The Journal of Bone and Joint Surgery (American) 83:900-906 (2001)
© 2001 The Journal of Bone and Joint Surgery, Inc.
Prevention of Venous Thromboembolic Disease Following Primary Total Knee Arthroplasty
A Randomized, Multicenter, Open-Label, Parallel-Group Comparison of Enoxaparin and Warfarin
R. H. Fitzgerald, MD, Jr,
T. E. Spiro, MD,
A. A. Trowbridge, MD,
G. A. Gardiner, Jr., MD,
T. L. Whitsett, MD,
M. B. O’Connell, PharmD,
J. A. Ohar, MD and
T. R. Young, DO, for the Enoxaparin Clinical Trial Group
R.H. Fitzgerald Jr., MD
Department of Orthopaedic Surgery, Silverstein Pavilion, Hospital
of the University of Pennsylvania, 3400 Spruce Street,
Second Floor, Philadelphia, PA 19104
T.E. Spiro, MD
Cardiovascular Therapeutic Area, European Operations Center, Aventis
Pharma S.A., 20 avenue Raymond Aron, 92165 Antony, France. E-mail
address: theodore.spiro{at}aventis.com
A.A. Trowbridge, MD
Division of Hematology, Department of Internal Medicine, Scott and
White Clinic, Texas A and M University College of Medicine, 2401
South 31st Street, Temple, TX 76508
G.A. Gardiner Jr., MD
Department of Radiology, Gibbon Building, Thomas Jefferson University
Hospital, 111 South 11th Street, Philadelphia, PA 19107
T.L. Whitsett, MD
Section of Cardiovascular Medicine, South Pavilion, University of
Oklahoma Health Sciences Center, Oklahoma City, OK 73104
M.B. O’Connell, PharmD
Department of Experimental and Clinical Pharmacology, College of
Pharmacy, University of Minnesota, 308 Harvard Street S.E., Minneapolis,
MN 55455
J.A. Ohar, MD
Division of Pulmonary Medicine, St. Louis University Medical Center,
St. Louis, MO 63110
T.R. Young, DO
Department of Orthopaedic Surgery, Medical College of Georgia, Augusta,
GA 30912
Funds were received in total or partial support of the research
or clinical study presented in this article. The funding source
was a grant from Aventis Pharmaceuticals, Incorporated, Bridgewater,
New Jersey (formerly known as Rhône-Poulenc Rorer Pharmaceuticals,
Incorporated, Collegeville, Pennsylvania). Benefits were directed
either to a research fund, foundation, educational institution, or
other nonprofit organization with which one or more of the authors
is associated or were directed to a commercial institution such
as a university hospital or a major medical center with which one
or more of the authors is associated. T.E. Spiro is a full-time
employee of Aventis Pharma, S.A., and holds stocks and options in
this company.
Background: Patients treated with total knee
arthroplasty are at high risk for the development of venous thromboembolism
postoperatively. This study compared the efficacy and safety of
two common thromboprophylactic agents, enoxaparin (a low-molecular-weight
heparin) and warfarin.
Methods: Three hundred and forty-nine patients
were included in a prospective, randomized, multicenter, open-label,
parallel-group clinical trial. Treatment with enoxaparin (30 mg,
administered subcutaneously twice daily) or warfarin (adjusted to
an international normalized ratio of 2 to 3) was initiated during
the immediate postoperative period, within eight hours after the
surgery, and was continued for four to fourteen days. Venous thromboembolism was
defined as deep-vein thrombosis documented by contrast
venography, symptomatic deep-vein thrombosis documented
by lower-extremity ultrasonography, or symptomatic pulmonary embolism confirmed
by a positive lung scan or pulmonary angiography.
Results: In the all-treated-patients group,
eighty (45%) of the 176 warfarin-treated patients
had venous thromboembolism: fifty-nine (34%) had
distal deep-vein thrombosis; twenty (11%), proximal
deep-vein thrombosis; and one (0.6%), pulmonary
embolism. Venous thromboembolism developed in significantly fewer
(p = 0.0001) enoxaparin-treated patients (forty-four
of 173; 25%): forty-one (24%) had distal
deep-vein thrombosis, three (2%) had proximal
deep-vein thrombosis, and none had pulmonary embolism.
The enoxaparin-treated patients also had a significantly
lower prevalence of proximal deep-vein thrombosis (p = 0.002).
The estimated odds for the development of venous thromboembolism
were 2.52 times greater (95% confidence interval, 2.00
to 3.19) with warfarin than they were with enoxaparin. Major hemorrhage occurred
in four warfarin-treated patients and nine enoxaparin-treated
patients; with the numbers available, this difference was not significant
(p = 0.17). Clinically important operative-site
hemorrhage occurred in six (3%) of the warfarin-treated patients
and twelve (7%) of the enoxaparin-treated patients (p = 0.15).
Conclusions: A fixed 30-mg subcutaneous dose of
enoxaparin, administered twice daily, with the first dose administered
within eight hours after the completion of surgery, was significantly
more effective than adjusted-dose warfarin in reducing
the occurrence of asymptomatic venous thromboembolism, including
proximal deep-vein thrombosis, in patients undergoing total
knee arthroplasty. With the numbers available, there was no significant
difference between groups with regard to the occurrence of major
hemorrhagic complications; however, the rate of overall hemorrhagic
complications was higher in the enoxaparin group.
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