weight heparins is dose-dependent, and therefore the trend to lower rates with twice-daily dosing could have been due to the dosage rather than the schedule.
In European studies, once-daily dosing and twice-daily dosing yield similar thrombosis rates, and once-daily dosing has become the standard of practice3. However, in Europe treatment with low-molecular-weight heparin is started preoperatively, which may explain why thrombosis rates there are consistently lower than those in North America, where postoperative dosing has been the standard. We are currently engaged in a multicenter study comparing preoperative and postoperative low-molecular-weight heparin, with warfarin used as a control.
Drs. Lotke and Ecker point out that although the postoperative rate of deep-vein thrombosis was moderately high in our study, the incidence of pulmonary embolism was low. With case finding by venography, deep-vein thrombosis was identified and treated, and therefore the incidence of pulmonary embolism was low, supporting the effectiveness of anticoagulants in this setting. The evidence linking deep-vein thrombosis and pulmonary embolism (venous thromboembolism) is compelling, and we are therefore convinced that preventing deep-vein thrombosis will prevent pulmonary embolism, fatal or otherwise.
We agree that as the length of stay and the period of prophylaxis for these high-risk patients become shorter, concern about venous thromboembolism after discharge increases. At present, there are insufficient data to support the universal use of home prophylaxis, and this issue should be assessed in appropriate clinical trials with objective end points.
3 ReferencesRussell D. Hull, M.B., B.S., M.Sc.
Graham F. Pineo, M.D.
University of Calgary, Calgary, AB T2E 0A1, Canada1
Heit J ,Kessler C ,Mammen E , et al. Efficacy and safety of RD heparin (a LMWH) versus warfarin for prevention of deep-vein thrombosis after hip or knee replacement. Blood 1991;78:Suppl:187A-187A abstract.2
Spiro TE, Enoxaparin Clinical Trials Group
Web of Science3
Hirsh J ,Levine MN . Low molecular weight heparin. Blood 1992;79:1-17
Web of Science | Medline
