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Prolonged Thromboprophylaxis With Oral Anticoagulants After Total Hip Arthroplasty
A Prospective Controlled Randomized Study
Paolo Prandoni, MD, PhD;
Olinto Bruchi, MD;
Paola Sabbion, MD;
Cinzia Tanduo, MD;
Alberta Scudeller, MD;
Corrado Sardella, MD;
Gabriella Errigo, MD;
Francesco Pietrobelli, MD;
Gianni Maso, MD;
Antonio Girolami, MD
Arch Intern Med. 2002;162:1966-1971.
ABSTRACT
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Background The optimal duration of thromboprophylaxis after major orthopedic surgery
is controversial. Although oral anticoagulants are still widely used for the
prevention of venous thromboembolism after hip replacement, to our knowledge
no study has assessed the benefit of prolonging anticoagulation beyond the
hospital stay.
Methods Consecutive patients who had received warfarin sodium prophylaxis after
total hip arthroplasty were randomized to stop taking the drug at the time
of hospital discharge or to continue taking it for 4 more weeks. The rate
of symptomatic and asymptomatic venous thromboembolic events (as shown by
compression ultrasonography of the proximal-vein system) occurring during
the study period was compared between the 2 groups. The study was prematurely
terminated after the inclusion of the first 360 patients because a statistically
significant and clinically relevant superiority of extended over short-term
thromboprophylaxis was observed.
Results Objectively confirmed venous thromboembolic complications were recorded
in 10 patients: 9 (5.1%) in the group of 176 control patients, and 1 (0.5%)
in the group of 184 patients who continued the warfarin treatment. The absolute
difference in the incidence of events was 4.57% (95% confidence interval [CI],
1.15-7.99). The relative risk of venous thromboembolism developing in control
patients compared with patients assigned to extended thromboprophylaxis was
9.4 (95% CI, 1.2-73.5). The number needed to treat was 22. Major bleeding
developed in 1 patient who was randomized to the extended prophylaxis group
(0.5%; 95% CI, 0.02-3.0) compared with none in the control group.
Conclusion Extending prophylaxis with warfarin for a few more weeks beyond the
hospital stay has the potential to considerably improve the outcome of patients
who undergo hip arthroplasty.
INTRODUCTION
DESPITE ADEQUATE antithrombotic prophylaxis, more than 15% of patients
who undergo total hip arthroplasty still develop (mostly asymptomatic) postoperative
deep venous thrombosis (DVT) of the legs, as shown by bilateral ascending
phlebography performed at the time of hospital discharge.1
Although most of these thrombi are confined to the calf vein system, approximately
10% involve the proximal veins and therefore carry the potential risk of later
complications.2
Concern about the risk of pulmonary embolism (PE) developing as a result
of asymptomatic DVT has led investigators and clinicians to consider extending
the duration of postoperative prophylaxis for up to 6 weeks after hospital
discharge in all patients who undergo hip arthroplasty.3-9
Despite minor variations in design and results, the findings of these randomized
studies are consistent in showing that prolonged thromboprophylaxis with unfractionated9 or low-molecular-weight heparin (LMWH)3-8
decreases the frequency of venographically detected DVT by approximately 50%
without enhancing the hemorrhagic risk.
Despite the increasing availability of LMWHs, oral anticoagulants are
still widely used for the prevention of postoperative DVT in patients who
have undergone major orthopedic surgery.1 However,
unlike LMWHs, which have been studied extensively, oral anticoagulants have
not been the subject of controlled studies to assess the benefit of prolonging
anticoagulation beyond the hospital stay. We therefore undertook a prospective
controlled study of patients who received warfarin sodium prophylaxis after
undergoing total hip arthroplasty. Patients free from proximal vein thrombosis,
as assessed by an ultrasound examination at the time of hospital discharge,
were randomized to discontinue taking the drug or to continue taking it for
4 more weeks. The main study outcome was to compare the rate of symptomatic
and asymptomatic thromboembolic events that occurred during this period. Also,
we tried to identify clinical parameters associated with the development of
late postoperative thromboembolism. The study was prematurely terminated after
the inclusion of 360 patients because a statistically significant and clinically
relevant superiority of extended thromboprophylaxis over short-term thromboprophylaxis
was observed.
PATIENTS AND METHODS
This trial was conducted at the University Hospital of Padua, Padua,
Italy, from September 1998 to December 2000. The research protocol was approved
by the local ethics board.
STUDY POPULATION
Consecutive patients who underwent elective total hip arthroplasty and
received warfarin prophylaxis during hospitalization were potentially eligible
for the study provided they had not undergone previous hip surgery on the
same side or did not have a history of thromboembolic disorders. Eligible
patients received 5 mg/d of sodium warfarin starting on the second preoperative
day; after the intervention, the dosage was adjusted to increase the international
normalized ratio (INR) between 2.0 and 3.0. Eligible patients were excluded
from the study if they developed venous thromboembolic complications or major
bleeding during hospitalization. Patients with asymptomatic proximal DVT,
as shown by a bilateral compression ultrasound (CUS) examination performed
before hospital discharge, were also excluded, as were those who needed long-term
anticoagulation, were unavailable for long-term follow-up, or refused to give
their written informed consent.
BASELINE CUS AND RANDOMIZATION
Compression ultrasound examination was performed with a high-resolution
echo-color Doppler ultrasound system (Acuson XP 128; Ambassador Medical Inc,
Carmel, Ind) with 7.5- and 5-MHz probes. Of the proximal deep venous system,
the common femoral vein, the superficial femoral vein at the mid thigh, and
the popliteal vein up to its trifurcation into the calf veins were evaluated
for compressibility. The results of CUS were classified as diagnostic of proximal
vein thrombosis in case of vein incompressibility. In patients with positive
test results, anticoagulant treatment was continued for 3 months.
A careful history detailing the presence of risk factors for DVT was
obtained from all consenting patients with a normal CUS test result at baseline;
then, according to a list generated by a computer, the patients were randomly
assigned to discontinue oral anticoagulant therapy or to continue it for 4
more weeks, with the dosage adjusted to maintain the INR between 2.0 and 3.0.
FOLLOW-UP
After randomization, the patients were discharged and were invited to
return for clinical and ultrasound examinations after 1, 2, and 4 weeks. During
each follow-up examination, bilateral CUS was performed and the results were
interpreted using the criteria that had been adopted at baseline by an operator
who was totally blind to the patients' details and study arm. After discharge,
the patients who were randomized to the extended-therapy group were encouraged
to have their INR blood testing performed once a week, or more frequently
in case of inadequate anticoagulation, at the local anticoagulation surveillance
center, where dedicated and trained physicians, with the help of computer-assisted
programs, could provide a high standard of care. After the completion of the
first 4 weeks of therapy, the patients were clinically followed up for 2 more
months.
The patients were asked to present immediately for medical attention
if signs or symptoms of venous thromboembolism developed. Venous thromboembolism
was considered present if (1) symptomatic DVT was confirmed by new abnormalities
observed on CUS or by an intraluminal filling defect on ascending phlebography;
(2) symptomatic PE was confirmed by a high-probability ventilation-perfusion
lung scan, a spiral computed tomographic scan, or an abnormal finding on angiography;
or (3) (in case of death) PE was confirmed by autopsy or could not be ruled
out. Any major bleeding event occurring in the study patients was recorded.
Bleeding was defined as major if it (1) was clinically overt and associated
with either a decrease in hemoglobin of at least 2.0 g/dL or a need for a
transfusion of 2 or more units of red blood cells; (2) was intracranial or
retroperitoneal; or (3) resulted in the permanent discontinuation of anticoagulation.
In case of death, the cause of death was either investigated by autopsy or
adjudicated according to the opinion of a physician who was unaware of the
study aims. Information on all suspected (both asymptomatic and symptomatic)
outcome events was reviewed and classified by an independent adjudication
committee whose members were unaware of the treatment assignment.
STUDY OUTCOMES AND ANALYSIS
The main aim of the study was to compare the efficacy of the 2 treatment
strategies regarding a composite outcome of symptomatic venous thromboembolic
complications and asymptomatic proximal DVT occurring during the first 4 weeks
of follow-up. Furthermore, we determined the efficacy of the 2 treatment strategies
during the complete 3-month follow-up period. Finally, we assessed the association
of a number of clinical parameters (eg, age, sex, obesity, prolonged immobilization,
length of hospital stay, quality of in-hospital anticoagulation, and presence
of varicose veins, cancer, heart/lung failure, and estrogen therapy) with
the development of late postoperative thromboembolism.
Based on the results of a previous study that suggested that withholding
extended thromboprophylaxis from patients who received warfarin treatment
during hospitalization was safe provided they had negative results on bilateral
ultrasound examination before discharge,10
the present study was designed to demonstrate the equivalence between the
2 study groups. We calculated that approximately 600 patients per group would
be required to demonstrate equivalence between the 2 study groups. The study
was prematurely terminated by the steering committee after the inclusion of
the first 360 patients because of the finding of an unexpected statistically
significant and clinically relevant superiority of extended thromboprophylaxis
over short-term thromboprophylaxis.
The efficacy analysis was intention-to-treat and included all patients
who were randomly assigned to either strategy. We determined the proportion
of patients who developed DVT in each group, as well as the absolute difference
between proportions and its 95% confidence intervals (CIs). We calculated
the relative risk (RR) for the development of thromboembolic complications
(and its 95% CIs) by dividing the incidence rate in the control group by the
incidence rate in the warfarin group. The RR was considered to be statistically
significant when the lower limit of the 95% CI was greater than 1.0. Also,
we calculated the number needed to treat to prevent 1 thromboembolic event.
Odds ratios (ORs) and their 95% CIs were used to describe the association
between clinical variables and postoperative thromboembolism. An OR was considered
to be statistically significant when the lower limit of the 95% CI was greater
than 1.0. For the comparison of patient characteristics at the time of study
entry, we used the  2 test for qualitative variables and the t test for quantitative variables. The 95% CIs and P values were calculated according to the normal approximation
of the binomial distribution. The individual quality of warfarin anticoagulation
was considered high if the INR was within or above the therapeutic range in
more than 70% of determinations.
RESULTS
STUDY POPULATION
Over the 27-month recruitment period, 383 eligible patients underwent
hip arthroplasty at St Anthony Hospital, Padua. Eighteen patients were excluded
from enrollment because of the development of venous thromboembolic complications2 or major bleeding1
during hospitalization, detection of an asymptomatic proximal DVT before hospital
discharge,10 need for long-term anticoagulation,1 and unavailability for long-term follow-up.4 Of the remaining 365 patients, 5 refused to give their
informed consent. Therefore, 360 patients were randomized to discontinue anticoagulant
therapy (n = 176) or to continue it for 4 more weeks (n = 184). The main demographic
and clinical characteristics of the study patients are shown in Table 1. No appreciable differences were observed between the warfarin
group and the control group.
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Table 1. Characteristics of Study Patients*
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No patient was unavailable for clinical follow-up. Three patients per
group violated the protocol. In the control group, 2 patients resumed anticoagulant
therapy (because of a reintervention and the identification of atrial fibrillation,
respectively), and the third refused to undergo the serial ultrasound examinations.
In the oral anticoagulant group, 2 patients stopped taking warfarin after
a short period (one of them without valid reasons, and the other because of
a reintervention), and the third patient did not undergo the serial ultrasound
examinations. In the group of patients who were randomized to continue warfarin
treatment, the quality of oral anticoagulation was satisfactory, being high
in 131 (72%) of the 182 patients who completed the 4-week period of extended
prophylaxis.
VENOUS THROMBOEMBOLISM
During the first 4 weeks of follow-up, objectively confirmed venous
thromboembolic complications were recorded in 10 patients: 9 (5.1%) of the
176 control patients, and 1 (0.5%) of the 184 patients who continued the warfarin
treatment. The absolute difference in the incidence of events was 4.57% (95%
CI, 1.15-7.99). The RR of venous thromboembolism developing in control patients
compared with patients assigned to extended thromboprophylaxis was 9.4 (95%
CI, 1.2-73.5). The number needed to treat was 22. Of the 9 events observed
in the control group, 4 were symptomatic (proximal DVT in 3 patients, and
PE in 1 patient), while the remaining 5 were asymptomatic (Table 2). The only event observed in the warfarin group was an asymptomatic
proximal DVT recorded after 4 weeks.
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Table 2. Venous Thromboembolic Complications During the Study Period
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In the following 2 months, 2 more symptomatic events were recorded,
both of them in patients who had received prolonged thromboprophylaxis. The
RR of objectively confirmed venous thromboembolism developing in control patients
compared with patients assigned to extended thromboprophylaxis during the
whole 3-month follow-up period was still substantial, albeit nonsignificant
(RR, 3.1; 95% CI, 0.9-11.4).
MAJOR BLEEDING
Of the 184 patients randomized to extended prophylaxis, 1 developed
major (retroperitoneal) bleeding after 3 weeks of warfarin therapy. The INR
at the time of the bleeding exceeded by far the upper limit of the targeted
range (INR, 5.9). Therefore, the frequency of major bleeding in the group
of patients who were randomized to prolonged prophylaxis was 0.5% (95% CI,
0.02-3.0). No control patients developed hemorrhagic disorders during the
study period.
OTHER EVENTS
No patient died during the follow-up period or experienced any other
adverse event potentially related to the study drug.
PARAMETERS ASSOCIATED WITH LATE VENOUS THROMBOEMBOLISM
Of the tested parameters, only old age (8 of the 9 patients who developed
venous thromboembolism compared with 77 of the 167 patients who did not [OR,
9.35; 95% CI, 1.14-76.4]) and varicose veins (4 of the 9 patients who developed
venous thromboembolism compared with 10 of the 167 patients who did not [OR,
12.6; 95% CI, 2.9 -54.2]) were found to be associated with the development
of late postoperative thromboembolism in the control patients, whereas the
others were not.
COMMENT
The optimal duration of thromboprophylaxis after major orthopedic surgery
is controversial.1 Although recent clinical
trials have consistently demonstrated that, at least in hip replacement surgery,
prolonging prophylaxis with LMWH for a few more weeks after hospital discharge
considerably reduces the incidence of venographically detected DVT,3-9
several cohort and randomized studies have shown that the rate of late symptomatic
venous thromboembolic complications in patients who receive proper LMWH prophylaxis
during hospital stay after major orthopedic surgery is acceptably low.11-15
It should be noted, however, that according to the results of 2 recent meta-analyses
of comparative studies, prolonging thromboprophylaxis is also likely to lower
the rate of late symptomatic clinical events.16-17
As this strategy does not appreciably enhance the risk of major bleeding,3-9
it has the potential to offer a better perspective than prophylaxis administered
only during hospital stay.
Despite the growing availability of LMWHs, oral anticoagulants are still
widely used for prophylaxis of postoperative DVT in patients who have undergone
major orthopedic surgery.1, 18
Although they have been reported to be less effective than LMWHs for the prevention
of DVT as detected by venography,7, 19-22
no difference has been observed between the 2 therapeutic strategies in terms
of clinically symptomatic end points in either the hospital stay or the long-term
follow-up after hospitalization.7, 13, 19-23
Also, oral anticoagulants are associated with a lower hemorrhagic risk7, 13, 19-23
and are likely to be more cost-effective than LMWHs for this indication, at
least in the United States.24 Finally, in a
recent retrospective case-control survey of a wide series of patients drawn
from the California Medicare records, the use of warfarin after discharge
from the hospital was found to be independently associated with a significant
protection against rehospitalization for symptomatic thromboembolism after
total hip surgery.25 Unlike LMWHs, which have
been studied extensively, however, oral anticoagulants have not been the subject
of controlled studies assessing the benefit of prolonging anticoagulation
beyond the hospital stay.
The results of our prospective randomized study strongly suggest that
in patients who undergo hip surgery and who are treated with warfarin during
hospitalization (9 days on average), prolonging the administration of the
drug for 4 weeks beyond hospital discharge significantly reduces the incidence
of late venous thromboembolic complications without enhancing the hemorrhagic
risk compared with prophylaxis that is administered only during the hospital
stay. Although patients with asymptomatic proximal DVT, as assessed by ultrasonography
before discharge, were excluded from randomization, the rate of venous thromboembolism
in the control group during the first 4 weeks (5.1%) was approximately 10
times as high as that observed in the warfarin group (0.5%), accounting for
a statistically significant RR (9.4; 95% CI, 1.2-73.5). According to these
results, only 22 patients need to be treated to prevent 1 episode of venous
thromboembolism. It is worthy of mention that of the 9 observed events in
the control group, 4 were symptomatic (including an episode of PE), whereas
only 1 episode of asymptomatic DVT was observed in the warfarin group. Also,
only 1 patient in the warfarin group (0.5%) experienced major bleeding.
Because the clinical follow-up evaluation after the first 4 weeks of
observation disclosed 2 additional episodes of symptomatic thromboembolism,
both of them in the group of patients who had received 1 month of warfarin
therapy (Table 2), we cannot exclude
the possibility that anticoagulant therapy for an even longer period (for
8-12 weeks after surgery) might further improve the clinical outcome of patients
after hip surgery. The benefit-risk ratio of such an extensive regimen of
prophylaxis should be properly investigated.
The results of the present study are apparently in striking contrast
to those recently demonstrated in a cohort of patients who were followed up
prospectively at our institution after receiving a warfarin thromboprophylaxis
during their hospital stay.10 After excluding
from follow-up patients with a negative ultrasound test result before discharge,
we recorded only 2 asymptomatic cases of proximal DVT in a series of 193 (1.0%)
consecutive patients who underwent hip surgery and who were treated with warfarin
during hospitalization. It should be noted, however, that the length of hospital
stay in the current investigation (9 days on average) was considerably shorter
than that observed in our previous study (18 days on average). The unusually
long hospital stay and duration of anticoagulation in the patients who were
enrolled in our previous study most likely accounted for the low rate of subsequent
cases of thromboembolism, a finding that is fully consistent with that observed
in the patients who were randomized to the extended-prophylaxis group in the
current investigation.
The low rate of venous thromboembolism in patients who were randomized
to the warfarin group is at variance with that observed by Caprini et al26 in their recent cohort study. Of 125 patients who
underwent a total hip replacement and received warfarin therapy until 1 month
after surgery, more than 10% developed proximal DVT (which was mostly asymptomatic),
as assessed by duplex ultrasonography. However, in their study, a remarkably
high proportion of patients failed to reach a therapeutic INR, which is in
contrast to our results. Therefore, effective monitoring and dosage adjustment
of warfarin therapy constitute an important component of the success of prolonged
warfarin prophylaxis in major orthopedic surgery.
For the purpose of our study, we used a composite outcome of symptomatic
and asymptomatic venous thromboembolic complications. The introduction in
the last 2 decades of the use of ascending phlebography as a diagnostic tool
for the detection of postoperative DVT in high-risk surgical patients has
led to the demonstration of (asymptomatic) thrombosis in up to 15% of patients
who undergo total hip arthroplasty.1 Most of
those thrombi probably carry a low risk of complications, as several clinical
studies have consistently reported an acceptably low rate of symptomatic thromboembolic
events in the follow-up of patients who received their antithrombotic protection
only during hospitalization.11-15
If this is likely to be true for isolated calf vein thrombi, which form the
large majority of postoperative thromboses, we suspect that this is not the
case for proximal vein thrombosis, which was the target of our investigation.
We thought it important to document the asymptomatic involvement of the proximal
vein system, because in patients with previously unaffected deep veins (as
in our investigation) the involvement of the popliteal and particularly the
common femoral veins is an essential requirement for the development of more
serious complications, such as fatal or nonfatal PE. It is interesting to
note that in the group of patients who were treated with prolonged warfarin
therapy, in whom no symptomatic events developed during the 4-week follow-up
period, only 1 case of asymptomatic proximal DVT was recorded, which contrasts
with findings observed in the control group (4 symptomatic events and 5 cases
of asymptomatic proximal DVT). We believe that every future study that addresses
the prevention of DVT in high-risk surgical patients should rely on either
systematic bilateral phlebography or a combination of clinically symptomatic
events and bilateral assessment of the proximal vein system.
Despite the early termination of the study and the relatively low number
of patients who were enrolled in the current investigation, old age and varicose
veins were found to be significantly associated with the development of late
venous thromboembolism. These findings, along with those detected by White
et al25 (ie, obesity and previous thromboembolism)
in their retrospective study of a large number of patients, may help identify
patients who could benefit from prolonged anticoagulation to reduce the incidence
of thromboembolism after hip arthroplasty.
We are aware of at least 4 potential limitations of our study. First,
our study, as well as others involving oral anticoagulants, was not a placebo-controlled
double-blind trial. However, our findings are likely to be valid because a
number of measures were taken to avoid bias: (1) inclusion of consecutive
patients; (2) follow-up of all randomized patients; (3) central adjudication
of all outcome events by a committee whose members were unaware of the treatment
assigned; (4) assessment of venous thromboembolism and episodes of bleedings
on the basis of objective predetermined criteria; and (5) inclusion of all
randomized patients in the study analysis. Second, the sensitivity of CUS
for detection of postoperative symptomless DVT is generally considered low.27-28 The use of this technique might have
resulted in the recruitment of patients with (asymptomatic) DVT not detected
by CUS, as well as in the underestimation of thrombotic episodes in the 4
weeks of follow-up in each patient group. However, the sensitivity of this
diagnostic technique for the development of thrombosis involving the proximal
vein system in orthopedic patients has been found to be acceptably high.27, 29 Also, as we used the same follow-up
procedure in both patient groups, the RR of developing thrombotic complications
(as predefined by us) in the control group compared with the warfarin group
is likely to be valid. Third, the complete identification of clinical parameters
associated with the development of late postoperative thromboembolism after
total hip replacement was hindered by the early termination of the study and
the relatively small number of patients available for this potentially important
calculation. Fourth, as we did not enroll patients who were candidates for
major knee surgery, we do not know whether our conclusions would also be applicable
to this category of patients, who might differ in this regard from patients
who undergo hip surgery.8, 18
In conclusion, extending prophylaxis with warfarin for a few weeks beyond
the hospital stay has the potential to considerably improve the outcome of
patients who undergo hip arthroplasty. Further studies are needed to better
identify predictors of late postoperative thromboembolism after major orthopedic
surgery, which might enable physicians to target those patients who would
benefit the most from extended prophylaxis.
AUTHOR INFORMATION
Accepted for publication January 31, 2002.
Corresponding author: Paolo Prandoni, MD, PhD, Department of Medical
and Surgical Sciences, Second Chair of Internal Medicine, University Hospital
of Padua, Via Ospedale Civile 105, 35128 Padua, Italy (e-mail: paoprand{at}tin.it).
From the Department of Medical and Surgical Sciences, Second Chair
of Internal Medicine (Drs Prandoni, Sabbion, Tanduo, Scudeller, Sardella,
Errigo, Pietrobelli, and Girolami), and the Orthopaedic Department and Unit
Care of Anesthesiology, St Anthony Hospital, University Hospital of Padua
(Drs Bruchi and Maso), Padua, Italy.
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