Abstract
Background: Although the risk of thromboembolism after total hip
arthroplasty continues beyond hospital discharge, the cost-effectiveness of
extending prophylaxis beyond hospitalization is unclear. We compared the
cost-effectiveness of an extended duration of antithrombotic prophylaxis
following total hip arthroplasty, with use of low-molecular-weight heparin or
warfarin administered for twenty-eight days beyond hospital discharge, in
terms of incremental cost per quality-adjusted life year gained.
Methods: The economic analysis was structured around a decision tree
characterizing the consequences of extended prophylaxis choices following
total hip arthroplasty. The health benefits of extended antithrombotic
prophylaxis, measured as the reduction in symptomatic venous thromboembolic
events and deaths for each treatment alternative, were determined through a
systematic review of the literature. Gains in quality-adjusted life years were
based on the distribution of life years remaining for all patients undergoing
total hip arthroplasty in Canada in 2003, weighted by utilities derived from
the literature. The cost analysis, in 2006 Canadian dollars, took a direct
payer perspective with a ninety-day time horizon.
Results: There was a net gain in quality-adjusted life years in both
cohorts that received extended prophylaxis relative to the cohort that
received no extended prophylaxis (7.5 quality-adjusted life years per 1000
patients treated with low-molecular-weight heparin and 5.5 quality-adjusted
life years per 1000 patients treated with warfarin), although these gains were
not significant. The net treatment costs per 1000 patients treated were
$799,104 with low-molecular-weight heparin and $72,236 with warfarin. In
comparison with the cohort that received no extended prophylaxis, the
cost-effectiveness of low-molecular-weight heparin was $106,454 per
quality-adjusted life year gained and the cost-effectiveness of warfarin was
$13,115 per quality-adjusted life year gained.
Conclusions: There is insufficient economic evidence to support
extended thromboprophylaxis with low-molecular-weight heparin following total
hip arthroplasty. Although the cost-effectiveness of warfarin was potentially
quite favorable, this finding was based on limited clinical evidence. Further
research is required to clarify the benefits of extended prophylaxis,
particularly with warfarin.
Level of Evidence: Economic and decision analysis, Level
I. See Instructions to Authors for a complete description of levels of
evidence.
Prior to the routine use of antithrombotic prophylaxis following total hip
arthroplasty, pulmonary embolism was the most common cause of death in these
patients. On the basis of multiple clinical trials and meta-analyses of
antithrombotic prophylaxis, seven to ten days of postoperative use of
antithrombotic prophylaxis with low-molecular-weight heparin or oral
anticoagulants has been recommended for the prevention of venous
thromboembolism following total hip
arthroplasty1. A
number of cost-effectiveness analyses of in-hospital use of antithrombotic
prophylaxis for the prevention of deep-vein thrombosis following total hip
arthroplasty have demonstrated that, compared with the alternative of no
prophylaxis, both low-molecular-weight heparin and oral anticoagulants are
associated with a reduction in the rate of thromboembolic complications and in
total costs2.
However, the peak incidence of postoperative deep-vein thrombosis occurs
two to three weeks after total hip
arthroplasty3. With
shorter durations of hospitalization following total hip arthroplasty,
consideration has been given to extending the duration of antithrombotic
prophylaxis beyond hospitalization for up to five weeks. Although extended
antithrombotic prophylaxis is becoming increasingly common, it is not yet
routine4. Six
clinical trials have found that an extended duration of prophylaxis with
low-molecular-weight heparin reduced the rate of venographically confirmed
asymptomatic deep-vein
thrombosis5-10,
and two meta-analyses have concluded that extended prophylaxis may reduce the
rate of symptomatic deep-vein thrombosis
complications11,12.
However, the only clinical trial evaluating the use of extended prophylaxis
for the prevention of symptomatic venous thromboembolism as the primary
outcome measure was a negative
study13. Another
recent meta-analysis also questioned the value of extended prophylaxis beyond
hospital
discharge14.
In this study, we systematically reviewed the literature to quantify the
benefits and the risks of extended antithrombotic prophylaxis and used this
information to compare patients undergoing elective total hip arthroplasty who
received extended prophylaxis with use of low-molecular-weight heparin or
warfarin and those who received no extended (in-hospital only) prophylaxis in
terms of cost per quality-adjusted life year gained in patients.
Systematic Literature Review
Our review identified relevant studies concerning the effectiveness and
safety of extended antithrombotic prophylaxis in reducing symptomatic venous
thromboembolic events and deaths with low-molecular-weight heparin, warfarin,
or aspirin, as well as the risk of adverse events due to extended prophylaxis,
compared with a baseline of in-hospital use of antithrombotic prophylaxis only
(no extended prophylaxis).
We queried MEDLINE for citations from 1966 to October 2003, EMBASE for
citations from 1977 to 2006, and the Cochrane Database of Systematic Reviews
from 1996 to 2006. The results were limited to citations with abstracts in
English. The databases were searched for derivations of "thrombo*"
or "embol*" in combination with the terms
"prophylaxis" or "prevention," "extended"
or "prolonged," and "hip" in combination with
"replacement" or "arthroplasty." The references in the
selected articles and the bibliographies of the investigators were also
reviewed for any relevant articles not identified with the initial search
strategy.
A study was potentially eligible if it met the following criteria: (1) it
evaluated agents for extended prophylaxis against deep-vein thrombosis
following total hip arthroplasty, and (2) it was a randomized controlled
trial. A study meeting the inclusion criteria was excluded if it met any of
the following exclusion criteria: (1) effective antithrombotic prophylaxis was
not administered to all patients while in the hospital, (2) a clinically
ineffective dose of prophylaxis was used, (3) prophylaxis was continued for
less than twenty-one days after discharge, (4) symptomatic thromboembolic end
points were not reported, or (5) there was a study population of less than
fifty patients. Potentially eligible studies were appraised independently by
two reviewers with a third reviewer arbitrating disagreements.
Where appropriate, multiple studies of a particular prophylaxis method were
combined into a meta-analysis and pooled event rates were
calculated15,16.
With use of these event rates, estimates of the absolute and relative risk
differences and associated 95% confidence intervals for symptomatic venous
thromboembolic events and major bleeding episodes were calculated, with use of
SAS software (version 8.0; SAS Institute, Cary, North Carolina), for each of
the three prophylaxis modalities relative to placebo.
Economic Modeling
The results of the systematic literature review formed the basis of an
economic model constructed in Excel (Microsoft, Redmond, Washington). The
model was structured around a decision tree that characterizes the
consequences of a given antithrombotic prophylaxis alternative (including no
extended prophylaxis) following total hip arthroplasty.
Figure 1 illustrates the
potential consequences of a hypothetical prophylaxis alternative. The decision
tree considered the potential short and long-term consequences of each
alternative to determine the costs of extended prophylaxis, as well as the
cumulative probability and costs of complications due to venous thromboembolic
events and major bleeding events stemming from the use of prophylaxis
itself.
Event Probabilities
Event probabilities were determined by applying agent-specific relative
risk reductions calculated in the systematic review and meta-analysis to the
placebo rates. When relative risks were not defined (i.e., there were no
events in one arm), absolute event rates for each alternative were taken from
the systematic review or meta-analysis. In the reference scenario, the placebo
rate was based on the pooled placebo arms of the trials comparing
low-molecular-weight heparin and a placebo that were included in the
meta-analysis, and it represents the baseline for all of the prophylaxis
alternatives. Warfarin rates were derived from the results reported in the
single trial comparing warfarin and
placebo17. The
secondary analysis used event rates based on a head-to-head comparison of
low-molecular-weight heparin and
warfarin18.
Venous thromboembolic complications were categorized as symptomatic
deep-vein thrombosis or pulmonary embolism, with pulmonary embolism further
stratified as fatal or nonfatal (Fig.
1). The relative proportion of deep-vein thrombosis to pulmonary
embolism was based on venous thromboembolic events observed across all
studies. Fatal pulmonary embolism was based on the pooled rate observed across
all studies. The probability of a major bleeding event was independent of the
risk of a venous thromboembolic event and was calculated as the placebo rate
weighted by the agent-specific relative risk. Fatal bleeding events were
conditional on the occurrence of major bleeding and the rate of fatal bleeding
was pooled across all studies. When no major bleeding event was reported in
the experimental treatment arm, event rates were set equal to the
placebo-comparator rate.
Costs
The model took a direct payer perspective, considering direct costs to the
health-care system and the patient. The relevant costs included the retail
costs of the drugs as well as the costs of administering and monitoring the
antithrombotic prophylaxis and the costs of diagnosing and managing deep-vein
thrombosis, pulmonary embolism, or major bleeding complications occurring
within three months of surgery. The costs are reported in 2006 Canadian
dollars, adjusted for inflation on the basis of the Canadian consumer price
index (healthcare
component)19. As
all costs in the model occur within one year, they were not discounted.
The cost per day for low-molecular-weight heparin and warfarin was based on
a pooled sample of prices from nine retail pharmacies in seven Canadian
provinces. These prices represent the costs of drug acquisition, pharmacy
markup, and professional fees of the pharmacist. The price of
low-molecular-weight heparin was based on the mean of the mean price for each
of the three low-molecular-weight heparin agents available in Canada. The cost
of warfarin management included the cost of international normalized ratio
monitoring: a twenty-eight-day course of warfarin was assumed to require five
international normalized ratio tests, along with ongoing physician
interpretation and monitoring of results.
The proportion of patients managed with low-molecular-weight heparin who
required home-care visits for prophylaxis injection and of patients managed
with warfarin who required home-care visits for international normalized ratio
blood sampling was assumed to be equal and was derived from a study of home
treatment of deep-vein
thrombosis20. In
the low-molecular-weight heparin cohort, home care involved a registered nurse
administering a daily injection and the cost was based on prices provided by a
national home-care
provider21. With
warfarin, home care consisted of a technician from a private blood-collection
service drawing blood samples on a weekly basis. Costs were based on the
average price of two blood-collection services in Nova
Scotia22.
The cost consequences of diagnosing and treating deepvein thrombosis and
pulmonary embolic events were limited to events originating within three
months from hospital discharge after total hip arthroplasty and were
stratified by outpatient compared with inpatient management. On the basis of
the reported rates, the model assumed that 90% of the patients with deep-vein
thrombosis and 33% of the patients with a pulmonary embolism that had occurred
following hospital discharge would be treated on an outpatient
basis23. The costs
of standard therapy for deep-vein thrombosis and pulmonary embolism included
five days of treatment with low-molecular-weight heparin and ninety days of
treatment with warfarin, along with associated home care, laboratory testing,
and physician management. The cost of this therapy was included for
outpatients as well as for inpatients who were discharged from hospital.
Outpatient costs were estimated by pooling published physician and
laboratory fees from Nova Scotia, Ontario, and British Columbia for family
practitioner and specialist consultations, diagnostic testing, drug therapy,
home-care visits, and international normalized ratio testing and
interpretation. The cost and length-of-stay data for managing inpatients with
a primary diagnosis of deep-vein thrombosis and pulmonary embolism, as well as
complications from antithrombotic prophylaxis (major bleeding), were derived
by means of a custom data request from the Ontario Case Costing Initiative
database, a project of the Ontario Ministry of Health and Long-Term Care. This
database combines discharge abstract data with patient-specific cost data from
thirteen participating hospitals in Ontario, Canada, and costs per case are
categorized by functional center and include salaries and benefits for
healthcare and administrative personnel, supplies, maintenance, depreciation,
and physician fees billed directly to the hospital. Records with diagnosis
codes indicating deep-vein thrombosis (451.1 and 444.22) or pulmonary embolism
(415.1) were extracted and stratified by the presence or absence of a major
bleeding event code (286.5 for a hemorrhagic disorder due to circulating
anticoagulants, 578.x for gastrointestinal hemorrhage, 996.77 to 996.79 for
other complications of an internal prosthetic device, implant, and graft, and
998.12 for hemorrhage or hematoma complicating a procedure), and by discharge
status (discharged alive or died in hospital). The mean costs and associated
95% confidence intervals were entered into the probabilistic model to
represent the inpatient management costs of deep-vein thrombosis and pulmonary
embolism. A second query returned admissions with a primary diagnosis of major
bleeding (same codes as above) within ninety days of an admission for total
hip arthroplasty (81.51). Because of the small numbers, the cost of a major
bleeding episode was based on the pooled average of all bleeding events and
was not stratified by discharge status. These data represent the management
costs of a major bleeding episode associated with the use of an antithrombotic
prophylaxis agent following total hip arthroplasty.
Outcomes
Outcomes of interest in the model included symptomatic venous
thromboembolic events, major bleeding events, deaths, and potential life years
gained per death avoided. Potential life years gained per death avoided were
based on the distribution of expected years of life remaining for all patients
undergoing total hip arthroplasty in Canada, with use of the 2003 annual
report of the Canadian Joint Replacement Registry of the Canadian Institute
for Health Information and the Statistics Canada life
tables24,25.
Expected life-year gains were adjusted for quality of life following total hip
arthroplasty, with quality penalties applied to cases of venous
thromboembolism or major bleeding. Utility weights for quality adjustments
were derived from the
literature26.
As survival benefits accrue over a number of years, quality-adjusted life
years were discounted by 3% per year to reflect societal preferences for
benefits occurring in the present over those occurring in the
future27.
Economic Analysis
The economic analysis compared twenty-eight days of extended prophylactic
therapy with low-molecular-weight heparin or warfarin with an alternative of
no extended prophylaxis. The primary analysis was an indirect comparison of
low-molecular-weight heparin and warfarin with the use of no further
prophylaxis as a common comparator. Event rates were based on a systematic
review and meta-analysis of the literature. The secondary analysis was based
on a single head-to-head trial of low-molecular-weight heparin compared with
warfarin. Both analyses were conducted in terms of incremental cost per
quality-adjusted life year gained.
Sensitivity Analysis
A multivariate sensitivity analysis was conducted with use of probabilistic
modeling to test the sensitivity of the cost-effectiveness results to the
uncertainty in the parameter estimates. Probabilistic modeling assigns a
probability distribution to uncertain parameters in a model and uses Monte
Carlo simulation to repeatedly resample values from that
distribution28. The
analysis was conducted with use of @Risk (Palisade, Newfield, New York) to
simulate each scenario with 10,000 iterations. Confidence intervals around
cost-effectiveness ratios were generated with use of a bootstrap
approach29.
Key cost drivers, such as the rates of venous thromboembolic events, rates
of major bleeding events, and the proportion requiring home care, were
specifically tested in a one-way threshold analysis to identify threshold
values that would meet a cost-effectiveness threshold of $50,000 per life year
gained.
Systematic Review
The systematic review identified twelve studies that evaluated prophylaxis
that was extended beyond the time of hospital discharge following total hip
replacement. Four studies were excluded; the first was not a controlled
trial30, the second
did not administer effective in-hospital
prophylaxis31, the
third did not report symptomatic
outcomes8, and the
fourth analyzed the same patients as an included
study32. Of the
eight eligible studies, six compared low-molecular-weight heparin with a
placebo
alternative5-7,9,10,13,
the seventh was a comparison of warfarin with
placebo17, and the
eighth was a head-to-head comparison of warfarin and low-molecular-weight
heparin18. No
studies of aspirin met the inclusion criteria, so no further analysis on the
use of aspirin for extended antithrombotic prophylaxis was performed. Event
counts and rates for all studies included in the systematic review are
presented in the electronic Appendix.
The primary economic analysis was based on a comparison of
low-molecular-weight heparin and warfarin event rates with a baseline derived
from the combined placebo arms of the low-molecular-weight heparin
meta-analysis (Table I).
Low-molecular-weight heparin event rates were derived from meta-analysis of
the six studies in which extended prophylaxis with low-molecular-weight
heparin was compared with placebo and involved 2144 eligible patients. The
meta-analysis found that low-molecular-weight heparin significantly reduced
the rate of symptomatic venous thromboembolism from 3.99% to 1.34% (absolute
risk reduction, 2.7%; 95% confidence interval, 1.2% to 4.1%). The relative
risk was 0.34 (95% confidence interval, 0.19 to 0.60). The relative risk of a
major bleeding event was undefined as no events were reported in the
low-molecular-weight heparin arms of the meta-analysis, so the rate of major
bleeding events in the low-molecular-weight heparin group was set equal to the
placebo rate. No significant heterogeneity was observed between studies in the
meta-analysis (chi square = 3.70, p = 0.59).
Warfarin event rates in the primary analysis were based on a single trial,
reported by Prandoni et al., in which warfarin and placebo were compared with
use of a composite end point of symptomatic venous thromboembolism and
asymptomatic proximal deep-vein thrombosis confirmed by
ultrasonography17.
On the basis of the primary composite end point, the trial found that warfarin
was associated with a significantly reduced risk of an event compared with the
placebo (absolute risk reduction, 4.6%; 95% confidence interval, 1.15% to
7.99%). When only symptomatic events were considered, there was a trend
favoring warfarin in reducing the risk of a symptomatic event, but the
differences were not significant (see Appendix). Warfarin event rates in the
primary analysis were based on the relative risk of a symptomatic venous
thromboembolic event with warfarin (0.48; 95% confidence interval, 0.09 to
2.58) applied to the baseline rate of venous thromboembolism derived from the
combined placebo arms from the low-molecular-weight heparin meta-analysis
(Table I). In the group of 184
patients managed with warfarin, one major bleeding episode (0.54%; 95%
confidence interval, 0.01% to 1.9%) was reported, but the relative risk of a
major bleeding episode was undefined as there were no events in the placebo
group. The risk of major bleeding with warfarin was based on the event rate
observed in the warfarin arm.
The secondary economic analysis was based on a head-to-head trial of
low-molecular-weight heparin and warfarin reported by Samama et al
18. This trial had
similar rates of thromboembolic events in both arms, although rates of major
bleeding episodes were considerably higher in the patients who received
warfarin (Table I). The risk of
a symptomatic venous thromboembolic event was 2.33% with low-molecular-weight
heparin compared with 3.77% with warfarin (absolute risk reduction, 1.44%; 95%
confidence interval, —0.4% to 3.3%). The relative risk of a symptomatic
event with low-molecular-weight heparin was 0.62 (95% confidence interval,
0.33 to 1.17) compared with warfarin. Notably, the rate of major bleeding
events was significantly higher in the warfarin group (thirty-five [5.5%] of
636 patients; 95% confidence interval, 3.9% to 7.4%) than in the group managed
with low-molecular-weight heparin (nine [1.4%] of 643 patients; 95% confidence
interval, 0.6% to 2.5%). The absolute reduction in the risk of major bleeding
with low-molecular-weight heparin compared with warfarin was 4.1% (95%
confidence interval, 2.1% to 6.3%), or a relative risk of 0.26 (95% confidence
interval, 0.13 to 0.54).
Economic Analysis
The economic model combined the costs and the event rates to compare the
cost-effectiveness of each prophylaxis alternative. Costs were grouped into
three major categories: extended prophylaxis therapy, inpatient management,
and outpatient management of venous thromboembolic or major bleeding events
(see Appendix). The incremental cost-effectiveness ratio was calculated as the
difference in expected costs over the difference in expected quality-adjusted
life years for each alternative.
The primary economic analysis compared low-molecular-weight heparin and
warfarin with an alternative involving no extended prophylaxis (a placebo).
The results of the primary analysis are shown in
Table II. In a hypothetical
cohort of 1000 patients, low-molecular-weight heparin was associated with an
incremental gain of 7.51 quality-adjusted life years compared with no further
prophylaxis, while warfarin had an incremental gain of 5.51 quality-adjusted
life years compared with no further prophylaxis. Compared with warfarin,
low-molecular-weight heparin had an incremental gain of 2.0 quality-adjusted
life years. Incremental costs per 1000 patients treated were $799,104 with
low-molecular-weight heparin and $72,236 with warfarin. The incremental
difference in treatment costs between low-molecular-weight heparin and
warfarin was $726,868. The incremental cost-effectiveness of warfarin was
$13,115 per quality-adjusted life year gained relative to no further
prophylaxis, while low-molecular-weight heparin had a cost-effectiveness of
$106,454 per quality-adjusted life year gained relative to no further
prophylaxis. The incremental cost-effectiveness of low-molecular-weight
heparin compared with warfarin was $363,689 per quality-adjusted life year
gained.
The secondary analysis was an incremental comparison of
low-molecular-weight heparin and warfarin based on event rates from the single
head-to-head
trial18. Results
are shown in Table II.
Low-molecular-weight heparin was associated with incremental gains in
quality-adjusted life years (8.46 per 1000 treated patients) compared with
warfarin. Incremental costs per 1000 patients treated with
low-molecular-weight heparin compared with warfarin were $193,812. The
incremental cost-effectiveness of low-molecular-weight heparin relative to
warfarin was $22,908 per quality-adjusted life year gained. The key
distinction between the primary and secondary analysis lies in the rates of
major bleeding events in the two warfarin studies. Major bleeding event rates
in the warfarin arm of head-to-head trial were eleven times higher than in the
warfarin-placebo trial (5.5% compared with 0.5%).
Sensitivity Analysis
A multivariate sensitivity analysis was conducted through probabilistic
modeling, with use of probability distributions to represent the uncertainty
in model parameters (see Appendix). The results are expressed as 95%
confidence intervals around point estimates from the primary and secondary
analyses. Probabilistic modeling of the primary analysis showed unadjusted
life-year gains with both low-molecular-weight heparin (8.9 life years gained;
95% confidence interval, 2.8 to 16.0) and warfarin (7.0 life years gained; 95%
confidence interval, 2.2 to 12.7) were significant at the 95% level. However,
when these life-year gains were adjusted for quality, the gains were no longer
significant, although both agents had trends toward significance. The
probabilistic analysis also confirmed the additional costs associated with
low-molecular-weight heparin compared with warfarin or no extended
prophylaxis. Bootstrapped 95% confidence intervals around the
cost-effectiveness ratio for low-molecular-weight heparin relative to no
extended prophylaxis ($97,479 to $121,187) and low-molecular-weight heparin
relative to warfarin ($268,003 to $640,521) confirmed a cost per
quality-adjusted life year gained well above $50,000 for both comparisons.
Confidence intervals for warfarin ($9341 to $15,981) supported its favorable
cost-effectiveness relative to no further prophylaxis.
In the secondary analysis, incremental gains in quality-adjusted life years
with low-molecular-weight heparin compared with warfarin (95% confidence
interval, 0.5 to 26.2) were significant. The incremental cost of
low-molecular-weight heparin was not significantly different from that of
warfarin. The bootstrapped 95% confidence interval for the cost-effectiveness
of low-molecular-weight heparin relative to warfarin showed an incremental
cost per quality-adjusted life year gained ranging from $19,221 to
$26,578.
The one-way threshold analysis of key model parameters, based on the
primary analysis, is shown in Table
III. The key cost driver for low-molecular-weight heparin was the
proportion of the cohort requiring home-nursing services. Low-molecular-weight
heparin would meet a cost-effectiveness threshold of $50,000 per
quality-adjusted life year relative to no further prophylaxis with home-care
proportions of <10%. Two-way sensitivity analysis showed that, relative to
warfarin, low-molecular-weight heparin only met a $50,000 threshold with the
extreme combination of low-molecular-weight heparin home-care rates of <10%
and warfarin rates of >90%. The key cost driver for warfarin was the rate
of major bleeding events, and warfarin would meet a $50,000 threshold with
major bleeding event rates of <1.7%. This threshold value is three times
the rate reported in the trial comparing warfarin and
placebo17, yet it
was only one-third of that reported in the trial comparing warfarin and
low-molecular-weight
heparin18. The
duration of extended prophylaxis was not a significant factor in the relative
cost-effectiveness of either agent. On the basis of the cost of therapy alone
(i.e., assuming health outcomes were constant), low-molecular-weight heparin
would require a duration of less than seven days to meet a $50,000 threshold,
while warfarin could meet the threshold with durations up to eighty-four days.
Changing the discount rate did not affect the relative cost-effectiveness of
either agent nor did applying the lowest, rather than the average, price for
each agent.
The systematic review conducted for this study confirmed the efficacy of
extended prophylaxis with low-molecular-weight heparin in reducing the risk of
symptomatic venous thromboembolic events following total hip arthroplasty
(absolute risk reduction, 2.7%; 95% confidence interval, 1.2% to 4.1%).
However, the primary economic analysis found that the cost-effectiveness of
low-molecular-weight heparin relative to no further prophylaxis ($106,454 per
quality-adjusted life year gained) was unattractive compared with many medical
interventions33.
The results of the probabilistic sensitivity analysis also questioned the
clinical benefit of antithrombotic prophylaxis because, although life-year
gains were significant at the 95% level, quality-adjusted life-year gains were
not.
Much less clinical information was available for the evaluation of the
effectiveness of extended prophylaxis with warfarin. The only trial comparing
warfarin and placebo demonstrated that warfarin reduced the composite rate of
symptomatic venous thromboembolic events and asymptomatic proximal deep-vein
thrombosis17. That
study was terminated prematurely because of the efficacy of warfarin. There
was a trend in that study favoring warfarin in reducing the rate of
symptomatic venous thromboembolic complications, but it did not achieve
significance. Only one major bleeding event (0.5%) in the warfarin arm was
observed. Nonetheless, we elected to include warfarin in the economic analysis
for two reasons. First, in a head-to-head comparison of low-molecular-weight
heparin and warfarin, rates of venous thromboembolic events after
hospitalization were similar between the two agents (1.4%; 95% confidence
interval, —0.4% to 3.3%) and suggested a trend in the reduction of
symptomatic
events18. That
study was powered for the detection of the composite outcome and was likely
insufficiently powered to demonstrate significance in the prevention of
symptomatic outcomes alone. Second, warfarin was highly efficacious at
preventing the composite end point of symptomatic venous thromboembolism and
asymptomatic proximal deep-vein thrombosis.
On the basis of this very limited evidence, the cost-effectiveness of
warfarin relative to no extended prophylaxis appeared favorable ($13,115 per
life year gained). As with low-molecular-weight heparin, however, incremental
gains in quality-adjusted life years relative to no extended prophylaxis were
not significant at the 95% confidence level.
The secondary analysis was an incremental evaluation of
low-molecular-weight heparin compared with warfarin. This analysis showed a
very favorable incremental cost-effectiveness for low-molecular-weight heparin
compared with warfarin ($22,908 per quality-adjusted life year gained). Again,
however, it is important to note these results are driven by very high rates
of bleeding events in the warfarin group reported by the single head-to-head
trial.
The primary cost driver in the low-molecular-weight heparin cohort was
found to be the proportion of patients who required home-nursing services for
drug injection. This means the method of administration has substantial
implications for the cost-effectiveness of low-molecular-weight heparin.
However, two-way sensitivity analysis showed that our conclusions regarding
the relative cost-effectiveness of low-molecular-weight heparin and warfarin
were stable across a wide range of home-care proportions. It was only at the
extremes—a home-care rate of <10% for low-molecular-weight heparin in
combination with a rate of >90% for warfarin—that our conclusions
would change. With warfarin, the primary cost driver was the rate of major
bleeding events. This highlights the widely discrepant estimates of major
bleeding events in the available studies of warfarin as extended prophylaxis
and emphasizes the need for an accurate estimate.
A key issue in considering the cost-effectiveness of extended
antithrombotic prophylaxis is the relative rarity of events. In the absence of
extended prophylaxis, the analysis shows that <4% of patients will
experience a symptomatic venous thromboembolic event and <3% of those
symptomatic events (1.2 per 1000 patients) will be fatal. Most patients who
have symptomatic deep-vein thrombosis or pulmonary embolism may be treated
with antithrombotic therapy with complete resolution of their symptoms. Given
the relative rarity of clinically important events, there is limited scope for
gaining years of life. These gains are further constrained by the (nominal)
risk of fatal complications associated with prophylaxis, as well as by
adjusting for the quality of these years of life. This is supported by the
fact that significant reductions in the rate of venous thromboembolic events
demonstrated by the clinical trials did not necessarily translate into
significant gains in quality-adjusted life years.
The cost-effectiveness of an extended duration of prophylaxis following
total hip arthroplasty has not been definitively established by the limited
number of evaluations conducted to date. Several of the studies did not
include an alternative involving no further
prophylaxis34,35,
and most of the studies used asymptomatic events avoided as their outcome
measure, overstating the benefit of
prophylaxis36-38.
Only two studies have described costs in terms of life years gained. A French
study found the cost-effectiveness of low-molecular-weight heparin compared
with no extended prophylaxis was 11,000 to 34,000 French francs (Can$12,000 to
$37,300) per life year
gained39. This
finding, which included the cost of home-care services for the entire cohort,
is much more favorable than the results of the present analysis. However, the
costs of adverse events due to prophylaxis were not included, and, contrary to
recommended economic methodology, the life years gained were not discounted.
Both of these omissions would have the effect of improving the
cost-effectiveness ratio. A Belgian study found an even more favorable
cost-effectiveness, with a cost of €6964 (Can$6385) per quality-adjusted
life year gained40.
However, that analysis used mortality rates that were higher than those
generally reported in the literature, which would inflate the potential
benefits of extended prophylaxis. In addition, the study did not consider the
costs of home care.
The current study rests on four key strengths. First, event rates were
based on a systematic review and meta-analysis of the literature rather than
on any individual trial. Second, the economic model accounted for all aspects
of care around venous thromboembolic events and prophylaxis-related
complications, including inpatient and outpatient management as well as home
care. Third, the model is based on symptomatic, clinically relevant end
points. Fourth, the results of the model were robust, and subjecting key
parameters to stress did not change the relative cost-effectiveness of the
alternatives.
There were limitations to the study. First, there were limited data
directly comparing low-molecular-weight heparin and warfarin, and many of the
results in the analysis were based on indirect comparisons. Second, given the
rarity of major and fatal bleeding events in published trials, there is
considerable uncertainty about the true rate of these events. Finally, the
analysis did not consider antiplatelet agents as there were no published
studies evaluating their use in extended-duration antithrombotic
prophylaxis.
In summary, while the meta-analysis conducted for the study demonstrates
the effectiveness of low-molecular-weight heparin in preventing symptomatic
venous thromboembolic events, its overall clinical benefit in terms of
quality-adjusted life years gained is unclear. In addition, there are
considerable costs associated with its acquisition and administration. The
cost-effectiveness of low-molecular-weight heparin, even relative to placebo,
exceeded common thresholds and was unattractive relative to many other medical
interventions. Although there is only very limited clinical evidence
supporting the use of warfarin, it does appear to have the potential to be a
cost-effective option. It is much less costly to purchase and administer than
low-molecular-weight heparin, and clinical evidence suggests that warfarin may
be similarly effective. The cost-effectiveness of warfarin is also potentially
quite favorable ($13,115 per life year gained relative to placebo).
We conclude that, although in-hospital antithrombotic prophylaxis has been
shown to be a dominant strategy, there is insufficient economic evidence to
support routine extended prophylaxis with low-molecular-weight heparin. There
is a need for further research into the long-term clinical benefit of extended
antithrombotic prophylaxis and, particularly, the role of warfarin.
Tables showing the results of the systematic review and meta-analysis
presenting the primary and secondary analysis factors and outlining the
parameters and distributions used in the probabilistic sensitivity analysis
are available with the electronic versions of this article, on our web site at
jbjs.org (go to the article citation and click on "Supplementary
Material") and on our quarterly CD-ROM (call our subscription
department, at 781-449-9780, to order the CD-ROM). ?
Note: The authors dedicate this paper to the memory of their
late friend, colleague, and coauthor Bernie O'Brien. They gratefully
acknowledge Jill Duncan, Audrey Skinner, Kym Paquette, and Pat Emerson of the
Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, and Cynthia
Hitsman of the Victorian Order of Nurses for Canada, Ottawa, Ontario, Canada
for their invaluable assistance.
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