The Cost-Effectiveness of Extended-Duration Antithrombotic Prophylaxis After Total Hip Arthroplasty

Skedgel, Chris MDE; Goeree, Ron MA; Pleasance, Sue BScN; Thompson, Kara MSc; O'Brien, Bernie PhD; Anderson, David MD

Journal of Bone & Joint Surgery - American Volume: April 2007 - Volume 89 - Issue 4 - p 819–828
doi: 10.2106/JBJS.F.00092
Scientific Articles

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.

1 Department of Medicine, Dalhousie University, Centre for Clinical Research, Room 207, 5790 University Avenue, Halifax, NS B3H 1V7, Canada. E-mail address for C. Skedgel: chris.skedgel@cdha.nshealth.ca

2 Program for Assessment of Technology in Health (PATH), St. Joseph's Hospital, 25 Main Street West, Suite 2000, Hamilton, ON L8P 1H1, Canada

3 Deceased

Article Outline

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.

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Materials and Methods

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.

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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.

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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.

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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.

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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.

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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.

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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.

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Results

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).

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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%).

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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.

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Discussion

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.

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Appendix

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.

Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from the Nova Scotia Health Research Foundation (PSO-Project-2003-339). At the time of the study, one author was a Research Scholar of the Faculty of Medicine, Dalhousie University. Neither the authors nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.

Investigation performed at the Centre for Clinical Research, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada

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