Patients treated with total knee or hip arthroplasty are
at a high risk for the development of deep-vein thrombosis
as well as pulmonary embolism1,2.
Both peripheral venous stasis and direct endothelial injury, factors
that play an important role in the etiology of venous thrombosis,
occur during total hip and knee arthroplasty3.
The prevalence of deep-vein thrombosis following total
knee replacement without prophylaxis has been reported to be 50% to
80% in series ranging in size from thirty to sixty-one
patients1,4-7.
Warfarin is an effective prophylactic agent that is commonly
prescribed for patients undergoing total hip arthroplasty8-11. Two recently completed clinical
trials compared the effectiveness of the low-molecular-weight
heparins ardeparin (446 patients) and tinzaparin (535 patients)
with that of warfarin in patients treated with total hip or knee
arthroplasty12,13. The prevalence
of all types of asymptomatic deep-vein thrombosis after
total knee arthroplasty was significantly lower when low-molecular-weight
heparin had been used (p = 0.004 for ardeparin, and p = 0.02
for tinzaparin). However, the difference in the prevalence of proximal deep-vein
thrombosis was not significant.
Enoxaparin is a low-molecular-weight heparin
used clinically for prophylaxis against venous thromboembolism associated
with hip and knee replacement procedures1.
Pharmacokinetic and pharmacodynamic studies have demonstrated little
intra-individual or inter-individual variability in the effects
of enoxaparin and, in contrast to warfarin, enoxaparin does not require
biological monitoring and dosage adjustments14.
We report the results of a prospective, randomized, multicenter,
open-label, inpatient, parallel-group study performed to
compare the safety and efficacy of fixed-dose enoxaparin
with that of adjusted-dose warfarin in the prevention of
venous thromboembolism in patients treated with total knee arthroplasty.
Study Populations
Men and women, thirty-eight years of age or older, undergoing
a primary unilateral total knee arthroplasty were eligible for inclusion
in the study. Approval by the institutional review board and informed
consent by the patients were obtained in each of the twenty-two
medical centers involved in the study. Premenopausal women were
included only if there was documentation that they were surgically
sterile or not pregnant. The all-treated-patients study population
consisted of all randomized patients who were scheduled for a primary total
knee arthroplasty and had received at least one dose of study medication.
Each center was provided with sealed medication kits containing
either syringes filled with enoxaparin or warfarin tablets. Randomization
numbers generated by the study sponsor were affixed to the exterior
of each kit; randomization was performed by the investigator allocating
the kits in ascending order.
The evaluable-patients population consisted of patients who
had undergone primary unilateral total knee arthroplasty; had received
the study medication for at least four days; and had an evaluable venogram
of the surgically treated lower extremity and adequate contrast
venography or ultrasonography of the contralateral extremity, symptoms
of deep-vein thrombosis confirmed by ultrasonography or
venography, and/or symptoms of pulmonary embolism confirmed
by a lung scan or pulmonary angiography. Exclusion criteria included
wound hemorrhage continuing for longer than eight hours after wound
closure; generalized hemorrhagic disorders or hypercoagulable syndrome,
including clinical evidence of chronic or acute deep-vein thrombosis
or a documented history of venous thromboembolism; allergy to unfractionated
heparin, warfarin, fish or swine products, iodine, or contrast medium;
a history of heparin-associated thrombocytopenia or heparin
or warfarin-associated skin rash or necrosis; asthma not
under medical control; surgery (other than arthroscopy) on the ipsilateral
knee within the previous six months or on the ipsilateral hip, contralateral
hip, or contralateral knee within the preceding three months; any clinically
important disease or requirement for treatment during the study
period that could interfere with the action, kinetics, or evaluation
of the study medications; hepatic disease with a bilirubin level
of 2 mg/dL (= 34 mmol/L); renal disease with a creatinine
level of 2 mg/dL (= 177 mmol/L); evidence of current
abuse of drugs (excluding tobacco products) or alcohol; surgery
involving the eye, spinal cord, or central nervous system within three
months before study entry; active ulcerative disease or angiodysplasia
of the gastrointestinal tract or active gastrointestinal hemorrhage
within the previous six months; hypertension not under medical control
(defined as systolic blood pressure of 180 mm Hg or diastolic blood
pressure of 105 mm Hg); stroke or myocardial infarction within the previous
three months; and treatment with aspirin, aspirin-containing products,
or nonsteroidal anti-inflammatory drugs on a regular basis
for the four days immediately preceding hospitalization or regular
treatment with these products during hospitalization (products with
a short half-life, such as ibuprofen and naproxen, could
be continued until two days preceding hospitalization). Sequential compression
devices were not permitted, but graduated compression stockings
were. Use of a continuous-passive-motion device was permitted for
a total of six hours per day.
Study Evaluations
Prestudy evaluations consisted of a medical history including
documentation of concomitant medications; a complete physical examination;
a twelve-lead electrocardiogram (optional); a chest roentgenogram;
bilateral lower-extremity duplex or B-mode ultrasonography
(optional); urinalysis; and a complete blood-cell count with differential
and platelet count (hematological studies), measurement of activated
partial thromboplastin time and prothrombin time (coagulation studies),
and determination of levels of total bilirubin, creatinine, aspartate
aminotransferase, and alanine aminotransferase (biochemistry studies).
On the first study day (that is, the day of the surgery), before
the first dose of study medication was administered, surgical, transfusion,
and anesthesia data were recorded for each patient, and each patient
was assessed for hemorrhage and with hematological studies (excluding
white blood-cell differential), coagulation studies (activated partial thromboplastin
time for all patients and prothrombin time for warfarin-treated
patients only), and a biochemistry profile.
Treatment with warfarin or enoxaparin began on the day of the
surgery, as soon as hemostasis was achieved and within eight hours
after surgical wound closure, and it was continued for a minimum
of four days and a maximum of fourteen days. Warfarin therapy was
initiated orally, with a dose of 7.5 mg, followed by subsequent
daily adjustment of the dose as necessary to maintain the international normalized
ratio between 2 and 3. A 30-mg dose of enoxaparin was administered
every twelve hours by deep subcutaneous injection in the abdominal
area.
During the treatment period, evaluations included daily assessment
of vital signs, abbreviated physical examination, and assessments
for any adverse experiences, concomitant medications, hemorrhage,
and blood transfusion. Patients with clinical evidence of deep-vein
thrombosis were evaluated with bilateral lower-extremity ultrasonography. Patients
with a positive ultrasonogram had contrast venography performed.
Patients with clinical evidence of pulmonary embolism had a ventilation-perfusion
lung scan and/or pulmonary angiography, at the discretion
of the investigator. The study medication was discontinued, and
all end-of-treatment and follow-up procedures
were performed in all patients who underwent venography, irrespective
of the outcome, and in all patients with a confirmed diagnosis of
pulmonary embolism. Patients who had a negative ultrasonogram continued
treatment with the study medication. Patients with pulmonary embolism
did not undergo venography.
During the treatment period, hematological and biochemistry evaluations
were carried out on the second, third, and fourth postoperative
days and on alternate days thereafter. For warfarin-treated patients,
an international normalized ratio was determined prior to administration
of the study drug; on the second, third, and fourth postoperative days;
and on alternate days thereafter.
Within twenty-four hours following either the last dose
or the discontinuation of the study medication, the evaluations
included assessment of vital signs; abbreviated physical examination;
assessments for any adverse experiences, concomitant medications, hemorrhage
(at the operative site and elsewhere), and blood transfusion; bilateral
lower-extremity ultrasonography; unilateral venography of the treated
extremity in all patients, regardless of the ultrasonographic results;
bilateral venography if the untreated extremity had clinical signs
and symptoms indicating deep-vein thrombosis or a positive ultrasonogram;
and determination of hematological and biochemistry values, urinalysis,
measurement of activated partial thromboplastin time, and, for warfarin-treated
patients only, determination of the international normalized ratio.
At the follow-up visit, approximately three weeks following
the final dose of study medication, the evaluations included assessment
of vital signs; abbreviated physical examination; assessments for any
adverse experiences, concomitant medications, hemorrhage (at the
operative site and elsewhere), and blood transfusion; as well as
determination of hematological and biochemistry values and urinalysis.
Efficacy Assessments
The primary efficacy variable was the occurrence of deep-vein
thrombosis or pulmonary embolism during the postoperative period.
The diagnosis of deep-vein thrombosis in asymptomatic patients
was based on the findings of lower-extremity contrast venography.
The diagnostic criteria for deep-vein thrombosis included
the demonstration of an intraluminal filling defect within a deep-vein
segment or an occluded deep-vein segment with a filling
defect at one or both ends. If the venographic findings were uncertain,
ultrasonography of the lower extremity was used to confirm or rule
out the presence of a thrombus. A positive ultrasonogram was sufficient
for the diagnosis of symptomatic deep-vein thrombosis.
The diagnosis of symptomatic pulmonary embolism required a high-probability
ventilation-perfusion lung scan or a positive pulmonary angiogram.
In addition to the assessment by the investigator, a blinded, independent review
of all venograms and ultrasonograms was carried out by a panel of
vascular imaging specialists. The consensus method was used to determine the
final diagnosis that was used in the data analysis.
Safety Assessment
The primary safety variable was overt hemorrhage, which was categorized
as major or minor. An episode of hemorrhage was defined as major
if it fulfilled at least one of the following criteria: resulted in
transfusion of at least two units of packed red blood cells; resulted
in a decrease in the hemoglobin concentration of 20 g/L
compared with the postoperative hemoglobin concentration before
the administration of any study medication; was retroperitoneal,
intracranial, or intraocular; or resulted in a serious life-threatening
clinical event or death.
Statistical Methods
For the primary efficacy analysis, the occurrence of venous thromboembolism
was assessed with use of data from the all-treated-patients
group. A multivariate logistic regression model with explanatory variables
for investigator and treatment (without interaction terms) was used
to compare the prevalences of venous thromboembolism between the warfarin
and enoxaparin groups. The test was two-tailed, at the
5% level. The Fisher exact test was used for the primary
safety analysis, with treatment groups compared with regard to the
rates of hemorrhagic episodes, adverse events, and selected hematological
and biochemistry values of clinical concern. Changes in laboratory
parameters and vital signs compared with baseline values were summarized
by descriptive statistics; no formal statistical tests of hypotheses
were performed.
Patient Disposition and Demographics
A total of 349 patients, thirty-eight to eighty-nine years
of age, received at least one dose of study medication: 176 received
warfarin and 173 received enoxaparin (Table I). These patients were included
in the all-treated-patients analysis. Twenty-nine
patients (fourteen in the warfarin group and fifteen in the enoxaparin group)
did not complete the study. Premature withdrawal was most commonly
due to an adverse clinical event, with eight warfarin-treated and
eleven enoxaparin-treated patients withdrawing for this reason.
None of these adverse events were related to the study medications.
Two warfarin-treated patients were withdrawn because of
abnormal laboratory findings (decreased hemoglobin concentration
or hematocrit and blood in the urine), and one enoxaparin-treated
patient was withdrawn because of an abnormal laboratory finding
(decreased hemoglobin concentration). Other reasons for withdrawal
primarily included protocol deviations and the patient’s
withdrawal of consent because of abnormal laboratory findings. Seven
patients (four in the warfarin group and three in the enoxaparin group)
were treated with heparin after deep-vein thrombosis developed.
The all-treated-patients group included 196 women (56%)
and 153 men (44%). There was no difference between the
warfarin and enoxaparin groups with regard to age, gender, race,
height, or weight (see Appendix). The demographic characteristics
of the evaluable patients were similar to those of the all-treated-patients
group.
A minimum of three days of warfarin therapy was required before
the international normalized ratio reached a desirable therapeutic
range (2 to 3) in an appreciable number of patients (see Appendix). There
was a high degree of variability in the international normalized
ratios throughout the study period, with a nearly symmetrical distribution
of values falling above and below the therapeutic range of 2 to
3. The mean duration from the time that an international normalized
ratio of =2 was achieved until hospital discharge was 3.3 ± 2.0 days.
Two hundred and thirty patients—122 in the warfarin
group and 108 in the enoxaparin group—were included in
the evaluable-patients analysis. The most common reason for a patient
to be classified as not evaluable was that end-of-study vascular examinations
were not done or were inadequate. The venogram was inadequate for
twenty warfarin-treated patients and forty enoxaparin-treated patients,
and venography was not performed for twenty warfarin-treated
patients and sixteen enoxaparin-treated patients. Ultrasonography
was not performed for three warfarin-treated patients.
Primary Diagnosis and Surgical Data
Osteoarthritis was the primary diagnosis for the majority of
patients (see Appendix). Most patients underwent a tricompartmental
arthroplasty with cement under general anesthesia. The mean duration
of surgery, the mean duration of tourniquet use, the performance
of lateral retinacular release, and the use of intramedullary alignment
guides were similar in the warfarin-treated and enoxaparin-treated
patients. The intraoperative blood loss averaged 211 mL overall
(231 mL in the warfarin group and 191 mL in the enoxaparin group). An
average of 594 mL of salvaged blood was reinfused in thirty-five
warfarin-treated patients, and an average of 617 mL was reinfused
in thirty-five enoxaparin-treated patients.
Efficacy
In both the all-treated-patients and the evaluable-patients efficacy
analysis, the prevalence of venous thromboembolism associated with
the use of enoxaparin was significantly lower than that associated with
the use of warfarin (Table II). In the all-treated-patients population,
eighty (45%) of the 176 warfarin-treated patients had venous
thromboembolism: fifty-nine (34%) had only distal
deep-vein thrombosis, twenty (11%) had only proximal
or proximal and distal deep-vein thrombosis, and one (0.6%)
had pulmonary embolism. In comparison, a significantly smaller (p = 0.0001)
fraction of the enoxaparin-treated patients (forty-four
of 173; 25%) had venous thromboembolism. None of the 173
enoxaparin-treated patients had pulmonary embolism, whereas
forty-one (24%) had distal deep-vein
thrombosis and three (2%) had proximal and distal deep-vein
thrombosis. The estimated odds for the development of venous thromboembolism
in the warfarin group was 2.52 times greater (95% confidence
interval, 2.00 to 3.19) than those for the enoxaparin group. Similar
results were observed in the evaluable-patients population. Venous
thromboembolic disease occurred in seventy-two (59%)
of the 122 warfarin-treated patients and forty-one (38%)
of the 108 enoxaparin-treated patients (p = 0.0043; odds
ratio, 2.26; 95% confidence interval, 1.71 to 2.98).
In the all-treated-patients population, twenty of the seventy-nine
deep-vein thrombi documented in the warfarin group were
in the proximal venous system (popliteal, femoral, or iliac veins),
whereas only three of the forty-four deep-vein thrombi
in the enoxaparin group were in the proximal venous system. Similarly,
in the evaluable-patients population, proximal deep-vein
thrombosis developed in sixteen of the warfarin-treated patients
and three of the enoxaparin-treated patients. The prevalence
of proximal deep-vein thrombosis was significantly reduced
in the enoxaparin-treated patients in both the all-treated
(p = 0.002) and the evaluable (p = 0.01) patient
populations (odds ratios of 7.3 and 5.3, respectively).
The distribution of deep-vein thrombosis by treatment
group was examined according to the primary diagnosis, type of surgery,
type of anesthesia during surgery, use of surgical cement, use of
compression stockings, use of alignment guides, race, gender, age,
body-mass index (body weight in kilograms divided by height in meters
squared), and history of tobacco use or of a specific medical condition
(obesity, diabetes mellitus, congestive heart failure, varicosities,
and cancer). The occurrence of deep-vein thrombosis within
each subgroup with at least fifteen patients in each treatment group
was similar to the overall occurrence in each treatment group. Male
patients and patients with varicose veins had a higher prevalence
of thromboembolic disease.
Among all patients diagnosed with venous thromboembolism, forty-seven
(59%) treated with warfarin and twenty-one (48%)
treated with enoxaparin received treatment and/or had extended
hospitalization because of the thromboembolic disease. Twenty-six
warfarin-treated patients and twenty enoxaparin-treated
patients had their hospital stay prolonged as a result of the thromboembolism.
Safety
Within the all-treated-patients population, major hemorrhagic
episodes occurred in four (2%) of the 176 warfarin-treated
patients and in nine (5%) of the 173 enoxaparin-treated
patients; this difference was not significant (p = 0.17),
with the numbers available (Table III). The prevalence of major and minor
hemorrhagic episodes in the warfarin-treated patients (forty-one of
176; 23%) was lower than that in the enoxaparin-treated
patients (fifty-eight of 173; 34%) (p = 0.04). A
clinically important hemorrhagic episode occurred at the operative
site in six (3%) of the warfarin-treated patients and twelve
(7%) of the enoxaparin-treated patients (p > 0.05).
However, no patient required a reoperation, and only one (enoxaparin-treated)
patient had to stop using the study medication, on the fourth day
of the study. A superficial infection at the incision site developed
in this same patient, forty days after discontinuation of use of
the study drug.
The major hemorrhagic episodes in the warfarin group included
ecchymoses of >5 cm in three patients (2%) and
retroperitoneal hemorrhage (resulting in death) in one patient (0.6%).
In the enoxaparin group, the major hemorrhagic episodes included
clinically important wound drainage in three patients (2%),
wound hematoma in three patients (2%), ecchymoses of >5
cm in two patients (1%), and hematuria and tracheotomy-site
hemorrhage in one patient (0.6%).
Minor hemorrhagic events in the warfarin-treated group
included ecchymoses not at the operative site in twenty patients
(11%), hematuria in ten patients (6%), gastrointestinal
bleeding in three patients (2%), and other hemorrhagic
episodes in twelve patients (7%). In the enoxaparin-treated
group, ecchymosis not at the operative site was seen in twenty-five
patients (14%); hematuria, in thirteen patients (8%);
gastrointestinal hemorrhage, in five patients (3%); and
other hemorrhagic episodes, in eleven patients (6%).
Three patients in the warfarin group died; one death was due
to multiple organ failure secondary to retroperitoneal hemorrhage,
one was due to postoperative respiratory failure, and one was due
to unknown causes. One patient in the enoxaparin group died of postoperative
respiratory and cardiac complications.
Thrombocytopenia, defined as a platelet count of <100,000/mm3 or mL, was not observed in either
treatment group.
Enoxaparin, administered within eight hours after primary total
knee arthroplasty, was more effective than warfarin in the prevention
of venous thromboembolism, including proximal deep-vein
thrombosis, in this study. Three recent studies have compared the
efficacy of low-molecular-weight heparins with
that of warfarin, and two have compared the efficacy of low-molecular-weight
heparin with that of unfractionated heparin, in the prevention of
deep-vein thrombosis after total knee replacement12,13,15-17. Overall, low-dose
warfarin appears to be less effective than the low-molecular-weight
heparins in the prevention of deep-vein thrombosis after
total knee arthroplasty.
The prevalence of deep-vein thrombosis after primary
total knee arthroplasty has been reported to be higher than that
after primary total hip arthroplasty. Calf-vein thrombosis in patients
treated with total knee arthroplasty is largely responsible for
this difference13. In the present
study, enoxaparin (administered within eight hours after the surgery)
decreased the prevalence of deep-vein thrombosis, both in the proximal
veins alone and in the proximal and distal veins combined, as compared
with warfarin. In a similar study17,
however, enoxaparin (first administered the morning of the day following
the surgery) was noted to decrease the overall occurrence of deep-vein
thrombosis but not that of proximal deep-vein thrombosis,
indicating that the preventive effect was only on distal deep-vein
thrombosis when the initiation of treatment was delayed. In the
present study, the eight-hour treatment window was chosen
in order to provide effective thromboprophylaxis as soon as possible
after the initiation of the thrombotic process by the operative
procedure itself.
Hemorrhagic events occurred more frequently in patients who received
enoxaparin than in those who received warfarin in the present study.
This increased risk may be related to differences in the time-interval
between the administration of the drug and the onset of the anticoagulant
effect, which is short (three to four hours) with low-molecular-weight
heparins and long (forty-eight to seventy-two
hours) with oral anticoagulants. Indeed, in the present study, warfarin
did not provide adequate anticoagulation (as indicated by an international normalized
ratio of 2 to 3) in any patient during the first two days following
surgery; it was not until the third postoperative day that a substantial
number of patients had values within this therapeutic range. The
increase in hemorrhagic wound complications may be avoided when
the onset of treatment is delayed for twelve to twenty-four
hours, as was the case in the enoxaparin study in which all patients received
their first injection the morning of the day following the surgery17.
Several limitations of this study should be noted. The study
was conducted in an open-label manner. As safety outcomes
were assessed by investigators who were aware of the assignments
of the study treatments, bias in favor of either the standard or the
experimental care may have affected sensitive outcomes—in
particular, the occurrence and severity of hemorrhage. In addition,
the study outcomes and population calculations were based on the occurrence
of predominantly clinically asymptomatic deep-vein thrombosis.
Accordingly, the study lacked the power required to assess reductions
in the prevalences of clinical outcomes.
In conclusion, in patients undergoing elective knee replacement
surgery, fixed-dose enoxaparin, administered subcutaneously
within eight hours after the completion of the surgery, significantly reduced
the prevalence of asymptomatic venous thromboembolism compared with
that associated with adjusted-dose warfarin. The prevalence
of proximal deep-vein thrombosis in the enoxaparin-treated
patients was also significantly lower than that in the warfarin-treated
patients. The enoxaparin group did not have a significant increase
in the prevalence of major hemorrhage compared with the warfarin
group, but it did have a significantly higher rate of overall hemorrhagic
complications.
A list of the study participants, a figure showing the international
normalized ratios according to the day of the study, and two additional
tables giving patient characteristics (gender, race, age, height, and
weight) and diagnostic and surgical data (primary diagnosis, type
of surgery, use of cement, type of anesthesia, duration of surgery,
and duration of tourniquet use) for the all-treated-patients population
are available with the electronic versions of this article, on our
web site (www.jbjs.org) and on our CD-ROM (call 781-449-9780, ext.
140, to order).