In addition to overall effectiveness, a critical factor that will probably influence the choice between low-molecular-weight heparin and standard heparin as a primary prophylactic modality will be the relative cost-effectiveness of these two agents. In Europe, low- molecular-weight heparin is more expensive than standard heparin, but its ultimate price in North America is unknown. The cost-effectiveness of low-molecular-weight heparin will depend not only on the relative prices of low-molecular-weight heparin and standard heparin but also on the costs of treating patients developing thrombotic and bleeding complications related to these therapies.

To help determine whether low-molecular-weight heparin or standard heparin would be the more appropriate agent for the prevention of deep vein thrombosis after total hip arthroplasty, we compared both the efficacy and the cost-effectiveness of these two agents. To determine valid estimates of the rates of thrombotic and bleeding complications associated with the use of low-molecular-weight heparin and standard heparin after total hip arthroplasty, we did a meta-analysis of the randomized trials directly comparing these two agents. The costs of treating postoperative thrombotic and bleeding complications were estimated using actual patient data from a recently completed clinical trial at our center comparing low-molecular-weight heparin with standard heparin for the prevention of deep vein thrombosis after total hip arthroplasty [7]. Because the North American price of low-molecular-weight heparin is unknown, we estimated its price based on the price ratio between low-molecular-weight heparin and standard heparin in France. Then, in our sensitivity analysis, we compared the cost-effectiveness of these agents over a range of price ratios.

Our approach of comparing the efficacy and cost-effectiveness of a novel drug with a standard treatment could be useful for determining the appropriate role of other innovative but often expensive new agents. This type of analysis is especially pertinent if it is done before the price of the drug is established and it is released onto the marketplace.

Methods

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Meta-analysis

Articles were obtained from a search of MEDLINE using the key words "venous thrombosis," "hip arthroplasty," and "heparin". All relevant studies were reviewed and the bibliographies were searched for additional articles. Abstracts from recent meetings were also reviewed. When necessary, authors were contacted and requested to provide additional information about study methods.

Published randomized controlled trials directly comparing a low-molecular-weight heparin preparation with standard heparin for the prevention of deep vein thrombosis after hip arthroplasty were eligible for inclusion in the meta-analysis. Potentially eligible studies were excluded if the diagnostic end point of deep vein thrombosis was not made by mandatory venography interpreted by blinded observers or if the study did not use the manufacturer's currently recommended dose of low- molecular-weight heparin or standard heparin for the prevention of deep vein thrombosis after hip arthroplasty. Two investigators independently assessed all retrieved articles for eligibility and extracted the results. Disagreements were settled by consensus with the aid of a third independent reviewer.

The principal outcome measure of efficacy in the analysis was total deep vein thrombosis. Deep vein thrombosis was subdivided into proximal (involving the popliteal or more proximal leg veins) and distal (isolated to the deep veins of the calf). Evaluable patients in the efficacy analysis included only those successfully completing venography before hospital discharge. The principal safety outcome was bleeding, which was subdivided into major and minor bleeding as was defined by each study. All patients entered in each trial were included in the bleeding analysis. Secondary outcomes of the meta-analysis were symptomatic pulmonary embolism, diagnosed by either high-probability lung scan or pulmonary angiography, and death. We made pulmonary embolism a secondary outcome because its incidence was expected to be low (<1%) and because studies did not distinguish between patients developing isolated pulmonary embolism or pulmonary embolism in combination with deep vein thrombosis.

The relative odds of low-molecular-weight heparin versus standard heparin was determined for each of the outcome measures in each trial. Under the assumption of a fixed-effect model, the Breslow-Day test was used to test heterogeneity of outcomes among studies [8]. To combine study results, a common odds ratio was estimated for each outcome using the method of Mantel and Haenszel [9]. A common odds ratio of less than 1.0 favored low-molecular-weight heparin and was statistically significant if the upper bound of the 95% CI was also less than 1.0 [10]. Although the best estimate of relative effectiveness is through odds, we converted odds into rates for use in our economic analysis. This conversion was achieved by first calculating typical event rates in the standard heparin group as weighted averages of observed event rates. The absolute event rates that were expected with low-molecular-weight heparin treatment were then calculated by converting the standard heparin rates to odds, multiplying the odds by the appropriate pooled odds ratio, and then converting the odds back into rates.

Cost and Cost-Effectiveness Analyses

Two distinct but related analyses were done, both from the perspective of a third-party payer responsible for the reimbursement of all hospital costs. First, we compared the expected costs of managing 1000 patients with either low-molecular-weight heparin or standard heparin after total hip arthroplasty. The cost estimates included the prices of and the administration costs of prophylaxis and the expected costs of managing deep vein thrombosis and bleeding events on either therapy. The expected costs of deep vein thrombosis (proximal or distal) and bleeding (major or minor) were the product of our estimates of the cost of each event and the corresponding event rates from the meta-analysis. Next, a cost-effectiveness analysis was done that quantified the incremental cost of low-molecular-weight heparin for each additional deep vein thrombosis its use averted compared with standard heparin. Costs that were common to both therapy groups or unrelated to the use of deep vein thrombosis prophylaxis were excluded from both analyses.

Cost of Prophylaxis

The price of low-molecular-weight heparin in North America has not yet been determined. To estimate the cost for the purposes of this analysis, the parent drug company's (Rhone-Poulenc Rorer Inc.; Paris, France) recommended price for the low-molecular-weight heparin, Enoxaparin, in France was obtained and compared to a manufacturer's recommended French price of standard heparin (Calciparine, Sanofi-Choay Laboratories; Paris, France). Using this ratio, the price of low-molecular-weight heparin was determined based on the Henderson Hospital's (Hamilton, Ontario) formulary price for standard heparin. It was assumed that all patients received twice daily subcutaneous injections of prophylaxis (30 mg of enoxaparin and 7500 units of standard heparin, respectively) over a 14-day period.

Costs of Deep Vein Thrombosis and Bleeding Complications

The hospital resource consequences of bleeding and deep vein thrombosis events were estimated by doing a retrospective analysis of patient-specific data from the hospital charts of all 447 patients who were managed in Hamilton, Ontario as part of a randomized trial [7]. (This was one of the studies included in the meta-analysis.) All patients in this study were screened for deep vein thrombosis by venography before hospital discharge, and deep vein thrombosis and bleeding complications were managed at the discretion of the individual practitioners.

The direct resource consequences of bleeding events were tabulated from the hospital charts of patients who were judged to have developed bleeding complications during this trial. Costs attributed to bleeding included investigations, consultations, and treatment that directly resulted from the bleeding episode. In cases where bleeding may have resulted in reoperation, rehospitalization, or transfer to the intensive care unit, the cases were reviewed by two experienced clinicians who were blinded to the treatment allocation of the patients. They decided whether the complications and their economic consequences were the result of the bleeding event.

To determine whether deep vein thrombosis (proximal or distal) or bleeding [major or minor] events were associated with prolongations in hospitalization we did a multiple regression analysis in which the dependent variable was the length of stay for all patients from both arms of the trial. The validity of pooling these data was based on the assumption that although event rates may vary between therapy groups, the effect of an event on length of stay was independent of treatment assignment for prophylaxis. Explanatory variables entered in the regression model were from four categories: 1) demographic: patient age, sex, hospital where surgery was done; 2) preoperative medical status: previous arthroplasty, current medical illnesses; 3) postoperative complications: proximal deep vein thrombosis, distal deep vein thrombosis, major bleeding, minor bleeding, hip dislocation, other medical or surgical complications; and 4) social issues: companion at home, more than five stairs to climb daily. A priori, the dependent variable, length of stay, was defined as the number of days between total hip arthroplasty and the first of the following events: hospital discharge, a second elective arthroplasty procedure, or transfer to the rehabilitation ward.

Mean costs for major and minor bleeding were determined. The cost of managing patients with deep vein thrombosis was based on the results of the regression analysis that determined the increased length of hospital stay associated with proximal and distal deep vein thrombosis. It was assumed patients developing deep vein thrombosis remained on the orthopedic ward to receive intravenous heparin therapy and were subsequently discharged and given warfarin for 6 weeks (distal deep vein thrombosis) or 12 weeks (proximal deep vein thrombosis).

Methods for Estimating Costs

Costs of procedures and additional length of stay associated with deep vein thrombosis or bleeding were based on hospital expenditures at Chedoke-McMaster hospital in Hamilton, Ontario, Canada. We used a method of weighted per diem expenditures per patient that allowed for overhead allocation from service departments to patient care functions. Procedure costs were calculated using the relation between standard hospital workload units per procedure and departmental expenditures. Costs for physician services were based on the Ontario Ministry of Health schedule of benefits. Drug costs were taken from the pharmacy formulary at the Henderson General Hospital, Hamilton, Ontario. The costs of blood products were taken from the Canadian Red Cross, which based these costs on the American Red Cross processing fees. All costs were adjusted to 1992 prices using the Canadian consumer price index [11] and converted to U.S. dollars based on a 1.24 exchange rate with the Canadian dollar.

Sensitivity Analysis

We examined the effect of altering some of the uncertain rates and prices on the cost-effectiveness of low-molecular-weight heparin compared with standard heparin. In particular, the price of low-molecular-weight heparin was varied to determine the threshold value at which the two therapies would be cost-equivalent. Given the uncertainty about the effect of out-of-hospital deep vein thrombosis that would develop if patients were not screened for asymptomatic deep vein thrombosis before hospital discharge, we created a hypothetical model where between 20% and 60% of patients with asymptomatic proximal deep vein thrombosis and 10% of patients with distal deep vein thrombosis would develop symptomatic venous thromboembolism (deep vein thrombosis or pulmonary embolism) after discharge that would result in an 8-day rehospitalization.

Results

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Meta-analysis

Six studies fulfilled the eligibility criteria for the meta-analysis (Table 1 [references 7, 12-16]). All of the studies required that patients be older than 40 years. Three studies were double-blind [4, 14, 16]. Four trials required patients to have had general anesthesia [12-15], and three studies used elastic stockings in combination with anticoagulant prophylaxis [12-14]. In all studies except one [7], the first dose of standard or low-molecular-weight heparin was administered preoperatively.

Symptomatic pulmonary embolism was significantly less common in patients receiving low-molecular-weight heparin (common odds ratio, 0.22; CI, 0.05 to 0.88); however, few events were noted with either treatment. Only four deaths were observed in the six trials, three in patients receiving standard heparin and one in a patient receiving low-molecular-weight heparin.

Regression Analysis

Fourteen covariates (including major bleeding, minor bleeding, proximal deep vein thrombosis, and distal deep vein thrombosis) were entered into the multiple regression model for length of hospital stay. The correlation between any two covariates in this model was less than 0.20. Twelve of these factors were independently associated with prolonged hospitalization (P < 0.05), and the model accounted for 56% of the variance associated with length of hospital stay. Major bleeding and proximal and distal deep vein thrombosis were each associated with extending length of stay by 3.2, 5.0, and 2.9 days, respectively. Minor bleeding was not associated with prolonged hospitalization. No major violations of the assumptions of the multiple regression analysis model were observed using the nontransformed variable of length of stay. Analysis for possible interactions between covariates did not alter the model coefficients.

Cost and Cost-Effectiveness Analysis

Estimates of absolute rates of deep vein thrombosis (proximal and distal) and bleeding (major and minor) used in the cost-effectiveness analysis are shown in Table 3. The costs involved in managing deep vein thrombosis prophylaxis after hip arthroplasty are presented in Table 4. The prices per low-molecular-weight heparin and standard heparin dose were $3.83 and $1.48, respectively, with an additional cost of $2.92 for administering the drug. The estimated cost of managing a proximal deep vein thrombosis was $1394 and for a distal deep vein thrombosis the estimate was $860. The mean cost of a major bleeding event was $2791 and of a minor bleeding event, $189.

The cost-effectiveness of low-molecular-weight heparin is a function of the drug price ratio (see Table 5). At a low-molecular-weight heparin/standard heparin price ratio of 3.7, the two treatment strategies are cost-equivalent. Above this price ratio, it is useful to calculate the incremental cost-effectiveness of low-molecular-weight heparin (the ratio of additional cost to additional effect), which ranges from $1020 per deep vein thrombosis averted (for a price ratio of five) to $5082 per deep vein thrombosis averted (for a price ratio of 10).

The expected costs of managing deep vein thrombosis and bleeding events are dependent on our rate estimates from the meta-analysis, which are associated with measurable uncertainty in the form of 95% confidence intervals. Figure 1 shows the relationship between the difference in net therapy costs for the two prophylaxis regimens (low-molecular-weight heparin minus standard heparin) within a sensitivity range (that represents the variation in cost over the 95% CI of the common odds ratios for deep vein thrombosis and bleeding) over a range of drug price ratios. This two-way analysis of sensitivity suggests that, even at the French drug price ratio of 2.6 (our baseline assumption), the sensitivity range of the expected cost difference crosses zero and low-molecular-weight heparin may not reduce costs. In addition, the derivation of the 3.7 threshold price ratio is statistically uncertain. Accounting for the sensitivity range, the low-molecular-weight heparin/standard heparin price ratio at which the two treatment strategies are cost-equivalent lies between 0.8 and 5.5.

View larger version (14K): [in this window] [in a new window]   Figure 1. Cost difference over range of price ratios. Difference in total cost of managing 1000 patients with low-molecular-weight heparin compared with standard heparin after total hip arthroplasty over a range of low-molecular-weight heparin/standard heparin ratios. Negative dollars indicate cost saving for use of low-molecular-weight heparin. Sensitivity range represents the variation in costs over the 95% CI of the common odds ratio for deep vein thrombosis and bleeding.

Our primary cost analysis was based on the premise that all patients were screened postoperatively for deep vein thrombosis with venography before hospital discharge and that those patients confirmed to have asymptomatic deep vein thrombosis were treated with anticoagulant therapy. We created a hypothetical model to estimate the economic consequences of asymptomatic deep vein thrombosis if patients were not screened for deep vein thrombosis before hospital discharge. This analysis determined that the use of low-molecular-weight heparin still reduced costs at a price ratio of 2.6 if at least 20% of patients with asymptomatic proximal deep vein thrombosis later developed symptomatic venous thromboembolism that required rehospitalization.

Discussion

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Meta-analysis is a valuable technique for combining data from several clinical trials to provide valid estimates of the efficacy or safety, or both, of therapeutic interventions. Our results showed that low-molecular-weight heparin prophylaxis was more effective at preventing thrombotic complications and was at least as safe as standard heparin after total hip arthroplasty. Given that the rates of distal deep vein thrombosis were similar in the two groups, its benefit was restricted to the prevention of proximal deep vein thrombosis. The increased effectiveness of low-molecular-weight heparin at preventing proximal deep vein thrombosis is of considerable clinical importance because these patients are at higher risk for developing pulmonary embolism than are those with isolated distal deep vein thrombosis [17]. The concern about proximal vein thrombosis was reflected in the actual management of our patients; those with proximal deep vein thrombosis remain hospitalized at our medical center for an average of 2 days longer than those with distal deep vein thrombosis. Low-molecular-weight heparin appeared to be more effective at preventing symptomatic pulmonary embolism than did standard heparin, but event rates were low and most of the symptomatic pulmonary emboli occurred in nonblinded studies, introducing the possibility that diagnostic suspicion bias could have influenced the results. No significant differences were observed in the frequency or severity of bleeding complications between the two groups.

Our efficacy and safety data are consistent with the findings of a recent meta-analysis by Nurmohamed and associates [6] who also reported similar findings after orthopedic surgery. Unlike the analysis of Nurmohamed and associates, however, our study included the results of the largest comparative trial of low-molecular-weight heparin and standard heparin published to date [7]. The new information provided by our analysis shows that the benefit of low-molecular-weight heparin is greater for the prevention of proximal deep vein thrombosis.

In doing the meta-analysis, we assumed that the low- molecular-weight heparins tested were clinically equivalent. Although this assumption is likely to be true (we found little evidence of statistical heterogeneity in deep vein thrombosis and bleeding rates between the studies for the low-molecular-weight heparin arms), no direct comparisons of the clinical effectiveness and safety of the various low-molecular-weight heparins have been reported to date.

On the basis of the 2.6 to 1 price ratio between low-molecular-weight heparin and standard heparin in France, our data suggest that the costs averted due to reduced deep vein thrombosis and bleeding more than offset the increased price of low-molecular-weight heparin. For every 1000 patients treated with these regimens, use of low-molecular-weight heparin generates cost savings of about $50 000 to the health care system. However, our sensitivity analysis showed that the cost-effectiveness of low-molecular-weight heparin is dependent on the price ratio between the two drugs and that once this ratio exceeds 3.7, the reduction in the incidence of deep vein thrombosis associated with low-molecular-weight heparin is purchased at an extra cost (see Table 5). The derivation of the 3.7 ratio is statistically uncertain. A conservative estimate is that the threshold value where the use of low-molecular-weight heparin and standard heparin are cost-equivalent lies between 0.8 and 5.5, based on the extremes of the 95% CI of the common odds ratios for deep vein thrombosis and bleeding (see Figure 1).

Several cost-effectiveness analyses have compared alternative methods for the prevention of deep vein thrombosis after orthopedic surgery [18-20]. No previous study, however, has compared the cost-effectiveness of standard heparin with that of low-molecular-weight heparin. In addition, a major limitation of earlier cost-effectiveness studies was their reliance on expert judgment to estimate event rates and costs. A strength of our study is that we were able to determine the resource consequences of deep vein thrombosis and bleeding by secondary analysis of patient-specific data from a clinical trial.

Although we believe our analysis provides a reliable estimate of the cost-effectiveness of low-molecular-weight heparin compared with standard heparin for the prevention of deep vein thrombosis after hip arthroplasty, it has several limitations. First, the cost of treating patients with postoperative deep vein thrombosis was based on a management strategy that may not be regarded as standard care in some North American hospitals. In the trial by Levine and associates [7], which was our main source of cost data, all patients were diagnosed with deep vein thrombosis by postoperative screening venography; those confirmed to have deep vein thrombosis were treated with anticoagulant therapy. This approach is probably the safest for managing deep vein thrombosis after major orthopedic surgery, but it is also relatively expensive because some patients with likely clinically unimportant asymptomatic venous thrombosis remained hospitalized for treatment. In our sensitivity analysis we estimated the cost-effectiveness of low-molecular-weight heparin compared with standard heparin in a hypothetical model where patients did not have routine postoperative screening for deep vein thrombosis. Instead, we modeled that 20% to 60% of patients developing asymptomatic postoperative proximal deep vein thrombosis and 10% of patients with distal deep vein thrombosis subsequently developed symptomatic deep vein thrombosis or pulmonary embolism that required rehospitalization. On the basis of these figures, use of low-molecular-weight heparin still saved money. In addition, our analysis did not include the cost of managing recurrent deep vein thrombosis and the post-thrombotic syndrome, two potentially important long-term complications of deep vein thrombosis. Patients with previous postoperative venous thrombosis have been shown to be at increased risk for recurrent postoperative thrombosis. Also, patients who have been hospitalized in the previous 6 months are at increased risk for developing symptomatic venous thromboembolism [21], possibly because they developed undetected asymptomatic venous thrombosis during their previous admission. Because the post-thrombotic syndrome and recurrent deep vein thrombosis may be chronic disorders that are expensive to treat, their inclusion in the cost analysis would favor the use of low-molecular-weight heparin.

Also, although we have reported costs in U.S. dollars, this should not be taken to mean that these data are generalizable to the United States or other countries without caveats, because health care costs vary between and within countries. However, the cost inferences we draw should be valid in alternate settings provided that the relative prices of resources are similar (for example, the price of physician services relative to that of pharmaceutical agents).

Finally, an unusual feature of our economic evaluation is that it was done before the North American price for low-molecular-weight heparin has been set. We had no information from the manufacturer about the probable price of low-molecular-weight heparin, but we assumed that it would be in the same ratio to the price of standard heparin as found in France. Because of the uncertainty about the North American price of low- molecular-weight heparin, we also compared the cost-effectiveness of low-molecular-weight heparin and standard heparin over a range of price ratios.

On the basis of our study we recommend the use of low-molecular-weight heparin prophylaxis over standard heparin after total hip arthroplasty. Low-molecular-weight heparin is more effective in preventing serious thrombotic complications and it is at least as safe as standard heparin. Further, based on the current French price ratio between the two drugs, the use of low-molecular-weight heparin is likely to be cost-reducing because of the lower costs of managing thrombotic and bleeding complications associated with it. However, our analysis clearly indicates that this cost conclusion is sensitive to the assumed price ratio between the drugs. A new therapeutic intervention need not reduce costs to be cost-effective [22]; however, if low-molecular-weight heparin increases costs, then the issue becomes a judgment of whether the added benefits in terms of deep vein thromboses averted are worth the extra expense. The results of this analysis are probably generalizable to other high-risk situations (such as knee replacement and hip fracture repair). They may not apply to general surgery, however, where the rates of postoperative deep vein thrombosis are lower [6]. Further research is needed to compare the cost-effectiveness of low-molecular-weight heparin with other prophylactic regimens and postoperative deep vein thrombosis management strategies.