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ORIGINAL RESEARCH |
From the Divisions of Gynecologic Oncology and General Obstetrics and Gynecology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina.
Address reprint requests to: Daniel L. Clarke-Pearson, MD Division of Gynecologic Oncology Duke University Medical Center Box 3079 Durham, NC 27710
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Abstract |
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Methods: A model was constructed to estimate the costs and outcomes associated with the use of external pneumatic compression, unfractionated heparin, and low molecular weight heparin in women with cervical, endometrial, and ovarian cancer. We estimated cost per DVT prevented, per fatal pulmonary embolus (PE) prevented, and per life-year saved. Probability estimates for various outcomes and efficacies were obtained from the literature, using data specific for gynecologic patients when available.
Results: Cost-effectiveness estimates ranged from $27 per life-year saved for a 55-year-old endometrial cancer patient to $5132 per life-year saved for a 65-year-old with ovarian cancer. Although low molecular weight heparin and unfractionated heparin were cost-effective compared with no prophylaxis, each was less effective than external pneumatic compression in the base case. The results of the analysis were sensitive to assumptions about the relative risk of DVT, the life expectancy of the patient, the costs of future treatment, and the relative effectiveness of the different strategies: If unfractionated heparin or low molecular weight heparin is at least 2–3% more effective than external pneumatic compression, then the incremental cost per life-year of either would be less than $50,000 compared with external pneumatic compression.
Conclusion: Prophylaxis of DVT is cost-effective in terms of life-years gained even for patients with relatively short life expectancies, such as ovarian cancer patients. External pneumatic compression appears to be the most cost-effective strategy under our baseline assumptions, but further studies in gynecologic cancer are needed to validate our conclusions.
Deep venous thrombosis (DVT) and pulmonary embolism (PE) are two major complications that result in significant morbidity and mortality after surgery for gynecologic malignancy. Deep venous thrombosis has been observed postoperatively in approximately 38% of postoperative gynecologic oncology patients.1 Pulmonary embolism accounts for 3% of all deaths following gynecologic surgery2 and is a leading cause of postoperative death in the highest risk patients with uterine, ovarian, or cervical carcinoma.3 The majority of patients experiencing fatal thromboembolism are diagnosed at autopsy.4,5 Prophylaxis against DVT should therefore be used in an effort to decrease the incidence of PE. In addition, the incidence of recurrent DVT and postthrombotic syndrome may be as high as 28% in patients with ongoing risk factors such as cancer.6
Gynecologic oncologists in the perioperative setting use pharmacologic and mechanical methods of thromboembolism prophylaxis. Low-dose unfractionated heparin given 5000 units subcutaneously every 8 hours significantly lowers the rate of postoperative thromboembolic events, whereas a regimen of 5000 units subcutaneously every 12 hours is ineffective for gynecologic oncology patients.7 External pneumatic compression when compared with low-dose unfractionated heparin provides a similar risk reduction in DVT without an increased frequency of bleeding complications.8 Recent studies suggest that low molecular weight heparin also is associated with fewer bleeding complications when compared with unfractionated heparin, making it more cost-effective among some patient populations.9,10 At our institution, the cost of external pneumatic compression and low molecular weight heparin is approximately three-fold higher than the cost of unfractionated heparin given over the same perioperative interval. The objective of this investigation was to estimate the cost-effectiveness of these three commonly used methods of thromboembolism prophylaxis in patients undergoing major pelvic and abdominal surgery for gynecologic malignancy.
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Methods |
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). This model was applied to three hypothetical populations of patients routinely seen in gynecologic oncology: a 35-year-old woman with stage IB cervix cancer, a 55-year-old woman with stage IA endometrial cancer, and a 65-year-old woman with stage IIIC ovarian cancer. The model was constructed and all calculations performed using DATA 3.0 (Tree-Age Software, Boston, MA).
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).11–71 We estimated a baseline risk for DVT in patients without malignancy of 6%, based on data from our previous studies.11
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We assumed that the risk of DVT would vary among our three populations. We previously have shown a greater than four-fold difference in risk of DVT between patients with gynecologic malignancy and patients with benign disease.11 For our base case estimates of risk in each type of cervical cancer, we made the following assumptions. First, because previous data have shown that the risk of coagulation abnormalities associated with gynecologic cancer is related directly to the stage of disease, age greater than 40, and length of surgery,72 we assumed that a 35-year-old patient undergoing a radical hysterectomy for stage IB cervical cancer had a DVT risk of 50% higher than that of a patient with benign disease. Second, we assumed that, based on age and the association of obesity with endometrial cancer, that a 55-year-old with stage I endometrial cancer had a two-fold increase in DVT risk. Finally, we assumed that a 65-year-old with stage IIIC ovarian cancer has a four-fold relative risk of DVT compared with the patient with cervical cancer.
The direct medical costs associated with each of the prophylactic methods were determined using a medical center perspective and Duke University Health System charges as a proxy for costs (Table 2). Although we were unable to measure the indirect costs of nursing, we assumed that most of these extra costs of prophylaxis are reflected in the charge. Costs were estimated in 1998 dollars, based on 5 days of treatment and discounted at 3% annually.
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Once a patient is diagnosed with DVT or PE, she typically undergoes anticoagulation with intravenous heparin started with a bolus of 5000 units followed by approximately 1300 units/hour (estimated total cost $28.09). On the second day of heparin infusion, warfarin is begun at a dosage of 10 mg/day for 2 days and then changed to 5 mg/day for days 4–90 (estimated total cost $3.60). Approximately seven activated partialthromboplastin tests are required for management of heparin infusion and international normalized ratio is checked daily on days 3–5 and weekly on days 6–90 (estimated total cost $470).
Calculating the costs associated with bleeding complications secondary to either heparin treatment was somewhat difficult because the practice at our institution for some time has been to use external pneumatic compression. We examined average charges for gynecologic malignancy related Diagnostic Related Groups (DRGs) in the Health Care Financing Administration Medicare Provider Analysis and Review database for 1997 (http://www.hcfa.gov/stats/medpar/ss97d&s.txt). For ovarian and cervical cancer, uncomplicated and complicated cases are given a single DRG. For endometrial cancer, the difference in average costs between a case with a complication or comorbidity (DRG 354) and one without complications or comorbidity (DRG 355) is $3300. The difference in average cost between admissions with a primary DRG for a surgical complication (DRG 442) and one with a medical complication (DRG 452) is approximately $6900. This reimbursement covers treatments (either surgical or medical) for injuries with complicating or comorbid conditions related to administration of anticoagulants. Using these estimates, we assumed that a medical complication would require 2 additional days in the hospital with blood transfusions, for an approximate excess cost of $1500. Similarly, a bleeding complication requiring reoperation was assumed to cost an additional $4500.
To estimate the cost of life-years saved in ovarian cancer patients, postoperative chemotherapy cost had to be considered because these costs would not be incurred if the patient died in the immediate postoperative period from a PE. Most of our patients undergo treatment with six cycles of carboplatin (area under curve 5) and paclitaxel (175 mg/m2) following primary cytoreduction. The dosages of chemotherapy were based on a 65-year-old woman with creatinine of 0.6 mg/dL, height of 55 inches, and weight of 140 lb.
We also performed analyses using cost estimates from two recently published economic analyses, one comparing low-dose and low molecular weight heparin for prevention of DVT in colorectal surgery,76 and one comparing unfractionated heparin with low molecular weight heparin in the treatment of thromboembolic disease (Table 2
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The cost-effectiveness of DVT prophylaxis was measured in three ways: cost per fatal PE prevented, cost per DVT prevented, and cost per life-year saved. Age-specific death rates from causes other than gynecologic cancer were obtained from published life-tables (http://www.cdc.gov/nchswww/daa/gm291_1.pdf). We used published 5-year survival rates for each stage of cancer78 and assumed that after 5 years survival was equivalent to women of the same age without cancer. Incremental cost-effectiveness ratios (the additional cost per additional unit of effectiveness) were calculated for the different prophylactic regimens for each patient population.
Because of a high degree of uncertainty about most parameters, especially the relative effectiveness of low molecular weight heparin compared with external pneumatic compression, we varied the values for costs and effectiveness across the ranges illustrated in Tables 1 and 2 to determine their effect on our estimates of cost-effectiveness.
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Results |
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. The average and incremental cost per patient, the number of DVTs and fatal PEs prevented per 1000 women, the average life expectancy (discounted at 3% annually), and the incremental cost per life-year saved is listed for each of the three clinical scenarios under the base case assumptions. External pneumatic compression was the most cost-effective strategy in each of the three patient groups. None of the three methods of prophylaxis was cost-saving under our base case assumptions. In other words, the net costs of strategies involving prophylaxis for all patients are greater than the net costs of no prophylaxis and treating those women who do develop thromboembolism.
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In our sensitivity analysis, variables that had the strongest impact on cost-effectiveness estimates were the probability of DVT and PE, the cost of treating disease in patients who do not experience a fatal PE, and life expectancy as predicted from our findings in the three different clinical scenarios. However, even if the cost of treating ovarian cancer patients exceeds $100,000, the cost per life-year saved for prophylaxis compared with no prophylaxis is still $20,215, well below the costs of other interventions commonly believed to be cost-effective.79 Under many assumptions (higher probabilities of DVT and PE in cervical cancer and endometrial cancer, for example), prophylaxis results in cost savings compared with no prophylaxis.
Comparing unfractionated heparin with low molecular weight heparin, we found that unfractionated heparin was preferred unless the cost of surgical management of bleeding complications was greater than $11,500 or the cost of medical management was greater than $4000.
The risk reduction estimates for low molecular weight heparin and external pneumatic compression in the base case analysis were 68% and 69%, respectively. Variation of the risk-reduction estimate of DVT for low molecular weight heparin and external pneumatic compression was performed to determine the subsequent effects on cost analysis. We identified thresholds in each of the three clinical scenarios at which the incremental cost-effectiveness ratio for low molecular weight heparin compared with external pneumatic compression became less than $50,000 per life-year saved. This threshold in low molecular weight heparin risk reduction for the 35-year-old cervical cancer patient, 55-year-old endometrial cancer patient, and 65-year-old ovarian cancer patient was 72%, 71%, and 70%, respectively (compared with 69% for external pneumatic compression). A risk-reduction estimate below this threshold indicated that low molecular weight heparin was cost-effective compared with external pneumatic compression. Similar findings were found for unfractionated heparin.
Because compliance with pneumatic compression devices may not be optimal in some clinical settings,79 we also varied the relative efficacy of intermittent pneumatic compression compared with the base case estimates for low molecular weight and unfractionated heparins. Even at levels of effectiveness 50% lower than the base case, intermittent pneumatic compression remained the least costly strategy. However, because the effectiveness of intermittent pneumatic compression was decreased, we were able to identify thresholds at which the incremental cost-effectiveness of unfractionated heparin was less than $50,000 per life-year. In all scenarios, this reduction was approximately 5% from the baseline; in other words, if the effectiveness of intermittent pneumatic compression was 95% of the baseline estimate of 69% (0.95 x 0.69, or 65.5%), then the incremental cost/life-year saved for unfractionated heparin was less than $50,000.
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Discussion |
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Under our base case assumptions, external pneumatic compression was the most cost-effective modality, followed by unfractionated heparin, then by low molecular weight heparin. External pneumatic compression is preferred over unfractionated heparin, despite its significantly higher cost, because of a slightly higher effectiveness estimate and because of the lack of bleeding complications, which add significantly to the average cost. Unfractionated heparin is preferred over low molecular weight heparin because of lower treatment costs and only slightly lower complication rates; if the costs of complications increase significantly, then low molecular weight heparin is favored.
Cost-effectiveness varied based on the risk of DVT/PE, the underlying life expectancy of a given patient, and the costs associated with treating cancer in patients who do not experience a fatal PE. Although external pneumatic compression was found to be the most cost-effective method using our model, sensitivity analysis indicated that relatively small changes in the DVT risk-reduction estimate for low molecular weight heparin or unfractionated heparin (69% to 72%, 71%, or 70%, respectively) resulted in a threshold at which the added cost per life-year saved was reasonable (less than $50,000) in each of the three clinical scenarios. Alternatively, reduced efficacy of external compression secondary to poor compliance outside of clinical trials or centers with experience in the use of this modality makes the use of unfractionated heparin well within accepted ranges for cost-effectiveness. Randomized trials directly comparing low molecular weight heparin and external pneumatic compression will allow more precise estimation of their relative cost-effectiveness in gynecologic oncology patients. However, the sample size needed to demonstrate a small difference in efficacy would be quite large. For example, if the baseline incidence of DVT in a given population of high-risk patients is 20%, the effectiveness of external pneumatic compression is 70% (ie, reduction in incidence from 20% to 6%), and the effectiveness of low molecular weight heparin is 75% (reduction to 5%), the number of subjects per treatment needed to demonstrate this difference with an 
of .05 and a ß of .20 is 6445.
For a 65-year-old with advanced ovarian cancer with a high risk of DVT but a low life expectancy, the cost per life-year saved ($5132) is well below the commonly used threshold of $50,000 per life-year gained used to assess cost-effectiveness.79 Although incorporating the cost of chemotherapy into the evaluation of DVT prophylaxis may seem unethical to some, including these costs in a cost analysis is supported by some experts.81 If these costs are ignored, the cost-effectiveness ratio remains quite low, only $2505 per life-year saved. Our estimates probably underestimate the true cost of ovarian cancer care after the initial surgical procedure because most patients receive additional chemotherapy regimens as well as other surgical procedures in the treatment of their disease. Our cost estimate for chemotherapy ($20,801) was based on a patient who received six cycles of carboplatin and paclitaxel after undergoing primary debulking. Our model suggests that DVT prophylaxis is cost-effective even in ovarian cancer patients who went on to receive future salvage chemotherapy because the incremental cost-effectiveness ratio remained well below $50,000 even if the estimated cost of treatment was $100,000. Incorporating the costs of care for those patients with cervical or endometrial cancer who require adjunctive treatment also did not affect our findings.
Our life expectancy estimates may seem abnormally low for early stage cervical and endometrial cancer patients and abnormally high for advanced stage ovarian cancer patients. In the case of cervical and endometrial cancer patients, this is because of discounting, for which the value of future health is decreased by a fixed percentage each year to account for preferences for present health over future health. In the case of ovarian cancer patients, this is because of the use of mean rather than median life expectancy in our calculations. Although the median life expectancy of ovarian cancer patients is on the order of 3 years, the 50% of patients with life spans longer than 3 years make the mean life expectancy roughly 6 years.
Our analysis differs from previously published cost-effectiveness analyses of DVT prophylaxis in that we used cost per life-year saved, rather than cost per death prevented or cost per DVT prevented as our main measure. This allows comparison of DVT prophylaxis with other health interventions. For example, the cost per life-year saved for annual Papanicolaou smears compared with biennial smears is more than $100,000.82 Clearly, DVT prophylaxis, even for patients with relatively short life expectancies, is a reasonable use of health care resources.
There are several limitations to our study. First, our estimates for costs are based on several sources, primarily hospital charges. Although charges do not reflect true costs, they are a frequently used proxy when other measures are not available. Our estimates are somewhat lower than those of Etchells et al,76 but the marginal differences between unfractionated and low-molecular weight heparin are within $10 of each other. Because the cost-effectiveness ratio stayed below the $50,000 threshold in all sensitivity analyses, we believe our conclusions are robust across a wide range of possible probability estimates and treatment costs. Second, we did not incorporate patient preferences for treatments or outcomes. Patient values clearly play an important role, and incorporating quality-of-life measures may lead to somewhat different results. For example, some patients may strongly prefer daily injections with a low molecular weight heparin to compression boots. Our group currently is conducting a prospective trial to collect such patient information. Third, the quality of the evidence on the relative effectiveness of each of the regimens in gynecologic cancer patients is variable. Although there are randomized trial data comparing unfractionated heparin and external pneumatic compression in these patients, data on low molecular weight heparin, especially in comparison with the other modalities, is limited to observational studies. Given the relatively small differences in efficacy estimates, and the potential impact of variables such as compliance and relative efficacy on cost-effectiveness estimates, more precise estimates of relative efficacy are needed.
We conclude that DVT prophylaxis in all patients undergoing surgery for gynecologic malignancy is cost-effective using conventional criteria. Under our baseline assumptions, external pneumatic compression appears to be the most economical choice. However, in settings in which compliance with external pneumatic compression may be poor, unfractionated heparin may be preferred. Finally, further trials comparing external pneumatic compression and low molecular weight heparin that incorporate patient preference measures are needed to better estimate the relative cost-effectiveness of low molecular weight heparin in this patient population.
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Footnotes |
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Received March 8, 1999. Received in revised form July 20, 1999. Accepted August 5, 1999.
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