Study Design and Patient Characteristics
This was a prospective, parallel-group, multicenter study with
an open-label phase of treatment with 30 mg of subcutaneous enoxaparin
twice daily followed by a randomized, double-blind outpatient phase
comparing treatment with 40 mg of subcutaneous enoxaparin once daily
with a placebo. Institutional review boards approved the study protocol before
the study commenced. Fifty-seven investigators enrolled one or more
patients in the study between December 1994 and February 1996. Patients
undergoing elective primary total hip or knee replacement who gave
written informed consent were eligible for enrollment in the open-label phase.
Enoxaparin treatment was initiated twelve to twenty-four hours
postoperatively and was continued for seven to ten days. Patients
who received adequate medication during the open-label phase of the
study (the prescribed enoxaparin dose for at least seven days),
did not require a reoperation or have venous thrombosis or major
hemorrhage during hospitalization, and did not receive excluded concomitant
medications were eligible for inclusion in the outpatient double-blind
phase of the study. During the open-label period, use of nonsteroidal
anti-inflammatory agents, antiplatelet agents, and corticosteroids
was permitted whereas use of oral anticoagulants was prohibited.
Qualified health-care personnel administered all open-label inpatient
or outpatient treatments. Patients were then randomized to receive
double-blind therapy with either subcutaneous enoxaparin (40 mg
once daily) or matching injections of saline solution for three
weeks (eighteen to twenty-one days). The computer-generated randomization scheme
was stratified by surgical procedure. The double-blind therapy was
self-administered by the patients, with the administration of the
first dose witnessed by health-care personnel.
Patients undergoing multiple joint replacement or in whom hemostasis
was not achieved within twelve to twenty-four hours after the surgery
were excluded from the open-label phase of the study. Patients treated
with hip replacement who had undergone surgery on the ipsilateral
hip within the preceding six months or on the ipsilateral knee,
the contralateral knee, or the contralateral hip within the preceding
three months were excluded. Patients treated with knee replacement
who had undergone surgery on the ipsilateral knee within the preceding six
months or on the ipsilateral hip, the contralateral hip, or the
contralateral knee within the preceding three months were also excluded.
Other exclusion criteria were clinical evidence of chronic or acute
deep-vein thrombosis; a history of venous thromboembolic disease
within twelve months before the surgery; generalized hemorrhagic
diathesis or hypercoagulable syndrome; a documented allergy to unfractionated
heparin or a history of heparin-associated thrombocytopenia; a skin
rash or necrosis; allergy to fish or swine products, iodine, or
radiopaque contrast medium; current drug or alcohol abuse; surgery
on the eye, spinal cord, or central nervous system; documented stroke or
myocardial infarction within one month before entry into the study;
active ulcerative disease or angiodysplasia of the gastrointestinal
tract; active gastrointestinal bleeding within the last six months; uncontrolled
hypertension; use of aspirin-containing products or nonsteroidal
anti-inflammatory agents daily within the four days preceding hospitalization;
receipt of another investigational drug within the preceding four
weeks; and clinically relevant diseases or treatments that could
interfere with the study medications or their evaluation (including
severe hepatic disease or renal insufficiency). Patients could enter
the trial only once.
Assessment of Deep-Vein Thrombosis and Pulmonary
Embolism
The prevalence of objectively confirmed deep-vein thrombosis
or symptomatic pulmonary embolism during the double-blind phase
was the primary efficacy end point. Venous segment-filling defects
on lower-extremity ascending contrast venograms (on at least two
venograms for calf thrombi and on one for proximal thrombi) were
required to confirm the diagnosis of deep-vein thrombosis. A high-probability
ventilation-perfusion lung scan or pulmonary vein-filling defects
on a pulmonary angiogram were required to document the diagnosis
of pulmonary embolism. Throughout and at the end of the open-label
phase (on the seventh to tenth day), patients were examined for
clinical evidence of deep-vein thrombosis or pulmonary embolism. These
assessments were repeated at the beginning of the double-blind phase
(on the eighth to eleventh day) and during that phase (on the fifteenth
to twentieth day). Patients presenting with clinical evidence of
deep-vein thrombosis during either phase of the study underwent
lower-extremity ultrasonography to exclude or confirm the diagnosis
of acute deep-vein thrombosis. During the double-blind phase, confirmation
of the diagnosis of deep-vein thrombosis by venography was required.
A ventilation-perfusion lung scan or pulmonary angiography was performed
on patients with clinical evidence of pulmonary embolism. At the
end of double-blind treatment (on the twenty-seventh, twenty-eighth,
or twenty-ninth day), the protocol required bilateral venography
and ultrasonography to be performed on all patients. A central independent
expert panel composed of at least three vascular radiologists blinded
to the treatment assignment and outcome interpreted all venograms,
ventilation-perfusion lung scans, and pulmonary angiograms made
during the double-blind phase. The final diagnosis was assigned
by a consensus method. The expert panel did not assess ultrasonograms.
During a follow-up evaluation (on the ninetieth day, plus or minus
one week), patients were assessed to determine whether there had
been a recent hospitalization and whether venous thromboembolic
disease had developed.
Safety Assessment
The patients were assessed for hemorrhage daily during the hospitalization
and at outpatient visits. Hemorrhage was defined as major if it
was clinically overt and resulted in death, transfusion of two or
more units of blood products, a decrease in the hemoglobin level
of 2.0 g/dL (20 g/L) compared with the most recent
preceding postoperative value, or a serious or life-threatening
clinical event or one requiring surgical intervention or if it was
retroperitoneal, intracranial, or intraocular in location. The hemorrhage
was classified as minor if it was overt, did not meet the criteria
for major hemorrhage, and was associated with at least one of the
following features: epistaxis lasting more than five minutes or requiring
intervention, ecchymosis or hematoma larger than 5 cm at its greatest
dimension, hematuria not associated with urinary catheter-related trauma,
gastrointestinal hemorrhage not related to intubation or placement
of a nasogastric tube, wound hematoma or complications, or subconjunctival
hemorrhage necessitating cessation of medication.
Standard biochemistry and hematology tests were performed during
and at the end of each of the study phases. Details of all adverse
events, together with the investigator’s assessment of
their relationship to the study medication, were recorded.
Statistical Analysis
The estimation of the total sample size in each of the surgical
strata was based on a prevalence of venous thromboembolic disease
of 30% in placebo-treated patients and 15% in
enoxaparin-treated patients, a type-I error rate of 5%,
and a power of 80%. The sample size necessary for each
surgical stratum and treatment group was 268 patients. If it was
assumed that 35% of the randomized patients would not be
evaluable, then 824 patients had to be randomized to ensure 536
evaluable patients. The primary efficacy analysis was performed
on all randomized patients who received at least one dose of study
medication (the all-treated-patients population). All patients,
including those who did not have venography performed at the end
of the study, were included in this analysis. Such patients were assigned
an efficacy outcome on the basis of the results of ultrasonography,
if it had been performed, or on the basis of the occurrence of clinically
symptomatic venous thromboembolism that was documented by means
other than venography or ultrasonography. An analysis of patients
who completed the study according to the protocol (evaluable patients)
was likewise performed. Evaluable patients were defined as patients
treated with primary total hip or knee replacement who had received
at least 75% of the prescribed enoxaparin or placebo and
had undergone bilateral venography, had undergone unilateral venography
that was positive for deep-vein thrombosis, or had a confirmed diagnosis
of deep-vein thrombosis or pulmonary embolism during treatment.
The prevalences of venous thromboembolism and proximal deep-vein thrombosis
in the two treatment groups (both within the hip and knee replacement
groups and within a combined surgical group) were compared with
use of the chi-squared test. Odds ratios, 95% confidence
intervals, and relative risk reductions were calculated. The prevalences
of hemorrhagic episodes and adverse events in the groups were compared
within each surgical stratum with use of the Fisher exact test and
in the combined group with use of the chi-squared test. All comparisons were
two-tailed at the 5% significance level.
Patient Characteristics
In total, 968 patients were enrolled in the open-label phase
of the study. Ninety-five patients were not randomly assigned to
a study treatment: thirty-nine (41.1%), because of an adverse
event; twenty-four (25.3%), because they withdrew consent; twenty-one
(22.1%), because of a violation of the protocol; three
(3.2%), because of an abnormal laboratory test; two (2.1%),
because of an inability to administer the study medication; and
six (6.3%), because of other reasons. The remaining 873 patients
were randomly assigned and received at least one dose of a double-blind
treatment (432 received the placebo and 441, enoxaparin); they were
included in the all-treated-patients population (Table I). Of these
873 patients, 589 (67.5%) (282 who received the placebo
and 307 who received the enoxaparin) were in the evaluable population.
Two hundred and eighty-four patients (150 who received the placebo
and 134 who received the enoxaparin) were not evaluable: 259 (134
who received the placebo and 125 who received the enoxaparin) either did
not have the required final examination (venography, ultrasonography,
or ventilation-perfusion lung-scanning) or had an assessment that
was inadequate; twenty (fourteen who received the placebo and six
who received the enoxaparin) had received the therapy for an insufficient
duration; four (two who received the placebo and two who received
the enoxaparin) had an inappropriate open-label period; and one
who received the enoxaparin had an inappropriate surgical procedure
(Table I).
In all, 122 placebo-treated patients and 110 enoxaparin-treated
patients were considered by the investigators to have not completed
the study and were classified accordingly as having discontinued the
study. The reasons for discontinuing included deviation from the
protocol (ninety-six placebo and eighty-seven enoxaparin-treated
patients), a clinical adverse event (nine placebo and nine enoxaparin-treated
patients), withdrawal of consent (ten placebo and six enoxaparin-treated
patients), inability or unwillingness to self-administer the study
medication (four placebo and two enoxaparin-treated patients), abnormal
results on laboratory testing (zero placebo and two enoxaparin-treated
patients), and other reasons (three placebo and four enoxaparin-treated
patients). The most common protocol deviation was an incorrect dosage
of the study medication—that is, a too long or too short
duration of treatment or missed doses. Of the patients who discontinued
the study, sixty in each treatment group were still considered to
be evaluable (Table I)
and were included in the evaluable-patients analysis. All patients
who discontinued were included in the all-treated-patients analysis.
The treatment groups were similar with respect to demographic
characteristics, including gender and age, and in terms of physical
characteristics, including weight, body-mass index, and obesity
(Table II).
Similarly, there were no major differences between the treatment
groups with regard to surgical diagnosis, surgical procedure, or
type of anesthesia. The treatment groups were also similar with respect
to medical history and use of concomitant medications, although
estrogen-containing medications were used by slightly more patients
in the enoxaparin group (20.2%) than in the placebo group
(12.3%). The primary surgical diagnosis for the majority
of the patients was osteoarthritis resulting in unilateral total
joint replacement (Table II). Of the 873 patients, 616 (70.6%)
reportedly used graduated compression stockings. A tourniquet reportedly
had been used for 432 (98.6%) of the 438 patients treated
with knee replacement, and continuous passive motion reportedly
had been used for 354 (80.8%). The mean time from the surgery
to the administration of the first postoperative dose of enoxaparin
was 19.3 hours (range, -1.3 to 42.0 hours). The mean duration of
enoxaparin treatment was 8.1 days (range, five to twelve days) during
the open-label phase and 19.0 days (range, one to twenty-eight days)
during the double-blind phase. These variables were comparable across
the treatment groups and surgical procedures.
Prevention of Venous Thromboembolic Disease
In the combined surgical group (total hip and knee replacement),
the overall prevalence of venous thromboembolism after one month
of treatment in the enoxaparin-treated patients was significantly lower
(p < 0.001) than the prevalence in the placebo-treated
patients (12.7% [fifty-six] of 441 compared
with 22.0% [ninety-five] of 432; odds
ratio, 1.96; 95% confidence interval, 1.36 to 2.82; relative risk
reduction, 42.3%). In the hip replacement group, the prevalence
of venous thromboembolism in the enoxaparin-treated patients was
significantly lower (p < 0.001) than the prevalence in
the placebo-treated patients (8.0% [eighteen] of
224 compared with 23.2% [forty-nine] of
211; odds ratio, 3.62; 95% confidence interval, 2.00 to
6.55; relative risk reduction 65.5%) (Table III). In the
knee replacement group, there was no significant difference (p = 0.380)
between the prevalences in the enoxaparin and placebo-treated patients
(17.5% [thirty-eight] of 217 compared
with 20.8% [forty-six] of 221; odds ratio,
1.24; 95% confidence interval, 0.76 to 2.02; relative risk reduction,
15.9%). Analysis of the evaluable population revealed similar
results, with enoxaparin producing a significantly lower prevalence
of venous thromboembolism than the placebo in the hip replacement
group (9.9% compared with 28.3%; p < 0.001;
odds ratio, 3.83; 95% confidence interval, 1.97 to 7.44;
relative risk reduction, 65.0%) but not in the knee replacement
group (21.3% compared with 26.4%; p = 0.282;
odds ratio, 1.35; 95% confidence interval, 0.78 to 2.32;
relative risk reduction, 21.3%).
Enoxaparin treatment decreased the prevalence of venous thromboembolism
in men in the hip replacement group, but it did not lead to a meaningful
reduction in the prevalence of venous thromboembolic disease in
men in the knee replacement group (Table III). Enoxaparin reduced the prevalence
of venous thromboembolic disease in women in both the hip and the
knee replacement group. Patients with regional anesthesia had no
difference in the prevalence of venous thromboembolism when compared with
patients with general anesthesia. Obese patients were not at increased
risk for the development of venous thromboembolism when compared with
nonobese patients.
Enoxaparin was significantly superior (p < 0.001) to
the placebo in reducing the prevalence of proximal deep-vein thrombosis
in the hip replacement group (2.7% compared with 12.8%;
odds ratio, 5.33; 95% confidence interval, 2.15 to 13.19;
relative risk reduction, 78.9%) but showed no significant
benefit (p = 0.116) in the knee replacement group (4.1% compared
with 7.7%; odds ratio, 1.93; 95% confidence interval,
0.84 to 4.42; relative risk reduction, 46.8%). While the
percentage of patients with proximal deep-vein thrombosis was not
influenced by the type of joint replacement in the placebo group,
the prevalence of only distal deep-vein thrombosis in the enoxaparin
group was higher in the patients with a knee replacement (13.4%)
than in those with a hip replacement (5.4%). The proximal
and/or distal distribution of the thrombi in the evaluable
patients was similar to that in the all-treated-patients population.
Symptomatic pulmonary embolism occurred in three placebo-treated
patients (one patient with a hip replacement who also had deep-vein
thrombosis and two patients with a knee replacement) but in no enoxaparin-treated
patients.
During the study period, three (1.3%) of the 224 patients
with a hip replacement and seven (3.2%) of the 217 with
a knee replacement in the enoxaparin group were rehospitalized for
venous thromboembolic disease compared with twenty-two (10.4%)
of the 211 patients with a hip replacement and twelve (5.4%)
of the 221 with a knee replacement in the placebo group (Table IV). In both
surgical groups, the placebo-treated patients were rehospitalized
for a larger total number of days than were the enoxaparin-treated patients.
No statistical analysis of these results was performed.
Of the 151 patients in whom venous thromboembolic disease developed,
105 (69.5%) had thrombosis in only the extremity that had
been operated on; twenty-six (17.2%), in only the extremity
that had not been operated on; and eighteen (11.9%), in
both extremities (bilateral). The location of the thrombosis in
two patients, who had pulmonary embolism, was classified as unknown.
Bilateral thrombi were more common after hip replacement (16.4%)
than after knee replacement (8.3%), whereas thrombi in only
the operatively treated extremity were more common after knee replacement
than after hip replacement (64.2% compared with 73.8%).
Safety Results
Hemorrhagic Episodes
During the double-blind phase of the study, twenty-one hemorrhagic
episodes were reported in twenty-one (2.4%) of the 873
patients in the all-treated-patients population: eleven (2.5%)
of the patients in the placebo group and ten (2.3%) in
the enoxaparin group had such an episode (Table V). The differences between the placebo
and enoxaparin-treated patients in this respect were not significant
in either the combined surgical group (p = 0.811), the
hip replacement group (p = 0.272), or the knee replacement
group (p = 0.598). Hemorrhage occurred at a nonoperative
site in thirteen patients (1.5%) and at the operative site
in eight (0.9%). Only one major hemorrhagic episode (intraarticular
hemorrhage in a placebo-treated patient with a knee replacement)
was reported.
Abnormal Laboratory Tests
Abnormal laboratory tests were rare during the double-blind phase
(Table V). Mild,
transient thrombocytopenia occurred in four (0.9%) of the
placebo-treated patients and five (1.1%) of those treated
with enoxaparin. Increased alanine aminotransferase levels were
detected in three patients treated with enoxaparin but not in any treated
with the placebo. No differences with regard to the occurrence of
hyperkalemia were observed between the two treatment groups.
Adverse Events and Death
During the double-blind phase of the study, twenty-nine (6.7%)
of the placebo-treated patients and thirty-four (7.7%)
of the enoxaparin-treated patients reported at least one adverse
event that was considered to be related to the study medication
(Table V). All
of these events were mild or moderate in severity, and none had
a prevalence of more than 2%, with the exception of ecchymosis
in the enoxaparin-treated patients with a hip replacement (prevalence,
2.7%). Injection-site hemorrhage and pain and ecchymosis
were observed in approximately 1% of the patients in each
treatment group, with no apparent intergroup difference.
Only one death occurred in the randomized population: a patient
died from a suspected pulmonary embolism after receiving a single
dose of the placebo. No autopsy was performed. Pulmonary embolism
was stated to be the cause of death on the death certificate.
Follow-up Assessment
Follow-up assessment for clinical events occurring between one
month and three months was possible for 819 (93.8%) of
the 873 randomized patients: 406 placebo-treated patients and 413
enoxaparin-treated patients. Only two patients, both in the group
treated with enoxaparin and hip replacement (a prevalence of 0.9% of
224 in that group) were rehospitalized for treatment of clinically
symptomatic deep-vein thrombosis occurring after the end of the
treatment evaluation.
In this study, patients who received conventional short-term
enoxaparin therapy (30 mg twice daily) were approximately twice
as likely to have venous thromboembolic disease after elective hip
or knee joint replacement compared with those for whom the short-term
enoxaparin therapy was followed by a prolonged (three-week) course
of enoxaparin therapy (40 mg once daily). However, different patterns
of response were observed after the two types of surgery. While
the prolonged regimen reduced the likelihood of venous thromboembolism
developing in patients who had undergone hip replacement, it provided
no significant benefit following knee replacement. These conclusions
are based primarily on the occurrence of asymptomatic deep-vein
thrombosis detected by venography. No socioeconomic analysis was
performed in this study. No statistical analysis of symptomatic
venous thromboembolic disease was performed, and the follow-up duration
was not long enough to allow assessment of chronic venous insufficiency.
The difference observed between the two types of joint replacement
may have been influenced by differences in body weight or obesity.
The patients treated with knee replacement weighed more, had a higher
body-mass index, and were more often obese compared with those treated
with hip replacement. Additional differences in the patterns of
response emerged in the analysis of the subpopulations. The prolonged
enoxaparin treatment regimen was superior to the short-term regimen
in both male and female patients who underwent hip replacement.
However, in the knee replacement group, a benefit was observed only
in female patients. Enoxaparin did not reduce the prevalence of
venous thrombosis, compared with the placebo, in male patients treated
with knee replacement. It is possible that the dose of enoxaparin
was insufficient or the dosing interval was too long for the male
patients because of their greater weight, height, and body-surface
area relative to the female patients. The average weight of the
men undergoing knee arthroplasty was 96.8 kg compared with 83.1 kg
for the women. The prolonged regimen demonstrated a protective effect
in obese patients after both surgical procedures, although this
effect was more marked in the hip replacement group than in the
knee replacement group. No proven explanations for the differences
observed between women and men after total knee arthroplasty are
available. However, pharmacokinetic studies21 of
volunteers have revealed that body weight is associated with peak
anti-factor-Xa activity, with peak levels being decreased as body
weight increases. In our study, no tests of significance were performed
in any analysis of patient subgroups as they were not prespecified
in the protocol or in the plan for statistical analysis.
A survey of medical records in the state of California was performed
in order to estimate the frequency of venous thromboembolism within
three months after hip and knee replacements22.
The authors observed a significant difference between hip and knee
replacements with regard to both the number of clinical venous thromboembolic events
and the median time to diagnosis of the event (seventeen and seven
days, respectively). Seventy-six percent of the patients in whom
a clinical venous thromboembolic event developed following hip arthroplasty
were diagnosed after hospital discharge compared with 47% of
the patients in whom an event developed following knee arthroplasty.
A study comparing venographic findings at one and six days after
knee replacement in a cohort of fifty-nine patients (seventy-six
knees) showed that 86% of the limbs in which venous thrombosis
developed had it at the early time-period (at one day)22. The earlier appearance of clinical
venous thromboembolic events after knee replacement suggests that
there may be a lower prevalence of late-occurring venous thromboembolism
after this procedure, and this may have affected the overall benefit
of extended-duration enoxaparin thromboprophylaxis in the present
study.
Two studies of low-molecular-weight heparin demonstrated that
both fixed and weight-adjusted once-daily postoperative dosing regimens
may be less efficacious overall than twice-daily postoperative dosing
regimens after either hip or knee replacement7,24.
Studies of twice-daily dosing regimens with enoxaparin and ardeparin
demonstrated that fixed-dose (enoxaparin) and weight-adjusted (ardeparin)
regimens provided effective and safe thromboprophylaxis after knee
replacement when compared with heparin, warfarin, and placebo controls9,12,24,25. Enoxaparin and other low-molecular-weight
heparins have consistently been shown to be more effective for thromboprophylaxis
following hip replacement than for thromboprophylaxis following
knee replacement3,12,24,26.
The results of the present study support previous evidence of
the beneficial effect of extending the duration of thromboprophylaxis
after total hip replacement. In a recent double-blind study, patients
without deep-vein thromboembolism after total hip replacement were
randomized (after thirteen, fourteen, or fifteen days of hospitalization)
to receive twenty-one days of treatment with a placebo or subcutaneous
enoxaparin (40 mg once daily)19.
The enoxaparin-treated patients had a significantly lower prevalence
of deep-vein thrombosis (7.1% compared with 19.3% in
the placebo-treated patients; p = 0.018). In a study with
a design similar to that of the present study20,
patients were treated with enoxaparin from the evening before the
surgery until discharge (at a mean of ten or eleven days), at which
point the patients were randomly assigned to receive enoxaparin
therapy or a placebo for an additional twenty-one days. Again, the
prevalence of venous thromboembolic disease in the patients treated
with enoxaparin (18%) was significantly lower (p < 0.001)
than the prevalence in the patients treated with the placebo (39%).
These data are supported by those from studies of dalteparin, another
low-molecular-weight heparin, after hip replacement surgery27,28.
Clearly, the benefit of outpatient thromboprophylaxis must be
balanced against any potential increase in the risk of hemorrhagic
episodes. However, in this study such episodes were similarly infrequent
in the two treatment groups, and only one case, in a placebo recipient,
was considered major. Moreover, the prevalences of adverse events and
abnormal clinical laboratory tests associated with the long-term
enoxaparin therapy were comparable with those associated with the
placebo. Thrombocytopenia is a recognized complication of heparin
therapy29, with a prevalence of
about 1.7% in patients treated with intravenous porcine
heparin when the thrombocytopenia was defined as a platelet count
of <100 ¥ 109/L.
During the extended-therapy phase of the present study, there were
no platelet counts of <100 ¥ 109/L,
and only nine patients (four treated with a placebo and five treated
with enoxaparin) had mild thrombocytopenia (a platelet count of >100
to 125 ¥ 109/L). Increased
aminotransferase levels, which may occur with both conventional
and low-molecular-weight heparins30,31,
occurred only rarely with the enoxaparin regimen used during the
double-blind phase of this study.
In summary, these results, which are based primarily on venographic
evidence, indicate that the recommended seven to ten-day postoperative thromboprophylactic
regimen of 30 mg of enoxaparin twice daily for patients treated
with total hip replacement is suboptimal and that a substantial therapeutic
benefit is gained, without compromising safety, by prolonging the
enoxaparin treatment (at a dose of 40 mg once daily) for an additional three
weeks postoperatively (resulting in a total of four weeks of enoxaparin
treatment). This benefit was not observed in patients who underwent
knee replacement, and additional studies of this patient population
are warranted.
Note: The Writing Committee Members of the Enoxaparin Clinical
Trial Group included Philip C. Comp, MD, PhD, Oklahoma City, Oklahoma; Richard
J. Friedman, MD, Charleston, South Carolina; Geoffrey A. Gardiner
Jr., MD, Philadelphia, Pennsylvania; Gerhard J. Johnson, MD, Minneapolis,
Minnesota; Maurice Jové, MD, Decatur, Georgia; Glenn C.
Landon, MD, Houston, Texas; Theodore E. Spiro, MD, Antony, France;
and Thomas L. Whitsett, MD, Oklahoma City, Oklahoma. The Vascular
Imaging Committee Members of the Enoxaparin Clinical Trial Group
included Geoffrey A. Gardiner Jr., MD, Joseph Bonn, MD, Kevin J. Sullivan,
MD, David J. Eschelman, MD, and Marcel Schapiro, MD, Philadelphia,
Pennsylvania. Participating Investigators who enrolled one or more patients
in the study included Dennis L. Armstrong, MD, Mesa, Arizona (four
patients); David Attarian, MD, Fort Lauderdale, Florida (four patients);
Norman E. Beisaw, MD, Worcester, Massachusetts (six patients); John
D. Blaha, MD, Morgantown, West Virginia (seven patients); Robert
D. Bona, MD, Hartford, Connecticut (three patients); William J. Bose,
MD, Mobile, Alabama (four patients); Michael H. Bourne, MD, Salt
Lake City, Utah (fifteen patients); Allan L. Bucknell, MD, Houston, Texas
(sixteen patients); Frank A. Burke, MD, Lexington, Kentucky (eighteen
patients); Jacques R. Caldwell, MD, Daytona Beach, Florida (twelve patients);
Clifford W. Colwell Jr., MD, La Jolla, California (thirteen patients);
Philip C. Comp, MD, PhD, Oklahoma City, Oklahoma (200 patients); Edward
M. Condon, MD, Hyde Park, New Jersey (one patient); J. Robin de
Andrade, MD, Atlanta, Georgia (twelve patients); Donald G. Eckhoff,
MD, Denver, Colorado (six patients); Roger H. Emerson Jr., MD, Plano,
Texas (seventeen patients); Robert S. Ennis, MD, Hollywood, Florida
(nineteen patients); Joseph M. Erpelding, MD, Fort Gordon, Georgia
(twenty-two patients); Stuart P. Farber, MD, Hollywood, Florida
(thirteen patients); David N. Feldman, MD, Englewood, New Jersey
(three patients); Harold E. Fleming, MD, Greer, South Carolina (four
patients); Richard J. Friedman, MD, Charleston, South Carolina (forty
patients); Ronald W. Geckler, MD, Baltimore, Maryland (twenty-three
patients); Michael J. Grecula, MD, Galveston, Texas (seven patients);
Stephen F. Hoff, MD, Portland, Oregon (five patients); Thaddeus
W. Hume, MD, Houston, Texas (twenty-one patients); Gerhard J. Johnson,
MD, Minneapolis, Minnesota (twenty-one patients); Maurice Jové,
MD, Decatur, Georgia (thirty-one patients); Richard M. Konsens, MD,
Winter Park, Florida (eight patients); Michael J. Koren, MD, Jacksonville,
Florida (thirteen patients); Hau C. Kwaan, MD, Chicago, Illinois (thirteen
patients); Glenn C. Landon, MD, Houston, Texas (forty-five patients);
Edward J. Lisecki, MD, Aurora, Colorado (sixteen patients); Harry
Lockstadt, MD, Lexington, Kentucky (eight patients); Paul Lotke,
MD, Philadelphia, Pennsylvania (six patients); Roger M. Lyons, MD,
San Antonio, Texas (twelve patients); Benedict F. Magsamen, MD,
Fort Collins, Colorado (ten patients); John W. McCutcheon, MD, Winter
Park, Florida (twenty-eight patients); Hugh C. McLeod, MD, Marietta, Georgia
(three patients); S. Curtis Mull, MD, Salem, Virginia (fourteen
patients); Neil J. Negrin, MD, Austell, Georgia (eight patients);
H. Lynn Norman, MD, Jacksonville, Florida (four patients); Jill
A. Ohar, MD, St. Louis, Missouri (three patients); Rolf R. Paulson,
MD, Grand Forks, North Dakota (eight patients); Val M. Phillips,
MD, Lawrenceville, Georgia (three patients); Merrill Ritter, MD,
Mooresville, Indiana (nineteen patients); Rajnikant S. Shah, MD,
Levittown, Pennsylvania (twenty-nine patients); Thomas M. Shery, MD,
Culver City, California (seven patients); Randall S. Suarez, MD,
Greer, South Carolina (sixteen patients); Michael J. Sullivan, MD,
San Diego, California (ten patients); Todd V. Swanson, MD, Las Vegas,
Nevada (seven patients); Michael C. Tivnon, MD, Bakersfield, California
(thirty-nine patients); Melvin J. Tonkon, MD, Anaheim, California
(eighteen patients); Dean T. Tsukayama, MD, Minneapolis, Minnesota
(five patients); Charles Weiss, MD, Miami Beach, Florida (three
patients); Thomas L. Whitsett, MD, Oklahoma City, Oklahoma (fifty-one
patients); and Gregory R. Wise, MD, Loma Linda, California (fifteen
patients). Other Participating Investigators included Sunil Bohle,
MD, Duluth, Georgia; Larry Cordell, MD, Kansas City, Missouri; Ronald
Krasnick, MD, Marlton, New Jersey; and Arthur A. Trowbridge, MD,
Temple, Texas. Rhône-Poulenc Rorer Participants included Todd
Koser (Data Management); Sylvain Nicolas and James Stephens (Biostatistics);
Nancy Pultorak (Study Leader); and Theodore E. Spiro, MD (Project
Director). This study was monitored by PPD:::Pharmaco, a clinical
research organization. Arthur A. Trowbridge, MD, Temple, Texas,
provided consultation in the inception of this program and editorial
review of this manuscript.