The New England Journal of Medicine
e-mail icon  FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |    Advanced Search
Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe
 
Original Article
PreviousPrevious
Volume 329:1370-1376 November 4, 1993 Number 19
NextNext

A Comparison of Subcutaneous Low-Molecular-Weight Heparin with Warfarin Sodium for Prophylaxis against Deep-Vein Thrombosis after Hip or Knee Implantation
Russell Hull, Gary Raskob, Graham Pineo, David Rosenbloom, William Evans, Thomas Mallory, Kenneth Anquist, Frank Smith, Gary Hughes, David Green, C. Gregory Elliott, Akbar Panju, and Rollin Brant

 

This Article
-Abstract

Commentary
-Letters

Tools and Services
-Add to Personal Archive
-Add to Citation Manager
-Notify a Friend
-E-mail When Cited

More Information
-PubMed Citation
ABSTRACT

Background Deep-vein thrombosis is a potentially life-threatening complication of total hip or knee replacement. There are few data on the effectiveness and safety of warfarin as compared with low-molecular-weight heparin as prophylaxis against this problem.

Methods We therefore performed a randomized, double-blind trial in 1436 patients to evaluate the effectiveness and safety of low-molecular-weight heparin (given subcutaneously once daily) as compared with adjusted-dose warfarin to prevent venous thrombosis after hip or knee replacement. Treatment with the drugs was started postoperatively. The primary end point was deep-vein thrombosis as detected by contrast venography (performed a mean of 9.4 days after surgery in each group).

Results Among the 1207 patients with interpretable venograms, 231 of 617 patients (37.4 percent) in the warfarin group and 185 of 590 patients (31.4 percent) in the low-molecular-weight-heparin group had deep-vein thrombosis (P = 0.03). The reduction in risk with low-molecular-weight heparin as compared with warfarin was 16 percent, and the absolute difference in the incidence of venous thrombosis was 6 percent in favor of low-molecular-weight heparin (95 percent confidence interval, 0.8 to 11.4 percent). The incidence of major bleeding was 1.2 percent (9 of 721 patients) in the warfarin group and 2.8 percent (20 of 715 patients) in the low-molecular-weight-heparin group (P = 0.04), and the absolute difference was 1.5 percent in favor of warfarin (95 percent confidence interval, 0.1 to 3.0 percent).

Conclusions Our data demonstrate that the small reduction in the incidence of venous thrombosis with low-molecular-weight heparin, as compared with warfarin, was offset by an increase in bleeding complications. Although the use of low-molecular-weight heparin is simpler, because it is administered subcutaneously without the need for monitoring, it may be more costly than warfarin. Warfarin is inexpensive, but the overall cost of its use is increased by the need to monitor the intensity of anticoagulation. At this time it is unclear which of these approaches is the most cost effective.

Postoperative deep-vein thrombosis presents a major clinical threat to patients undergoing hip or knee replacement1,2,3,4. In the absence of prophylactic anticoagulation, this disorder occurs in 40 to 60 percent of patients receiving hip implants5,6,7,8,9 and in 60 to 70 percent of patients receiving knee implants10,11,12. Several approaches to prevention are accepted in North America1: less intense warfarin sodium (international normalized ratio, 2.0 to 3.0),13,14,15,16 pneumatic compression,10,11,14,15,16,17,18 and subcutaneous heparin19,20,21. Less intense prophylaxis with warfarin sodium has been recommended as a standard by the National Heart, Lung, and Blood Institute22 and by the Third Consensus Conference on Antithrombotic Therapy of the American College of Chest Physicians23 for patients receiving hip implants. Because of the acceptance of this therapy for hip surgery, many have inferred that it is suitable for patients undergoing major knee surgery.

A number of randomized trials in Europe24,25,26,27,28,29,30,31,32,33 have suggested that low-molecular-weight heparin may be as effective as or more effective than standard subcutaneous heparin. A recent North American trial supports the European findings34. Pharmacokinetic studies show that subcutaneous low-molecular-weight heparin has a high bioavailability35,36 and a long half-life37,38,39,40,41,42 and that monitoring of the degree of anticoagulation is unnecessary41. By comparison, warfarin sodium, although given orally, requires frequent monitoring.

To date, there are few data comparing less intense prophylaxis using warfarin sodium with prophylaxis using a low-molecular-weight heparin fraction. A comparison of effectiveness and safety would be important, given the widespread acceptance and use of less intense warfarin sodium prophylaxis to treat orthopedic patients in North America. We therefore performed a randomized, double-blind trial evaluating the effectiveness and safety of subcutaneous low-molecular-weight heparin given in a fixed dose per kilogram of body weight once daily, as compared with adjusted doses of oral warfarin sodium, for the prevention of venous thrombosis after hip or knee replacement.

Methods

Study Design

This study was a multicenter, randomized double-blind clinical trial comparing therapy with warfarin sodium (Coumadin, DuPont Merck) in an adjusted dose with low-molecular-weight heparin (Logiparin, Novo Nordisk) given once daily in patients undergoing total hip or knee arthroplasty. Four centers in the United States and Canada participated in the trial. The protocol was approved by the institutional review board at each center.

Patients

Consecutive eligible patients 18 years of age or older scheduled to undergo total hip or knee arthroplasty who gave informed consent were enrolled in the study. Patients were eligible if they had none of the following: currently active bleeding or disorders contraindicating anticoagulant therapy; a history of deep-vein thrombosis or pulmonary embolism; allergy to heparin, bisulfites, or fish; allergy to radiopaque contrast medium; documented deficiency of antithrombin III, protein C, or protein S; history of heparin-associated thrombocytopenia; pregnancy; severe malignant hypertension (blood pressure, >= 250 mm Hg systolic and >= 130 mm Hg diastolic); severe hepatic failure (hepatic encephalopathy); severe renal failure necessitating dialysis; or geographic inaccessibility preventing them from making follow-up visits. In all, 1759 patients were identified. A total of 323 eligible patients were excluded for the following reasons: treatment with warfarin sodium, low-molecular-weight heparin, or heparinoids within the seven days before study entry (15 patients); treatment with acetylsalicylic acid that could not be discontinued (e.g., in patients with cerebrovascular or coronary-artery disorders) (52 patients); a decision by the patient not to give written informed consent (234 patients); or miscellaneous reasons (22 patients).

Before randomization, the patients were stratified into groups according to the study center where they were treated, the surgeon performing the procedure, the use of spinal as compared with general anesthesia, the site of the joint replacement (hip or knee), and whether the procedure was a primary procedure or a revision arthroplasty. A randomized, computer-derived treatment schedule was used to assign the patients to receive warfarin sodium orally or low-molecular-weight heparin subcutaneously. Within each stratum, the randomization schedule was balanced in blocks of four.

Treatment Regimens

The patients assigned to receive warfarin sodium received an initial dose of 10 mg postoperatively on the evening of the day of surgery; thereafter, the daily dose of warfarin sodium was adjusted by a standardized prescriptive protocol according to the results of laboratory monitoring of the prothrombin time and according to a predefined warfarin nomogram. The therapeutic range was also standardized among the participating hospitals with use of the international normalized ratio. This ratio is the prothrombin-time ratio obtained by testing a given sample with the World Health Organization reference thromboplastin, which has an international sensitivity index of 1.043. The warfarin dose was adjusted daily to maintain equivalence with an international normalized ratio between 2.0 and 3.043.

The patients receiving low-molecular-weight heparin were given a fixed dose of 75 International Factor Xa Inhibitory Units per kilogram of body weight subcutaneously once daily. As compared with the dosage levels used for the treatment of deep-vein thrombosis (175 International Factor Xa Inhibitory Units per kilogram), the dosage level that we used for prophylaxis is moderate. The first injection was given 18 to 24 hours after surgery if there was no clinically evident bleeding or excessive drainage from the wound (>20 ml per hour between the 17th and 18th hours). In the event of excessive blood loss from the wound, the first injection was deferred until the bleeding was stopped. In both treatment groups, prophylaxis was continued until the 14th postoperative day, when venography was performed, or until discharge from the hospital, if this occurred earlier.

The patients randomly assigned to receive warfarin sodium by capsule also received a subcutaneous injection of placebo once every 24 hours. The patients assigned to receive low-molecular-weight heparin received placebo capsules.

To maintain blinding of each patient's treatment assignment, the prothrombin-time result was reported only to a member of the health care team not involved in assessing outcomes; this information was not recorded on the patient's chart or reported to other members of the health care team. Adjustments in the dose of warfarin sodium or placebo were made by the unblinded clinician according to a prescribed dosage schedule.

The use of drugs containing acetylsalicylic acid was prohibited during the study, and the use of sulfinpyrazone, dipyridamole, and indomethacin was strongly discouraged.

Surveillance and Follow-up

All the patients were examined daily. Bleeding episodes, perioperative and postoperative blood loss, and blood-replacement requirements were documented. Patients in whom overt symptoms and signs of deep-vein thrombosis or pulmonary embolism developed underwent objective testing. Noninvasive screening for deep-vein thrombosis was not performed in patients who had no symptoms suggestive of venous thrombosis, because such screening is relatively insensitive in this context44,45,46,47,48,49,50.

All the patients gave informed consent to undergo bilateral ascending radiocontrast venography. This was performed on day 14 or at the time of discharge from the hospital, if this occurred earlier. Venography was performed and the results interpreted according to a method described elsewhere17,51. Constant intraluminal filling defects in the popliteal, superficial femoral, common femoral, external iliac, or common iliac veins (with or without constant intraluminal filling defects in the deep veins of the calf) were classified as proximal-vein thrombosis. Constant intraluminal filling defects confined to the deep veins of the calf were classified as calf-vein thrombosis. The venographic findings were classified as normal if the deep veins of the calf and the proximal deep veins (including the popliteal, superficial femoral, common femoral, external iliac, and common iliac veins) were adequately visualized in both legs. Data on the outcome measures of effectiveness (venous thrombosis) and safety (bleeding complications) and on patients' deaths were interpreted by a central adjudicating committee. Two committee members not involved in the patient's care adjudicated, and disagreements were resolved by a third member.

Clinically overt bleeding was classified as major or minor, according to criteria described elsewhere52. Wound hematomas that occurred in the absence of clinically overt blood loss were documented, as were associated complications (infection, persistent drainage, wound dehiscence, and prolongation of the hospital stay).

All the patients were followed for three months postoperatively and were asked to return immediately if symptoms or signs of pulmonary embolism or venous thrombosis developed. All the patients were reevaluated at three months.

If the patients had clinically evident venous thrombosis, initial testing with noninvasive techniques was allowed, but documentation by ascending contrast venography was required. For patients with suspected pulmonary embolism, documentation was required by an angiogram, a high-probability lung scan, or autopsy. The methods of performing and interpreting the objective tests are reported in detail elsewhere52,53,54,55.

The venograms were interpreted independently and without the interpreter's being aware of the patient's clinical findings, the results of other diagnostic tests, or the treatment group. They were also interpreted by an independent reader in the Clinical Trials Unit. Disagreements between the initial radiologist and the independent reader were resolved by a third central independent reader.

Statistical Analysis

On the basis of a preliminary calculation of the target sample and an interim analysis, more than 1400 patients were enrolled in the study (795 undergoing hip surgery and 641 undergoing knee surgery). Fisher's exact test was used to compare the frequencies of death, venous thrombosis, and bleeding in the two treatment groups56. All P values were two-tailed. Ninety-five percent confidence intervals for the difference between the two treatment groups in the incidence of venous thrombosis and bleeding complications were calculated with the normal approximation to the binomial distribution56. Logistic regression was used to examine the homogeneity of results across strata and to assess which factors may have accounted for variability between centers56.

Results

Seven hundred ninety-five consecutive patients undergoing elective hip surgery and 641 consecutive patients undergoing elective knee surgery were enrolled in the study. In both populations, the characteristics of the treatment groups were similar at entry (Table 1). Seven hundred twenty-one patients received warfarin, and 715 patients received low-molecular-weight heparin. Adequate bilateral venography was performed in 603 of the 721 patients assigned to receive warfarin (83.6 percent) and 579 of the 715 patients assigned to receive low-molecular-weight heparin (81.0 percent) (Table 2). Venography was performed after a mean (±SD) interval of 9.4 ±3.47 days in the patients assigned to warfarin and 9.4 ±3.53 days in the patients assigned to low-molecular-weight heparin. Proximal-vein thrombosis could not be excluded in 25 patients who had calf-vein thrombosis only, 11 of whom were receiving low-molecular-weight heparin and 14 of whom were receiving warfarin; thus, these patients were considered to have calf-vein thrombosis with an equivocal venogram for the proximal veins. These 25 patients were included in the final analysis, giving a total of 617 patients in the warfarin group who had interpretable venograms and 590 patients in the low-molecular-weight-heparin group who had interpretable venograms.

View this table:
[in this window]
[in a new window]
  		Table 1. Clinical Characteristics of the Study Patients.

 
View this table:
[in this window]
[in a new window]
  		Table 2. Findings of a Pooled Analysis of the Two Treatment Groups.

 
Pooled Data

Analysis of the pooled data on all arthroplasty procedures showed significant differences in the rates of deep-vein thrombosis, major bleeding, and wound hematomas between the low-molecular-weight-heparin group and the warfarin group (Table 2). Since there were statistically significant differences in the incidence of deep-vein thrombosis and wound hematomas between the patients undergoing hip surgery and those undergoing knee surgery, separate results are reported for these groups as well.

The unstratified findings of the pooled analysis are shown in Table 2. When the results for all the patients in both treatment groups were pooled, the overall rates of deep-vein thrombosis were 37.4 percent (231 of 617 patients) in the warfarin group and 31.4 percent (185 of 590) in the low-molecular-weight-heparin group (reduction in risk, 16 percent; absolute difference, 6 percent in favor of low-molecular-weight heparin; 95 percent confidence interval, 0.8 to 11.4 percent; P = 0.03). The overall rate of major bleeding was 1.2 percent (9 of 721 patients) in the warfarin group and 2.8 percent (20 of 715 patients) in the low-molecular-weight-heparin group (absolute difference, 1.6 percent in favor of warfarin; 95 percent confidence interval, 0.1 to 3.0 percent; P = 0.04) (Table 3 and Table 4). The overall rates of wound hematomas were 4.0 percent (29 of 721 patients) in the warfarin group and 7.1 percent (51 of 715 patients) in the low-molecular-weight-heparin group (absolute difference in favor of warfarin, 3.1 percent; 95 percent confidence interval, 0.8 to 5.4 percent; P = 0.01). The analysis showed overall differences in the incidence of thrombosis and hematomas between the hip-surgery and knee-surgery groups but no evidence of heterogeneity in the associated odds ratios for warfarin as compared with low-molecular-weight heparin. Stratified analysis revealed a significant increase in the rate of deep-vein thrombosis (P = 0.03) and a decrease in the hematoma rate (P = 0.01) with warfarin as compared with low-molecular-weight heparin. Rates of bleeding did not differ significantly according to the site of surgery (the hip or the knee).

View this table:
[in this window]
[in a new window]
  		Table 3. Outcome Events in the Two Treatment Groups According to Whether Surgery Involved the Hip or the Knee.

 
View this table:
[in this window]
[in a new window]
  		Table 4. Complications Involving Bleeding in the Study Patients.

 
The mean hemoglobin levels (expressed in milligrams per deciliter) for the first five postoperative days were as follows in the warfarin and low-molecular-weight-heparin groups, respectively: day 1, 10.6 ±1.4 and 10.6 ±1.4; day 2, 10.3 ±1.4 and 10.1 ±1.5; day 3, 10.3 ±1.4 and 9.9 ±1.4; day 4, 10.3 ±1.3 and 10.0 ±1.4; and day 5, 10.5 ±1.3 and 10.1 ±1.3.

Surveillance and Follow-up

During the three-month study period, three patients (0.4 percent) in the warfarin group and seven patients (1.0 percent) in the low-molecular-weight-heparin group had symptomatic, objectively documented venous thrombosis. Among the three patients in the warfarin group, venous thrombosis occurred in two on days 20 and 21 after hip surgery and in one on day 22 after knee surgery; in the low-molecular-weight-heparin group, venous thrombosis occurred in six patients on days 22, 24, 26, 35, 39, and 42 after hip surgery and in one patient on day 20 after knee surgery. During the study period, two patients had symptomatic, objectively documented pulmonary embolism -- on day 69 in one patient after knee surgery in the warfarin group and on day 28 in one patient after hip surgery in the low-molecular-weight-heparin group. There were no deaths due to pulmonary embolism or bleeding.

Variability between Centers

There was a statistically significant and clinically important difference in the absolute rates of deep-vein thrombosis at each center between treatment groups (Table 5). Table 5 shows, however, that the relation between warfarin and low-molecular-weight heparin was consistent among hospitals whether rates of thrombosis were high, medium, or low. Logistic-regression analysis confirmed that no inconsistency was present. The observed differences between treatment groups in the frequency of deep-vein thrombosis were not affected by this variability. A number of factors, including imbalances with regard to clinical characteristics, prognostic strata, rates of venography, venographic interpretation, blood loss, surgical technique, operative incision, duration of operation, continuous passive motion, and compliance with the use of prophylaxis, were investigated as possibly responsible for the variation. A preliminary analysis revealed no simple explanation.

View this table:
[in this window]
[in a new window]
  		Table 5. Variability between Centers in Rates of Deep-Vein Thrombosis, According to Site of Surgery and Treatment Group.

 
Analysis of the anticoagulant response to warfarin in the various centers showed that the response was consistent. Each center achieved a therapeutic range equivalent to an international normalized ratio of 2.0 to 3.0. The observed variability between centers cannot be explained by differences in the prothrombin-time response.

Discussion

The findings of this multicenter clinical trial suggest that low-molecular-weight heparin is at least as effective as warfarin sodium for protection against venous thrombosis in patients undergoing hip or knee implantation. Overt bleeding and wound hematomas were uncommon in both groups. A low, but statistically higher, frequency of major bleeding complications and wound hematomas was observed in the patients receiving low-molecular-weight heparin.

The frequencies of venous thrombosis and bleeding complications observed in the patients undergoing hip implantation who received low-molecular-weight heparin were similar to those reported previously36. The frequency of deep-vein thrombosis in the knee-implant group assigned to receive low-molecular-weight heparin was similar to that observed in a large unblinded trial in which low-molecular-weight heparin was compared with warfarin sodium,57 but it was higher than that reported in another multicenter trial that evaluated knee-implant surgery58. Despite this improvement, the rates remain high and indicate a continued need for case finding with venography.

Our findings are based on the use of bilateral ascending venography. Analysis of the venographic findings demonstrated that failure to perform venography routinely on the limb not undergoing surgery would have resulted in failure to identify approximately 20 percent of the patients with deep-vein thrombosis.

Our findings cannot be attributed to bias; the randomization was successful, because the base-line characteristics of the patients were comparable in each group, and the study was conducted in double-blind fashion in order to avoid bias in searching for or interpreting outcome events. Because our study was stratified according to center, each center had its own study. There was a statistically significant difference between centers in the frequency of deep-vein thrombosis, which did not influence the observed difference between treatment groups. This observed variability between centers is not readily explained by a priori factors -- e.g., clinical characteristics, length of anesthesia, use of cement, surgical technique, type of operative incision, duration of operation, continuous passive motion, and perioperative or postoperative blood loss. Our findings with regard to effectiveness were consistent among centers despite the differences in absolute rates. The striking variability in the absolute rates of deep-vein thrombosis emphasizes the need for extreme caution in making clinical inferences on the basis of rates in different studies.

Our study evaluated the postoperative use of prophylactic anticoagulation. On the basis of our understanding of the pathogenesis of venous thrombosis in surgical patients, it is plausible that the observed frequencies of venous thrombosis might have been lower if preoperative prophylaxis had been used, without unnecessarily compromising safety. Arguing against the preoperative use of prophylactic anticoagulation is the finding that the frequencies of deep-vein thrombosis observed in patients undergoing elective hip surgery in two recent randomized trials of warfarin sodium prophylaxis that used a preoperative approach were 21 and 31 percent13,15. There was no increase in blood loss with preoperative warfarin sodium. The issue of preoperative as compared with postoperative prophylaxis should be addressed directly in future randomized trials.

Although our findings and those of others offer promise for patients undergoing hip-implant surgery, the rather high rates of deep-vein thrombosis in patients undergoing knee-implant surgery who received warfarin sodium prophylaxis are relatively disappointing. Either pneumatic leg compression or low-molecular-weight heparin prophylaxis may offer better protection against venous thrombosis in such patients10,58. For patients requiring hip implants, the orthopedic surgeon has the choice of using either less intense warfarin sodium, low-molecular-weight heparin, subcutaneous heparin in an adjusted dose, low-dose heparin, or pneumatic compression; the last three approaches may be less effective14,15,24,25,26,27,28,29,30,31,32,33,36.

Although low-molecular-weight heparin offers the advantage of simplicity because this antithrombotic agent is administered in a daily subcutaneous injection without the need for monitoring, it may prove to be more costly than warfarin sodium. Warfarin is inexpensive, but the cost of its administration is increased by the need for monitoring of the international normalized ratio. At this time it is unclear which of these approaches will be more cost effective.

In summary, our study shows that low-molecular-weight heparin given in a single subcutaneous injection per day is effective, as compared with warfarin sodium prophylaxis, and that it avoids the need to monitor the level of anticoagulation. The reduction in the rate of venous thrombosis with low-molecular-weight heparin, as compared with warfarin, is offset by an increase in the number of bleeding complications and wound hematomas.

Supported in part by a grant from the Heart and Stroke Foundation of Alberta and by Novo Nordisk.

We are indebted to the members of the medical, surgical, nursing, pharmacy, and support staff of all the study sites.


Source Information

From the Clinical Trials Unit, Faculty of Medicine, University of Calgary, Calgary, Alta., Canada (R.H., G.R., G.P., K.A., G.H., R.B.); Chedoke-McMaster Hospitals, Hamilton, Ont., Canada (D.R., F.S., A.P.); Ohio State University, Columbus (W.E., T.M.); Northwestern University, Chicago (D.G.); and LDS Hospital, Salt Lake City (C.G.E.).

Address reprint requests to Dr. Hull at the Department of Medicine, University of Calgary, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1, Canada.

References

  1. Harris WH, Sledge CB. Total hip and total knee replacement. N Engl J Med 1990;323:725-31, 801. [Medline]
  2. Coventry MB, Nolan DR, Beckenbaugh RD. "Delayed" prophylactic anticoagulation: a study of results and complications in 2,012 total hip arthroplasties. J Bone Joint Surg [Am] 1973;55:1487-92.
  3. Johnson R, Green JR, Charnley J. Pulmonary embolism and its prophylaxis following the Charnley total hip replacement. Clin Orthop 1977;127:123-132.
  4. Stulberg BN, Insall JN, Williams GW, Ghelman B. Deep-vein thrombosis following total knee replacement: an analysis of six hundred and thirty-eight arthroplasties. J Bone Joint Surg [Am] 1984;66:194-201.
  5. Stamatakis JD, Kakkar VV, Sagar S, Lawrence D, Nairn D, Bentley PG. Femoral vein thrombosis and total hip replacement. BMJ 1977;2:223-225.
  6. Harris WH, Salzman EW, Athanasoulis CA, Waltman AC, DeSanctis RW. Aspirin prophylaxis of venous thromboembolism after total hip replacement. N Engl J Med 1977;297:1246-1249. [Abstract]
  7. Johnson R, Carmichael JHE, Almond HGA, Loynes RP. Deep venous thrombosis following Charnley arthroplasty. Clin Orthop 1978;132:24-30.
  8. Nillius AS, Nylander G. Deep vein thrombosis after total hip replacement: a clinical and phlebographic study. Br J Surg 1979;66:324-326. [Medline]
  9. Evarts CM, Feil EJ. Prevention of thromboembolic disease after elective surgery of the hip. J Bone Joint Surg [Am] 1971;53:1271-80.
  10. Hull R, Delmore T, Hirsh J, et al. Effectiveness of intermittent pulsatile elastic stockings for the prevention of calf and thigh vein thrombosis in patients undergoing elective knee surgery. Thromb Res 1979;16:37-45. [CrossRef][Medline]
  11. McKenna R, Galante J, Bachmann F, Wallace DL, Kaushal PS, Meredith P. Prevention of venous thromboembolism after total knee replacement by high-dose aspirin or intermittent calf and thigh compression. BMJ 1980;280:514-517.
  12. Stringer MD, Steadman CA, Hedges AR, Thomas EM, Morley TR, Kakkar VV. Deep vein thrombosis after elective knee surgery: an incidence study in 312 patients. J Bone Joint Surg [Br] 1989;71:492-7.
  13. Francis CW, Marder VJ, Evarts CM, Yaukoolbodi S. Two-step warfarin therapy: prevention of postoperative venous thrombosis without excessive bleeding. JAMA 1983;249:374-378. [Free Full Text]
  14. Paiement G, Wessinger SJ, Waltman AC, Harris WH. Low-dose warfarin versus external pneumatic compression for prophylaxis against venous thromboembolism following total hip replacement. J Arthroplasty 1987;2:23-26. [Medline]
  15. Francis CW, Pellegrini VD Jr, Marder VJ, et al. Comparison of warfarin and external pneumatic compression in prevention of venous thrombosis after total hip replacement. JAMA 1992;267:2911-2915. [Free Full Text]
  16. Kaempffe FA, Lifeso RM, Meinking C. Intermittent pneumatic compression versus coumadin: prevention of deep vein thrombosis in lower-extremity total joint arthroplasty. Clin Orthop 1991;269:89-97.
  17. Hull RD, Raskob GE, Gent M, et al. Effectiveness of intermittent pneumatic leg compression for preventing deep vein thrombosis after total hip replacement. JAMA 1990;263:2313-2317. [Free Full Text]
  18. Woolson ST, Watt JM. Intermittent pneumatic compression to prevent proximal deep venous thrombosis during and after total hip replacement: a prospective, randomized study of compression alone, compression and aspirin, and compression and low-dose warfarin. J Bone Joint Surg [Am] 1991;73:507-12.
  19. Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. N Engl J Med 1988;318:1162-1173. [Medline]
  20. Paiement GD, Wessinger SJ, Harris WH. Survey of prophylaxis against venous thromboembolism in adults undergoing hip surgery. Clin Orthop 1987;223:188-193.
  21. Anderson FA Jr, Wheeler HB, Goldberg RJ, Hosmer DW, Forcier A, Patwardhan NA. Physician practices in the prevention of venous thromboembolism. Ann Intern Med 1991;115:591-595.
  22. Prevention of venous thrombosis and pulmonary embolism: NIH Consensus Development. JAMA 1986;256:744-749. [Free Full Text]
  23. Clagett GP, Anderson FA Jr, Levine MN, Salzman EW, Wheeler HB. Prevention of venous thromboembolism. Chest 1992;102:Suppl:391S-407S.
  24. Kakkar VV, Murray WJ. Efficacy and safety of low-molecular-weight heparin (CY216) in preventing postoperative venous thrombo-embolism: a co-operative study. Br J Surg 1985;72:786-791. [Medline]
  25. Bergqvist D, Matzsch T, Burmark US, et al. Low molecular weight heparin given the evening before surgery compared with conventional low-dose heparin in prevention of thrombosis. Br J Surg 1988;75:888-891. [Erratum, Br J Surg 1988;75:1077.] [Medline]
  26. Samama M, Bernard P, Bonnardot JP, Combe-Tamzali S, Lanson Y, Tissot E. Low molecular weight heparin compared with unfractionated heparin in prevention of postoperative thrombosis. Br J Surg 1988;75:128-131. [Medline]
  27. European Fraxiparin Study (EFS) Group. Comparison of a low molecular weight heparin and unfractionated heparin for the prevention of deep vein thrombosis in patients undergoing abdominal surgery. Br J Surg 1988;75:1058-1063. [Medline]
  28. Caen JP. A randomized double-blind study between a low molecular weight heparin Kabi 2165 and standard heparin in the prevention of deep vein thrombosis in general surgery: a French multicenter trial. Thromb Haemost 1988;59:216-220. [Medline]
  29. Planes A, Vochelle N, Mazas F, et al. Prevention of postoperative venous thrombosis: a randomized trial comparing unfractionated heparin with low molecular weight heparin in patients undergoing total hip replacement. Thromb Haemost 1988;60:407-410. [Medline]
  30. Dechavanne M, Ville D, Berruyer M, et al. Randomized trial of a low-molecular-weight heparin (Kabi 2165) versus adjusted-dose subcutaneous standard heparin in the prophylaxis of deep-vein thrombosis after elective hip surgery. Haemostasis 1989;19:5-12. [Medline]
  31. Eriksson BI, Kalebo P, Anthmyr BA, Wadenvik H, Tengborn L, Risberg B. Prevention of deep-vein thrombosis and pulmonary embolism after total hip replacement: comparison of low-molecular-weight heparin and unfractionated heparin. J Bone Joint Surg [Am] 1991;73:484-93.
  32. Leyvraz PF, Bachmann F, Hoek J, et al. Prevention of deep vein thrombosis after hip replacement: randomised comparison between unfractionated heparin and low molecular weight heparin. BMJ 1991;303:543-548. [Erratum, BMJ 1991;303:1243.]
  33. Nurmohamed MT, Rosendaal FR, Buller HR, et al. Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis. Lancet 1992;340:152-156. [CrossRef][Medline]
  34. Levine MN, Hirsh J, Gent M, et al. Prevention of deep vein thrombosis after elective hip surgery: a randomized trial comparing low molecular weight heparin with standard unfractionated heparin. Ann Intern Med 1991;114:545-551.
  35. Salzman EW. Low-molecular-weight heparin: is small beautiful? N Engl J Med 1986;315:957-959. [Medline]
  36. Verstraete M. Pharmacotherapeutic aspects of unfractionated and low molecular weight heparins. Drugs 1990;40:498-530. [Medline]
  37. Aiach M, Michaud A, Balian J-L, Lefebvre M, Woler M, Fourtillan J. A new low molecular weight heparin derivative: in vitro and in vivo studies. Thromb Res 1983;31:611-621. [CrossRef]
  38. Bergqvist D, Hedner U, Sjorin E, Holmer E. Anticoagulant effects of two types of low molecular weight heparin administered subcutaneously. Thromb Res 1983;32:381-391. [CrossRef][Medline]
  39. Bara L, Billaud E, Gramond G, Kher A, Samama M. Comparative pharmacokinetics of a low molecular weight heparin (PK 10 169) and unfractionated heparin after intravenous and subcutaneous administration. Thromb Res 1985;39:631-636. [CrossRef][Medline]
  40. Bratt G, Tornebohm E, Widlund L, Lockner D. Low molecular weight heparin (KABI 2165, Fragmin): pharmacokinetics after intravenous and subcutaneous administration in human volunteers. Thromb Res 1986;42:613-620. [CrossRef][Medline]
  41. Matzsch T, Bergqvist D, Hedner U, Ostergaard P. Effects of an enzymatically depolymerized heparin as compared with conventional heparin in healthy volunteers. Thromb Haemost 1987;57:97-101. [Medline]
  42. Frydman AM, Bara L, Le Roux Y, Woler M, Chauliac F, Samama MM. The antithrombotic activity and pharmacokinetics of enoxaparine, a low molecular weight heparin, in humans given single subcutaneous doses of 20 to 80 mg. J Clin Pharmacol 1988;28:609-618. [Abstract]
  43. Hirsh J, Dalen JE, Deykin D, Poller L. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 1992;102:Suppl:312S-326S. [Free Full Text]
  44. Harris WH, Athanasoulis C, Waltman AC, Salzman EW. Cuff-impedance phlebography and 125I fibrinogen scanning versus roentgenographic phlebography for diagnosis of thrombophlebitis following hip surgery: a preliminary report. J Bone Joint Surg [Am] 1976;58:939-44.
  45. Paiement G, Wessinger SJ, Waltman AC, Harris WH. Surveillance of deep vein thrombosis in asymptomatic total hip replacement patients: impedance phlebography and fibrinogen scanning versus roentgenographic phlebography. Am J Surg 1988;155:400-404. [Medline]
  46. Comerota AJ, Katz ML, Grossi RJ, et al. The comparative value of noninvasive testing for diagnosis and surveillance of deep vein thrombosis. J Vasc Surg 1988;7:40-49. [CrossRef][Medline]
  47. Cruickshank MK, Levine MN, Hirsh J, et al. An evaluation of impedance plethysmography and 125I-fibrinogen leg scanning in patients following hip surgery. Thromb Haemost 1989;62:830-834. [Medline]
  48. Borris LC, Christiansen HM, Lassen MR, Olsen AD, Schott P. Comparison of real-time B-mode ultrasonography and bilateral ascending phlebography for detection of postoperative deep vein thrombosis following elective hip surgery: the Venous Thrombosis Group. Thromb Haemost 1989;61:363-365. [Medline]
  49. Ginsberg JS, Caco CC, Brill-Edwards PA, et al. Venous thrombosis in patients who have undergone major hip or knee surgery: detection with compression US and impedance plethysmography. Radiology 1991;181:651-654. [Free Full Text]
  50. Davidson BL, Elliott CG, Lensing AWA, RD Heparin Arthroplasty Group. Low accuracy of color Doppler ultrasound in the detection of proximal leg vein thrombosis in asymptomatic high-risk patients. Ann Intern Med 1992;117:735-738.
  51. Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg 1972;104:134-144. [Free Full Text]
  52. Hull R, Delmore T, Genton E, et al. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. N Engl J Med 1979;301:855-858. [Abstract]
  53. PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). JAMA 1990;263:2753-2759. [Free Full Text]
  54. Hull RD, Hirsh J, Carter CJ, et al. Diagnostic value of ventilation-perfusion lung scanning in patients with suspected pulmonary embolism. Chest 1985;88:819-828. [Free Full Text]
  55. Bookstein JJ, Silver TM. The angiographic differential diagnosis of acute pulmonary embolism. Radiology 1974;110:25-33. [Medline]
  56. Armitage P, Berry G. Statistical methods in medical research. 2nd ed. Oxford, England: Blackwell Scientific, 1987:93-407.
  57. 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 
  58. 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. [Medline]
Appendix

The following persons and institutions also participated in the trial: University of Calgary, Calgary, Alta., Canada -- Calgary General Hospital: D. Bell, W. Blahey, J. Chenger, A. Costantini, R. Hollinshead, D. Jenkinson, N. Schachar, H. Swanson, J.F. Thaell, A. Urban, D. McKeage, and A. Wilson; Foothills Hospital: M. Austin, B. Baylis, F. Bazant, R. Bray, N. Campbell, R. Dewar, G. Edwards, C. Fairbanks, A. Ferland, T. Fong, C. Frank, C.B. Hatfield, R.E. Hatfield, J. Hunter, S. Miller, N. Mohtadi, C.D. Thompson, R. Powell, and L. Styner; Chedoke Hospital, Hamilton, Ont., Canada -- K. Chan, I. Dale, D. McLoughlin, B. McTaggart, J. Collingwood, and L. Reynolds; Grant Hospital, Columbus, Ohio -- K. Berry, A. Lombardi, T. Meyer, B. Vaughn, B. Vermillion, G. Vincent, and K. Kaple; Clinical Trials Group, University of Calgary -- B. Doucette and L. Guyn; Safety Monitor -- D. Bergqvist; Liaison with Novo Nordisk -- K. Birch, A. Brusby, K. Garre, S. Glazer, N. Griffin, and U. Hedner.


 

This Article
-Abstract

Commentary
-Letters

Tools and Services
-Add to Personal Archive
-Add to Citation Manager
-Notify a Friend
-E-mail When Cited

More Information
-PubMed Citation

Related Letters:

Low-Molecular-Weight Heparin vs. Warfarin for Prophylaxis against Deep-Vein Thrombosis
Hirsh J., Lotke P. A., Ecker M. L., Hull R. D., Pineo G. F.
Extract | Full Text  
N Engl J Med 1994; 330:862-863, Mar 24, 1994. Correspondence

This article has been cited by other articles:


HOME  |  SUBSCRIBE  |  SEARCH  |  CURRENT ISSUE  |  PAST ISSUES  |  COLLECTIONS  |  PRIVACY  |  TERMS OF USE  |  HELP  |  beta.nejm.org

Comments and questions? Please contact us.

The New England Journal of Medicine is owned, published, and copyrighted © 2009 Massachusetts Medical Society. All rights reserved.