 |
|
Comparison of the Oral Direct Thrombin Inhibitor Ximelagatran With Enoxaparin as Prophylaxis Against Venous Thromboembolism After Total Knee Replacement
A Phase 2 Dose-Finding Study
John A. Heit, MD;
Clifford W. Colwell, MD;
Charles W. Francis, MD;
Jeffrey S. Ginsberg, MD;
Scott D. Berkowitz, MD;
James Whipple, MS;
Gary Peters, MD;
for the AstraZeneca Arthroplasty Study Group
Arch Intern Med. 2001;161:2215-2221.
ABSTRACT
| |
Background Up to one third of patients who undergo total knee replacement develop
deep vein thrombosis after surgery despite receiving low-molecular-weight
heparin prophylaxis. Ximelagatran is a novel direct inhibitor of free and
clot-bound thrombin.
Methods We performed a randomized, parallel, dose-finding study of 600 adults
undergoing elective total knee replacement at 68 North American hospitals
to determine the optimum dose of ximelagatran to use as prophylaxis against
venous thromboembolism after total knee replacement. Patients received either
ximelagatran twice daily by mouth in blinded fixed doses of 8, 12, 18, or
24 mg or open-label enoxaparin sodium, 30 mg, subcutaneously twice daily,
starting 12 to 24 hours after surgery and continuing for 6 to 12 days. We
measured the 6- to 12-day cumulative incidence of symptomatic or venographic
deep vein thrombosis, symptomatic pulmonary embolism, and bleeding.
Results A total of 594 patients received at least 1 dose of the study drug;
443 patients were evaluable for efficacy. Rates of overall venous thromboembolism
(and proximal deep vein thrombosis or pulmonary embolism) for the 8-, 12-,
18-, and 24-mg doses of ximelagatran were 27% (6.6%), 19.8% (2.0%), 28.7%
(5.8%), and 15.8% (3.2%), respectively. Rates of overall venous thromboembolism
(22.7%) and proximal deep vein thrombosis or pulmonary embolism (3.1%) for
enoxaparin did not differ significantly compared with 24-mg ximelagatran (overall
difference, –6.9%; 95% confidence interval,
-18.0% to 4.2%; P = .3).
There was no major bleeding with administration of 24 mg of
ximelagatran twice daily.
Conclusion Fixed-dose, unmonitored ximelagatran, 24 mg twice daily, given after
surgery appears to be safe and effective oral prophylaxis against venous thromboembolism
after total knee replacement.
INTRODUCTION
VENOUS thromboembolism is a common complication after total knee replacement
surgery. In the absence of prophylaxis, approximately 60% of patients have
venographic evidence of deep vein thrombosis at hospital discharge.1 Although prophylaxis with low-molecular-weight heparin
is effective and safe, approximately 30% of patients still develop deep vein
thrombosis.2-5
Most of these thrombi are small, asymptomatic, and confined to the deep veins
of the calf. However, the prevalence of proximal (eg, popliteal or more proximal)
deep vein thrombosis, which is most frequently associated with symptomatic
venous thromboembolism and fatal pulmonary embolism, is still approximately
6%,5 possibly because heparins are poor inhibitors
of clot-bound thrombin.6 Moreover, low-molecular-weight
heparin currently must be given by subcutaneous injection, which is inconvenient
for some patients. Although oral warfarin sodium prophylaxis is convenient,
frequent laboratory monitoring and dose adjustment are required, and warfarin
is not as effective as low-molecular-weight heparin.3-5
Clearly, more effective and convenient prophylaxis is needed. Recently, prophylaxis
with a direct thrombin inhibitor (recombinant desulfato-hirudin or desirudin),
which potently inhibits clot-bound thrombin, was shown to be significantly
more effective than and as safe as low-molecular-weight heparin after total
hip replacement.7 However, the first dose was
given immediately after spinal anesthesia and before surgery, which might
increase the risk for operative bleeding and formation of spinal hematomas.8 In addition, desirudin has not been studied as prophylaxis
for total knee replacement; it also must be given as a subcutaneous injection,
which potentially limits its convenience.
Melagatran is a small molecule that provides potent, competitive, and
direct inhibition of free and clot-bound thrombin, but it must be administered
parenterally. Ximelagatran (formerly known as H 376/95; Exanta) is an oral
prodrug that is converted to melagatran, the active metabolite. In a recent
international clinical trial9 of preoperative
administration of subcutaneous melagatran followed by oral ximelagatran as
prophylaxis against venous thromboembolism after total hip or knee replacement,
the highest melagatran-ximelagatran dose was significantly more effective
than and as safe as low-molecular-weight heparin (dalteparin sodium) prophylaxis
started before surgery. In North America, however, prophylaxis usually is
started after surgery because of concerns about operative bleeding. Consequently,
we performed a phase 2 dose-finding study to assess the efficacy and safety
of 4 different postoperative, fixed-dose, oral ximelagatran regimens compared
with postoperative enoxaparin sodium as prophylaxis against venous thromboembolism
after total knee replacement.
PATIENTS AND METHODS
STUDY POPULATION
Patients were eligible for enrollment if they provided written informed
consent, were 18 years or older and not of childbearing potential if female
(eg, postmenopausal or surgically sterile), weighed 40 to 125 kg, and were
scheduled for elective primary unilateral total knee replacement surgery.
Patients were excluded for the following reasons: previous objectively confirmed
deep vein thrombosis or pulmonary embolism; anticipated use of an epidural
or spinal catheter for more than 12 hours after surgery or within 2 hours
of administration of the first dose of study medication; traumatic epidural
or spinal puncture; planned external pneumatic compression prophylaxis (except
passive antiembolism stockings); immobilization because of trauma or other
illness within 12 weeks of surgery; or long-term anticoagulant or antiplatelet
therapy. Use of aspirin and nonsteroidal anti-inflammatory drugs was discontinued
24 hours before surgery; use of all other anticoagulants was stopped 7 days
before surgery. Patients were also excluded if they had an allergy to contrast
media or iodine, a clinical bleeding disorder, renal impairment (serum creatinine
level >1.8 mg/dL [>160 µmol/L]) or a renal transplant, previous intracranial
or retinal bleeding, previous or current drug or alcohol abuse, an ischemic
stroke within the previous 3 months, gastrointestinal tract bleeding or ulcer
verified by endoscopy within the previous year, major surgery within the previous
3 months, a malignant neoplasm being actively treated, uncontrolled hypertension
(systolic blood pressure >180 mm Hg or diastolic blood pressure >100 mm Hg),
liver disease or impairment (aspartate aminotransferase or alanine aminotransferase
levels >2-fold higher than normal), anemia (hemoglobin level <10.0 g/dL),
or thrombocytopenia (platelet count <100 x 103/µL).
Patients who had previously participated in this study were excluded, as were
patients who had received another investigational agent within the previous
30 days. Similarly, mentally or legally incapacitated patients and those with
a condition that might interfere with study participation or for whom study
participation might cause significant risk were excluded.
STUDY DESIGN
Using a multicenter, randomized, parallel study design, patients were
randomly allocated to 1 of 5 treatment groups: ximelagatran at a fixed dose
of 8, 12, 18, or 24 mg given twice daily by mouth or enoxaparin sodium (Lovenox,
Rhone-Poulenc Rorer Pharmaceuticals Inc, Collegeville, Pa), 30 mg, given twice
daily by subcutaneous injection. For all 5 treatment groups, the intensity
of anticoagulation was not monitored and the drug dose was not adjusted. Randomization
was performed using a computer-generated randomization list provided by AstraZeneca
LP, Wayne, Pa; the randomization was stratified in blocks of 5 patients. Ximelagatran
administration was blinded and enoxaparin administration was open label. Study
drug was first administered after adequate hemostasis and within 12 to 24
hours after surgery and was continued for 6 to 12 days. Patients who were
discharged from the hospital within 6 days after surgery received their remaining
study drug as outpatients. Drug compliance was assessed by counting the number
of tablets or syringes (1) used during the inpatient period, (2) dispensed
at hospital discharge, and (3) returned unused by the patient at the end of
the study. All patients were followed up clinically for at least 4 weeks after
surgery. The study was conducted at 68 North American community, university,
or university-affiliated hospitals. The protocol was approved by the institutional
review board of each investigational center.
EVALUATION OF EFFICACY AND SAFETY
Patients were examined daily for symptoms and signs of venous thromboembolism
and bleeding while in the hospital. After a minimum of 6 and a maximum of
12 days of treatment, and within 12 hours after the last treatment dose, patients
underwent unilateral ascending venography of the operative leg.10-11
Each venogram was interpreted by an independent central adjudication committee
consisting of experts who were blinded to treatment allocation and who categorized
the venographic findings as diagnostic for deep vein thrombosis, normal, or
inadequate. A venogram that lacked adequate views of the distal external iliac,
common and superficial femoral, popliteal, and at least paired peroneal and
posterior tibial veins was categorized as inadequate; visualization of the
profunda femoris or anterior tibial veins was not a requirement. Deep vein
thrombosis was diagnosed when a constant intraluminal filling defect was seen
on at least 2 images; thrombi were further subcategorized as affecting the
proximal leg veins (popliteal or more proximal deep vein) or isolated to the
calf veins and as thrombi longer than 10 cm. Patients with clinically suspected
acute pulmonary embolism underwent a ventilation/perfusion lung scan; a high-speed,
high-resolution (eg, spiral or electron beam) computed tomographic scan of
the chest with appropriate contrast injection; or a pulmonary angiogram. For
patients undergoing a lung scan, pulmonary embolism was diagnosed when the
scan was interpreted as high probability based on a segmental or larger perfusion
defect(s) with normal ventilation.12 For patients
undergoing computed tomography or pulmonary angiography, pulmonary embolism
was diagnosed based on a constant intraluminal filling defect within 1 or
more pulmonary arteries or abrupt cutoff of a vessel 2.5 mm or larger in diameter.
Bleeding was categorized as major if it was clinically overt and involved
a critical site (eg, intracranial, retroperitoneal, intraocular, spinal, or
pericardial bleeding), caused a bleeding index of 2.0 or greater (defined
as the change in prebleed and postbleed hemoglobin levels plus the number
of red blood cell units transfused), or prompted medical or surgical intervention
at the operative site. Overt bleeding that did not meet these criteria was
categorized as minor. Bleeding episodes were also categorized as clinically
significant based on the judgment of the local investigator. In addition to
the venograms, all clinically suspected episodes of deep vein thrombosis,
pulmonary embolism, and major bleeding were adjudicated by the central adjudication
committee.
STATISTICAL METHODS
Baseline demographic and surgical characteristics were compared descriptively.
The primary study objective was to assess the dose range of ximelagatran.
The primary efficacy measure was the cumulative incidence of verified venous
thromboembolism. The primary analysis was intention to treat and included
all patients with an adequate venogram or symptomatic, objectively documented
venous thromboembolism. We estimated that the incidence of venous thromboembolism
would differ by 18% between the low- and high-dose ximelagatran groups. Assuming
a linear dose response, we estimated that 80 evaluable patients per dose group
would provide 80% power ( = .05) to detect a dose response, giving
a total sample size of 400 patients with adequate venograms. We increased
our total sample size to 600 patients to allow for inadequate venograms. The
incidence rates of venous thromboembolism were estimated using the observed
proportions (and corresponding 95% confidence intervals [CIs]) within treatment
groups, and the presence or absence of a linear dose response was estimated
using the Cochran-Armitage test for trend.13
The secondary objective was to compare the efficacy and safety of using ximelagatran
vs enoxaparin. In addition to the intention-to-treat analysis, we performed
a secondary efficacy analysis that included patients with an adequate venogram
who met our a priori definition for protocol compliance. The safety analysis
included all patients who took at least 1 dose of study medication. We estimated
differences in proportions (and 95% CIs) between treatments and tested for
treatment difference using the Fisher exact test. A central data coordinating
center (AstraZeneca) performed all statistical analyses. Data interpretation
and manuscript preparation were performed by the writing committee. However,
AstraZeneca retained the right to review and comment on the manuscript before
publication.
INTERIM ANALYSIS
An independent safety committee monitored the conduct of the study.
The safety committee received all fatal or life-threatening event reports
within one business day and all other reports within 5 calendar days. In addition,
the safety committee reviewed regular reports of bleeding and venous thromboembolism
event rates by treatment group and made recommendations regarding continuing
or stopping the study. At the recommendation of the safety and executive committees,
the protocol was amended on September 28, 1999, to discontinue enrollment
in the 8-mg ximelagatran arm. This recommendation was based on newly available
data indicating that 1 mg of melagatran started before surgery and given twice
daily by subcutaneous injection followed by 8 mg of oral ximelagatran twice
daily was significantly inferior to low-molecular-weight heparin (dalteparin
sodium) prophylaxis in a parallel study performed in Europe.9
To maintain blinding, investigators completed the existing blocks of drug
supplies. Thereafter, new drug supplies for ximelagatran with only 3 dose
levels (12, 18, and 24 mg) were provided. The original sample size was retained
across the remaining 4 treatment groups so that the numbers of patients in
the remaining groups increased by approximately 10%.
RESULTS
PATIENT POPULATION
A total of 600 patients were randomized into the study; the first patient
was randomized in October 1998, and the last patient completed the study in
January 2000. Patients in the 5 treatment arms were similar with regard to
baseline patient and surgical characteristics (Table 1). Fifty-five patients prematurely discontinued study treatment;
the 5 treatment arms did not differ significantly with regard to the reasons
for premature discontinuation of study treatment (Table 2). Combining patients who did not undergo venography with
patients who had an inadequate venogram, 157 patients had a nonevaluable study
efficacy measure and were excluded. The intention-to-treat analysis included
the remaining 440 patients plus 3 additional patients who had symptomatic,
objectively documented pulmonary embolism (Figure 1). No emergency unblinding occurred during the study. Twenty-eight
patients had 1 or more protocol violations (Table 2); the 5 treatment arms did not differ significantly with
regard to the percentage of patients with protocol violations. After excluding
these 28 patients, 415 patients remained and were included in the per-protocol
analysis. Finally, 594 patients received at least 1 dose of study medication
and were included in the safety analysis.
|
|
|
|
Table 1. Baseline Characteristics of 600 Patients Undergoing Total
Knee Replacement by Treatment Assignment
|
|
|
|
|
|
|
Table 2. Disposition of 600 Randomized Patients Undergoing Total Knee
Replacement by Treatment Assignment
|
|
|
|
|
|
|
Figure 1. Flow diagram detailing the study
design, drug intervention, patient enrollment, patient withdrawal, study drug
discontinuation, and duration of follow-up. PO indicates by mouth; bid, twice
daily; and SC, subcutaneously.
|
|
|
CUMULATIVE INCIDENCE OF VENOUS THROMBOEMBOLISM
As shown in Figure 2, the
distribution of total study medication doses was similar across the 5 treatment
arms. Among the 4 ximelagatran groups, the 24-mg dose had the lowest overall
incidence of venous thromboembolism (Table
3). Although the highest dose of ximelagatran (24 mg) provided a
42% relative risk reduction in the overall venous thromboembolism rate compared
with the lowest dose of ximelagatran (8 mg), the absolute difference was not
significantly different (absolute reduction, 11.2%; 95% CI, -2.0% to
24.4%; P = .11), possibly owing to the small sample
size. Similarly, the highest dose of ximelagatran provided a 52% relative
risk reduction in the rate of proximal deep vein thrombosis or pulmonary embolism
compared with the lowest dose of ximelagatran, but the absolute difference
also was not significantly different (absolute difference, 3.4%; 95% CI, -3.7%
to 10.5%; P = .4). Thus, the tests for a linear dose
response across the 4 ximelagatran groups for overall venous thromboembolism
and proximal deep vein thrombosis or pulmonary embolism were not statistically
significant (P = .3 and .7, respectively).
|
|
|
|
Figure 2. Distribution of total study medication
doses by treatment assignment.
|
|
|
|
|
|
|
Table 3. Cumulative Incidence of Venous Thromboembolism by Treatment
Group
|
|
|
The rates of overall venous thromboembolism and of proximal deep vein
thrombosis or pulmonary embolism among patients receiving enoxaparin were
22.7% and 3.1%, respectively (Table 3).
Compared with enoxaparin, the 24-mg dose of ximelagatran provided a 30% relative
risk reduction for overall venous thromboembolism. Again, however, the absolute
difference between the 2 groups was not significantly different (absolute
difference, -6.9%; 95% CI, -18.0% to 4.2%; P = .3). The rate of proximal deep vein thrombosis or pulmonary embolism
also was not statistically different between the 2 groups (absolute difference,
0.1%; 95% CI, -4.9% to 5.0%; P>.99). Among
patients with venographically demonstrated deep vein thrombosis, fewer in
the 24-mg ximelagatran group (5.3%) and the enoxaparin group (6.2%) had a
thrombus longer than 10 cm compared with patients in the other 3 ximelagatran
groups (7.9%-14.3%). In the per-protocol analysis, the cumulative incidence
of venous thromboembolism also was lowest in the 24-mg ximelagatran group,
and the difference between the enoxaparin and 24-mg ximelagatran groups was
not statistically different (P = .3) (Table 3).
Three cases of nonfatal pulmonary embolism occurred during treatment—2
in the 18-mg ximelagatran group and 1 in the 24-mg ximelagatran group. Two
additional patients developed pulmonary embolism during follow-up—both
were in the 24-mg ximelagatran group. One case occurred 2 months after
treatment ended, and the other occurred 7 days after treatment ended; the
latter patient subsequently died. The rate of pulmonary embolism among the
treatment groups was too low for meaningful comparison.
CUMULATIVE INCIDENCE OF BLEEDING
The total number of major bleeding events was low in the 4 ximelagatran
groups. There was no significant trend in major bleeding (P = .4), major or minor bleeding (P = .9),
or clinically significant bleeding events (P = .3)
by ximelagatran group (Table 4).
The number of wound hematomas also was low, and the incidence of wound hematomas,
the volume of postoperative blood loss or wound drainage, and the time to
onset of major or minor bleeding did not differ significantly among the 4
groups. Although the mean number of transfused red blood cell units was low
(<1) for all ximelagatran groups, there was a possible trend toward a higher
mean number of transfused units with increasing ximelagatran dose (P = .09). Compared with the 8-mg ximelagatran group, the mean number
of transfused units was marginally but significantly greater in the 24-mg
group (P = .048). However, the bleeding index did
not differ significantly among the 4 groups.
|
|
|
|
Table 4. Cumulative Incidence of Bleeding by Treatment Group
|
|
|
The rates of major bleeding, major plus minor bleeding, and clinically
significant bleeding events in the enoxaparin group were 0.8%, 9.6%, and 1.6%,
respectively; these rates did not differ significantly compared with the 24-mg
ximelagatran group (Table 4).
Moreover, the rate of wound hematomas, mean volume of postoperative blood
loss and wound drainage, mean number of transfused red blood cell units, and
bleeding index also were similar for the 2 groups. The bleeding indices, however,
were lower in the 18-mg (3.0) and 24-mg (3.0) ximelagatran groups compared
with the enoxaparin group (3.4), and these differences approached statistical
significance (P = .07 and .051, respectively). Compared
with the 8-mg ximelagatran group, the mean number of transfused units also
was marginally but significantly greater in the enoxaparin group (P = .047).
COMMENT
This study is the first, to our knowledge, to show that a direct thrombin
inhibitor given solely as a fixed oral dose and started after surgery is safe
and effective as prophylaxis against venous thromboembolism after total knee
replacement surgery. For ethical reasons, this study did not include a placebo
group. Based on previous studies, in the absence of prophylaxis the expected
incidence of venous thromboembolism after total knee replacement ranges from
40% to 84%.1 Using the most conservative expected
incidence (40%), ximelagatran provided a 33% to 61% relative risk reduction
in overall venous thromboembolism cumulative incidence from the lowest to
the highest ximelagatran group. In the only placebo-controlled prophylaxis
trial after total knee replacement, the incidence of major bleeding was 2%
in the placebo group,2 which compares favorably
with our observed 0% to 2.4% range of major bleeding rates among the 4 ximelagatran
groups.
The 24-mg dose of ximelagatran twice daily appeared to be the most effective
of the 4 doses tested, although the test for trend in ximelagatran dose efficacy
did not reach statistical significance. Compared with the 8-mg ximelagatran
dose, the 24-mg dose provided a 42% relative risk reduction in overall venous
thromboembolism and a 52% reduction in the relative risk of proximal deep
vein thrombosis or pulmonary embolism. Moreover, the 11.2% absolute difference
in overall venous thromboembolism in favor of the 24-mg dose approached statistical
significance (P = .11) and likely is clinically important.
The 24-mg dose of ximelagatran also appeared to be safe. There were no major
bleeding events in the 24-mg dose group. The major or minor bleeding, significant
bleeding event, and wound hematoma rates; the total volume of postoperative
blood loss and wound drainage; and the bleeding indices did not differ significantly
between the 8- and 24-mg dose groups. However, the 24-mg group had a slightly
but significantly higher transfusion requirement than the 8-mg group.
Administering 24 mg of ximelagatran twice daily also appears to be as
effective, or possibly even more effective, than the current standard of prophylaxis
in North America—low-molecular-weight heparin started after surgery.
Compared with enoxaparin, the 24-mg dose of ximelagatran provided a 30% relative
risk reduction in overall venous thromboembolism incidence in our study. Our
findings are consistent with the results of the METHRO II study,9
in which 3 mg of melagatran given by subcutaneous injection before surgery
followed by 24 mg of oral ximelagatran twice daily after surgery provided
a 35% relative risk reduction in overall venous thromboembolism compared with
administration of dalteparin sodium. In addition, our findings are also consistent
with those of other trials7, 14-16
investigating direct thrombin inhibitors as venous thromboembolism prophylaxis
after total joint replacement. For example, compared with enoxaparin, recombinant
desulfato-hirudin (desirudin) provided a 28% relative risk reduction in overall
venous thromboembolism in patients undergoing total hip replacement (absolute
difference, 7.1%; P = .001) and a 40% reduction in
the relative risk of proximal deep vein thrombosis (absolute difference, 3.0%; P = .01).16 Finally, our
data indicate that the safety of the 24-mg dose of ximelagatran and enoxaparin
(both started after surgery) appears to be comparable, with similar rates
of bleeding complications and blood loss, and similar transfusion requirements.
It is unlikely that the results of this study are due to bias. The treatment
groups had similar demographic and surgical characteristics. The efficacy
outcomes were determined by objective testing and were interpreted centrally
by experts who were blinded to treatment assignment. Unlike in total hip replacement,
deep vein thrombosis seldom occurs in the nonoperative leg after total knee
replacement.1 Therefore, we performed unilateral
venography of only the operative leg to avoid the additional contrast dye
volume from bilateral venography. The safety outcomes (eg, major and minor
bleeding) were also based on objective measures of hemoglobin change and transfusion
requirement. Moreover, the 4 ximelagatran groups were blinded, and all major
bleeding events were adjudicated centrally. The distribution of total study
medication doses was similar among treatment groups, and the results of the
per-protocol analysis were entirely consistent with those of the intention-to-treat
analysis.
In summary, oral administration of ximelagatran after surgery and continued
for at least 6 to 12 days appears to be safe and effective as prophylaxis
against venous thromboembolism after total knee replacement surgery. This
was accomplished without laboratory monitoring of the intensity of ximelagatran
anticoagulation or adjustment of the ximelagatran dose. Of the 4 postoperative
oral ximelagatran dose regimens tested, we believe that the most effective
is 24 mg twice daily; this regimen appears to provide at least comparable
efficacy and safety to postoperative low-molecular-weight heparin prophylaxis.
This hypothesis requires further testing in a phase 3 clinical trial.
AUTHOR INFORMATION
Accepted for publication June 11, 2001.
This study was supported by a grant from AstraZeneca LP.
We are indebted to the members of the surgical, nursing, pharmacy, and
support staff of all the study sites. The members of the Safety Committee
were Bruce Davidson, MD, Jack Hirsh, MD, and Robin Roberts.
| The AstraZeneca Arthroplasty Study Group
Jack Ansell, MD, Boston Medical Center, Boston, Mass; Stephen Bartol,
MD, Group North Windsor, Windsor, Ontario; William J. Bose, MD, Alabama Orthopedics,
Mobile; Timothy J. Bray, MD, Reno Orthopedic Clinic, Reno, Nev; Frank A. Burke,
MD, Bluegrass Orthopaedics, Lexington, Ky; Humayun Mahmood Cheema, MD, Saint
Barnabas Medical Center, Livingston, NJ; Clifford W. Colwell, Jr, MD, Scripps
Clinic, La Jolla, Calif; Larry D. Cordell, MD, Overland Park, Kan; Francisco
Cordova, MD, Southwest Clinical Research, Inc, Phoenix, Ariz; Mark A. Crowther,
MD, FRCPC, St Joseph's Hospital, Hamilton, Ontario; Victor deKorompay, MD,
FRSC, Manitoba Clinic, Winnipeg; David Drucker, MD, Staten Island University
Hospital, Staten Island, NY; Karen Duane, MD, James A. Haley Veterans Hospital,
Tampa, Fla; Gerald Dugan, MD, Kansas City, Mo; Donald G. Eckhoff, MD, Denver,
Colo; Roger H. Emerson, Jr, MD, Texas Center for Joint Replacement, Plano,
Tex; Bradley A. Fink, DO, Lower Bucks Orthopedic Group, Penndel, Pa; James
Sidney Finley III, MD, Green Clinic, Ruston, La; Charles W. Francis, MD, University
of Rochester Medical Center, Rochester, NY; Richard J. Friedman, MD, Department
of Orthopedic Surgery–Medical University of South Carolina, Charleston,
SC; Gurdev S. Gill, MD, Lubbock, Tex; Ian L. Gordon, MD, PhD, VA Long Beach
Healthcare System, Long Beach, Calif; John A. Heit, MD, Mayo Clinic, Rochester,
Minn; Steven F. Hoff, MD, Hill Top Research Inc, Portland, Ore; Michael G.
Hogan, MD, Cumming, Ga; Joseph J. Jankiewicz, MD, San Diego, Calif; Maurice
Jove, MD, Decatur, Ga; Joshua Kimelman, DO, Iowa Orthopedic Center, Des Moines;
William Lanzer, MD, Seattle, Wash; Paul Lotke, MD, Department of Orthopaedic
Surgery, Hospital of the University of Pennsylvania, Philadelphia; Terence
J. Matthews, MD, PA, Orthopaedic Associates Building, Ft Lauderdale, Fla;
Leon Mead, MD, Anchor Research Center, Naples, Fla; Ram Mudiyam, MD, Fountain
Valley, Calif; S. Curtiss Mull, MD, Lewis-Gale Clinic, Salem, Va; William
J. Navigato, MD, Riverside, Calif; Paul Nicholls, MD, Lexington, Ky; Jill
Ohar, MD, Saint Louis University Health Sciences Center, St Louis, Mo; David
Puskas, MD, Thunder Bay, Ontario; Hubert Riegler, MD, Lattimore Orthopedics,
Rochester, NY; Ronald Romanelli, MD, Orthopedic Center of Illinois, Springfield;
Aaron G. Rosenberg, MD, Midwest Orthopedics, Chicago, Ill; Robert Schmidt,
MD, PA, Fort Worth, Tex; Howard Schuele, MD, Clearwater, Fla; Mahipal M. Shah,
MD, Pomona, Calif; Sami Srour, MD, Bakersfield, Calif; Daniel M. Stormont,
MD, Monroe, Wis; James A. St. Ville, MD, Phoenix; Paul D. Stein, MD, Henry
Ford Health System, Detroit, Mich; Randall Suarez, MD, Hill Top–MedQuest
Research Inc, Greer, SC; Linda Vickars, MD, Vancouver, British Columbia; Philip
Wells, MD, Ottawa Hospital, Civic Parkdale Clinic, Ottawa, Ontario; Gregory
Wise, MD, Kettering, Ohio; Arnold A. Yashar, MD, Louisville, Ky; Rick Zarnett,
MD, MSc, FRCSC, North York, Ontario; and Joseph Zucker, MD, Nalle Clinic,
Charlotte, NC.
|
|
Corresponding author: John A. Heit, MD, Hematology Research, Plummer
549, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
From the Division of Cardiovascular Diseases, Mayo Clinic and Mayo
Foundation, Rochester, Minn (Dr Heit); the Department of Orthopedic Surgery,
Scripps Clinic, La Jolla, Calif (Dr Colwell); the Department of Medicine,
University of Rochester Medical Center, Rochester, NY (Dr Francis); the Division
of Hematology, McMaster University, Hamilton, Ontario (Dr Ginsberg); and AstraZeneca
LP, Wayne, Pa (Drs Berkowitz and Peters and Mr Whipple).
REFERENCES
| |
1. Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest. 2001;119(suppl):132S-175S.
2. 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.
ISI
| PUBMED
3. RD Heparin Arthroplasty Group. RD heparin compared with warfarin for prevention of venous thromboembolic
disease following total hip or knee arthroplasty. J Bone Joint Surg Am. 1994;76:1174-1185.
FREE FULL TEXT
4. Leclerc JR, Geerts WH, Desjardins L, et al. Prevention of venous thromboembolism after knee arthroplasty: a randomized,
double-blind trial comparing enoxaparin with warfarin. Ann Intern Med. 1996;124:619-626.
FREE FULL TEXT
5. Heit JA, Berkowitz SD, Bona R, et al. Efficacy and safety of low molecular weight heparin (ardeparin sodium)
compared to warfarin for prevention of venous thromboembolism following total
knee replacement: a double-blind, dose-ranging study. Thromb Haemost. 1997;77:32-38.
ISI
| PUBMED
6. Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin
III but is susceptible to inactivation by antithrombin III–independent
inhibitors. J Clin Invest. 1990;86:385-391.
7. Eriksson BI, Ekman S, Lindbratt S, et al. Prevention of thromboembolism with use of recombinant hirudin. J Bone Joint Surg Am. 1997;79:326-333.
FREE FULL TEXT
8. Horlocker T, Heit JA. Low molecular weight heparin: biochemistry, pharmacology, perioperative
prophylaxis regimens, and guidelines for regional anesthetic management. Anesth Analg. 1997;85:874-885.
FULL TEXT
|
ISI
| PUBMED
9. Eriksson BI, Lindbratt S, Kälebo P, et al. METHRO II: dose-response study of the novel oral, direct thrombin inhibitor,
H376/95, and its subcutaneous formulation melagatran, compared with dalteparin
as thromboembolic prophylaxis after total hip or total knee replacement. Haemostasis. 2000;30(suppl 1):20-21.
10. Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg. 1972;104:134-144.
ISI
| PUBMED
11. Kälebo P, Ekman S, Lindbratt S, et al. Percentage of inadequate phlebograms and observer agreement in thromboprophylactic
multicenter trials using standardized methodology and central assessment. Thromb Haemost. 1996;76:893-896.
ISI
| PUBMED
12. Hull RD, Hirsh J, Carter CJ. Pulmonary angiography, ventilation lung scanning and venography for
clinically suspected pulmonary embolism with abnormal lung scan. Ann Intern Med. 1983;98:891-899.
13. Margolin BH. Test for trend in proportions. In: Kotz S, Johnson NL, eds. Encyclopedia of Statistical
Sciences. Vol 9. New York, NY: John Wiley & Sons Inc; 1988:334-336.
14. Ginsberg JS, Nurmohamed MT, Gent M, et al. Use of hirulog in the prevention of venous thrombosis after major hip
or knee surgery. Circulation. 1994;90:2385-2389.
FREE FULL TEXT
15. Eriksson BI, Ekman S, Kälebo P, Cachrisson B, Bach D, Close P. Prevention of deep-vein thrombosis after total hip replacement: direct
thrombin inhibition with recombinant hirudin, CGP 39393. Lancet. 1996;347:635-639.
FULL TEXT
|
ISI
| PUBMED
16. Eriksson BI, Wille-Jørgensen P, Kälebo P, et al. A comparison of recombinant hirudin with low-molecular-weight heparin
to prevent thromboembolic complications after total hip replacement. N Engl J Med. 1997;337:1329-1335.
FREE FULL TEXT
RELATED ARTICLE
Archives of Internal Medicine Reader's Choice: Continuing Medical Education
Arch Intern Med. 2001;161(18):2271-2272.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Total Knee Arthroplasty
Lassen et al.
NEJM 2008;358:2776-2786.
ABSTRACT
| FULL TEXT
Prevention of Venous Thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Geerts et al.
Chest 2008;133:381S-453S.
ABSTRACT
| FULL TEXT
Antithrombotic Therapy in Atrial Fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Singer et al.
Chest 2008;133:546S-592S.
ABSTRACT
| FULL TEXT
Lower limb contrast venography: a modified technique for use in thromboprophylaxis clinical trials for the accurate evaluation of deep vein thrombosis
Sidhu et al.
Br. J. Radiol. 2007;80:859-865.
ABSTRACT
| FULL TEXT
Review: New anticoagulants: a story of promise and disappointment
Watson and Greaves
British Journal of Diabetes & Vascular Disease 2007;7:51-58.
ABSTRACT
A Preliminary Assessment of the Critical Differences Between Novel Oral Anticoagulants Currently in Development
McBride
J Clin Pharmacol 2005;45:1004-1017.
ABSTRACT
| FULL TEXT
Ximelagatran: An orally active direct thrombin inhibitor
Gulseth
Am J Health Syst Pharm 2005;62:1451-1467.
ABSTRACT
| FULL TEXT
Neuraxial Anesthesia and Low-Molecular-Weight Heparin Prophylaxis in Major Orthopedic Surgery in the Wake of the Latest American Society of Regional Anesthesia Guidelines
Rowlingson and Hanson
Anesth. Analg. 2005;100:1482-1488.
ABSTRACT
| FULL TEXT
Ximelagatran--Promises and Concerns
Gurewich
JAMA 2005;293:736-739.
FULL TEXT
Ximelagatran: Oral direct thrombin inhibition as anticoagulant therapy in atrial fibrillation
Halperin
J Am Coll Cardiol 2005;45:1-9.
ABSTRACT
| FULL TEXT
Ximelagatran: An Oral Direct Thrombin Inhibitor
Dager et al.
The Annals of Pharmacotherapy 2004;38:1881-1897.
ABSTRACT
| FULL TEXT
Prevention of Venous Thromboembolism: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy
Geerts et al.
Chest 2004;126:338S-400S.
ABSTRACT
| FULL TEXT
Antithrombotic Therapy in Atrial Fibrillation: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy
Singer et al.
Chest 2004;126:429S-456S.
ABSTRACT
| FULL TEXT
Ximelagatran: A New Antithrombotic Option in Atrial Fibrillation
Dager
J CARDIOVASC PHARMACOL THER 2004;9:151-162.
ABSTRACT
Relationship Between Deep Venous Thrombosis and the Postthrombotic Syndrome
Kahn and Ginsberg
Arch Intern Med 2004;164:17-26.
ABSTRACT
| FULL TEXT
Direct Thrombin Inhibitors for Anticoagulation
Nutescu and Wittkowsky
The Annals of Pharmacotherapy 2004;38:99-109.
ABSTRACT
| FULL TEXT
Thrombophilia and New Anticoagulant Drugs
Weitz et al.
ASH Education Book 2004;2004:424-438.
ABSTRACT
| FULL TEXT
Comparison of Ximelagatran with Warfarin for the Prevention of Venous Thromboembolism after Total Knee Replacement
Francis et al.
NEJM 2003;349:1703-1712.
ABSTRACT
| FULL TEXT
Secondary Prevention of Venous Thromboembolism with the Oral Direct Thrombin Inhibitor Ximelagatran
Schulman et al.
NEJM 2003;349:1713-1721.
ABSTRACT
| FULL TEXT
Emerging Anticoagulant Drugs
Bates and Weitz
Arterioscler. Thromb. Vasc. Bio. 2003;23:1491-1500.
ABSTRACT
| FULL TEXT
The Potential Role of Direct Thrombin Inhibitors in the Prevention and Treatment of Venous Thromboembolism
Heit
Chest 2003;124:40S-48S.
ABSTRACT
| FULL TEXT
Ximelagatran versus warfarin forstroke prevention in patientswith nonvalvular atrial fibrillation: SPORTIF ii: a dose-guiding, tolerability, and safety study
Petersen et al.
J Am Coll Cardiol 2003;41:1445-1451.
ABSTRACT
| FULL TEXT
Management of Venous Thromboembolism: Past, Present, and Future
Hyers
Arch Intern Med 2003;163:759-768.
ABSTRACT
| FULL TEXT
Absorption, Distribution, Metabolism, and Excretion of Ximelagatran, an Oral Direct Thrombin Inhibitor, in Rats, Dogs, and Humans
Eriksson et al.
Drug Metab. Dispos. 2003;31:294-305.
ABSTRACT
| FULL TEXT
Consultations on Patients with Venous or Arterial Diseases
Alving et al.
ASH Education Book 2003;2003:540-558.
ABSTRACT
| FULL TEXT
Ximelagatran versus Warfarin for the Prevention of Venous Thromboembolism after Total Knee Arthroplasty: A Randomized, Double-Blind Trial
Francis et al.
ANN INTERN MED 2002;137:648-655.
ABSTRACT
| FULL TEXT
How we diagnose and treat deep vein thrombosis
Hirsh and Lee
Blood 2002;99:3102-3110.
ABSTRACT
| FULL TEXT
|
