From Veterans Affairs Palo Alto Health Care System, Palo Alto, California; and Stanford University Medical Center and Stanford University, Stanford, California. For current author addresses, see end of text.
Background: Low-molecular-weight heparins are effective for treating venous thrombosis, but their cost-effectiveness has not been rigorously assessed.
Objective: To evaluate the cost-effectiveness of low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis.
Design: Decision model.
Data Sources: Probabilities for clinical outcomes were obtained from a meta-analysis of randomized trials. Cost estimates were derived from Medicare reimbursement and other sources.
Target Population: Two hypothetical cohorts of 60-year-old men with acute deep venous thrombosis.
Time Horizon: Patient lifetime.
Perspective: Societal.
Intervention: Fixed-dose low-molecular-weight heparin or adjusted-dose unfractionated heparin.
Outcome Measures: Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. An inpatient hospital setting was used for the base-case analysis. Secondary analyses examined outpatient treatment with low-molecular-weight heparin.
Results of Base-Case Analysis: Total costs for inpatient treatment were $26 516 for low-molecular-weight heparin and $26 361 for unfractionated heparin. The cost of initial care was higher in patients who received low-molecular-weight heparin, but this was partly offset by reduced costs for early complications. Low-molecular-weight heparin treatment increased quality-adjusted life expectancy by approximately 0.02 years. The incremental cost-effectiveness of inpatient low-molecular-weight heparin treatment was $7820 per QALY gained. Treatment with low-molecular-weight heparin was cost saving when as few as 8% of patients were treated at home.
Results of Sensitivity Analysis: When late complications were assumed to occur 25% less frequently in patients who received unfractionated heparin, the incremental cost-effectiveness ratio increased to almost $75 000 per QALY gained. When late complications were assumed to occur 25% less frequently in patients who received low-molecular-weight heparin, this treatment resulted in a net cost savings. Inpatient low-molecular-weight heparin treatment became cost saving when its pharmacy cost was reduced by 31% or more, when it reduced the yearly incidence of late complications by at least 7%, when as few as 8% of patients were treated entirely as outpatients, or when at least 13% of patients were eligible for early discharge.
Conclusions: Low-molecular-weight heparins are highly cost-effective for inpatient management of venous thrombosis. This treatment reduces costs when small numbers of patients are eligible for outpatient management.
This paper is also available at http: //www.acponline.org.
Ann Intern Med.1999;130:789-799.
Low-molecular-weight heparin preparations are as safe and effective as unfractionated heparin for the treatment of acute deep venous thrombosis [1-4]. These preparations have been shown to be cost-effective for thromboprophylaxis after hip replacement surgery compared with low-dose warfarin [5] or unfractionated heparin [6]. We hypothesized that despite their current higher price, low-molecular-weight heparins might also be cost-effective relative to unfractionated heparin for treating established deep venous thrombosis. If therapy with low-molecular-weight heparin resulted in fewer bleeding complications or more effectively prevented thromboembolic recurrences, the costs associated with these events would be reduced.
Substantial additional savings could be realized by avoiding or shortening hospitalization in selected patients who might be eligible for outpatient treatment with low-molecular-weight heparin. The feasibility of outpatient management of venous thrombosis was recently demonstrated in randomized trials [2-4]. Up to 50% of participants in these trials received low-molecular-weight heparin at home. In an uncontrolled trial of dalteparin, 35% of participants were discharged within 24 hours of hospitalization and another 29% were discharged within 72 hours [7]. In this study, low-molecular-weight heparin treatment resulted in large cost reductions compared with historical costs for inpatient care using unfractionated heparin.
We developed a decision model to compare the costs and health effects of low-molecular-weight heparins and unfractionated heparin for the treatment of acute deep venous thrombosis. In our base-case analysis, we assumed that all treatment occurred in an inpatient hospital setting. To fully quantify the potential economic impact of low-molecular-weight heparin treatment, we performed a secondary analysis' that allowed for the possibility of outpatient treatment with this drug.
Methods We performed a cost-effectiveness analysis by using a decision modeling approach [8-10]. We adopted the recommendations of the Panel on Cost-Effectiveness in Health and Medicine for conducting and reporting a reference-case analysis [11]. Accordingly, we assumed a societal perspective to produce results that would permit comparisons across different health care interventions [12]. We expressed our results in terms of costs, life expectancy, quality-adjusted life expectancy, and incremental cost-effectiveness ratios.
Decision Model Structure and Assumptions ( Figure 1) shows the structure of the decision model. The model specifies the clinical problem, treatment alternatives, early clinical outcomes, and late clinical outcomes.
Figure 1. The cost-effectiveness decision model. At left, a square node represents the decision to treat acute deep venous thrombosis (DVT) with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). In the primary analysis, low-molecular-weight heparin treatment always occurred in an inpatient hospital setting. In the secondary analysis, some patients were eligible for early discharge or outpatient treatment, as indicated by the first round uncertainty node. All patients were at risk for early complications. Probabilities for early complications depended on the type of treatment received. Two early complications, major bleeding and pulmonary embolism (PE), were potentially fatal. All patients who did not develop a fatal early complication were at risk for a fatal or nonfatal late complication. Late complications included episodes of recurrent deep venous thrombosis and pulmonary embolism that occurred more than 6 months after the initial episode of deep venous thrombosis, mild and severe postphlebitic syndrome, superficial venous thrombosis, cellulitis, venous ulcer, varicose veins, stasis dermatitis, and deep venous insufficiency. The diamond-shaped nodes at the end of each path in the decision tree represent both the costs and the health effects associated with the full sequence of events in that particular path.
Treatment Alternatives Patients in the unfractionated heparin cohort received continuous intravenous infusion of unfractionated heparin by automatic pump at an average dosage of 30 000 U/d. Treatment was administered for a total of 6 days in a monitored inpatient setting. We assumed that the partial thromboplastin time was monitored on nine occasions in each of these patients and that necessary dose adjustments were made on the basis of this monitoring. Patients in the low-molecular-weight heparin cohort received fixed-dose enoxaparin, 1 mg/kg of body weight subcutaneously, twice daily for 6 days. We assumed that daily phlebotomy for complete blood counts was performed in both cohorts to monitor all hospitalized patients for covert bleeding and thrombocytopenia. We also assumed that oral anticoagulation with warfarin commenced during heparin treatment and continued for at least 3 months.
In the base-case analysis, we assumed that low-molecular-weight heparin treatment was always given in the inpatient setting. In the secondary analysis, we assumed that some patients treated with low-molecular-weight heparin could be discharged from the hospital early or could be treated entirely as outpatients.
Early Complications We defined early complications as those that occurred during the initial heparin treatment period (fatal and nonfatal major bleeding, minor bleeding, and thrombocytopenia) or in the 6 months after the initial episode of deep venous thrombosis (recurrent deep venous thrombosis, fatal and nonfatal pulmonary embolism, or death from other causes). Each of these clinical outcomes was assumed to occur with a probability that depended on the choice of treatment but not on the treatment setting. Major and minor bleeding episodes that occurred during the period of oral anticoagulation were assumed to occur with equal frequencies in the two cohorts.
Late Complications Late complications included episodes of recurrent deep venous thrombosis and pulmonary embolism that occurred more than 6 months after the initial episode of deep venous thrombosis, mild and severe postphlebitic syndrome, superficial venous thrombosis, cellulitis, venous ulcer, varicose veins, stasis dermatitis, and deep venous insufficiency.
Data and Assumptions Probabilities for early and late complications, estimates of survival and quality-adjusted survival, and costs for initial treatment and subsequent care were derived from various clinical and administrative data sources.
Probabilities for Clinical Outcomes Probabilities for early and late complications are summarized in Table 1. Probabilities for early complications were derived from a meta-analysis of randomized trials that compared a low-molecular-weight heparin preparation with unfractionated heparin for treatment of acute deep venous thrombosis [17]. The meta-analysis identified 11 eligible studies [1-4,13-16,19-21]. Clinical outcomes included major and minor bleeding complications and thrombocytopenia during the initial heparin treatment period and recurrent deep venous thrombosis, pulmonary embolism, and mortality in the 6 months after the initial episode of deep venous thrombosis. Because several studies enrolled some patients with calf venous thrombosis [4,14-16,21] and because the natural history of calf venous thrombosis differs from that of proximal thrombosis [22,23], probability estimates for recurrent deep venous thrombosis, pulmonary embolism, and death were derived from a subgroup analysis restricted to patients with proximal thrombosis. We used meta-analysis results that were obtained with a random-effects statistical model because this model produced wider CIs than the fixed-effects model.
Table 1. Baseline Probabilities and Ranges for Clinical Outcomes
Estimation of Life Expectancy We constructed survival curves to model the life span of patients in each cohort from the time of the initial episode of venous thrombosis to death. We used mortality data from the previously described meta-analysis to estimate survival during the first 6 months after deep venous thrombosis. Survival during the next 18 months was based on a single randomized trial of low-molecular-weight heparin treatment in which patients were followed for 2 years [24]. We assumed that survival was identical for the two cohorts after this time. Survival for the period 3 to 15 years after deep venous thrombosis was based on an observational study of long-term complications and survival after acute deep venous thrombosis [25]. To complete survival curves up to 99 years of age, we used data from the 1994 U.S. Life Table formen [26].
Quality-of-Life Adjustments We adjusted life expectancy for quality of life by using health state utilities ( Table 2). Utilities represent an individual patient's preference for a given health state and are scaled from 0 to 1 [30,31]. Quality-adjusted life-years (QALYs) are calculated by multiplying the time spent in a given health state by the utility value for that health state. For the health state associated with no complication after acute deep venous thrombosis, we used age- and sex-specific time-tradeoff utilities obtained from a community sample of adults [27]. Quality weights for mild and severe postphlebitic syndrome were based on standard gamble utilities obtained from healthy volunteers [28]. We assumed that patients who received low-molecular-weight heparin and those who received unfractionated heparin had the same utility for the health state associated with the initial episode of deep venous thrombosis, regardless of whether low-molecular-weight heparin was given in the hospital or outpatient setting. Decrements in utility for recurrent thromboembolic events and treatment complications were expressed in days lost because of hospitalization [29].
Table 2. Estimates for Quality-of-Life Adjustments
Table 3. Cost Estimates*
Cost of Early Complications We assumed that minor bleeding complications and thrombocytopenia each resulted in 1 additional day of hospitalization and 1 additional day of physician services for subsequent hospital care. Because randomized trials have shown that more than half of all thromboembolic recurrences after acute deep venous thrombosis occur after the initial treatment period [1,2,4], we assumed that recurrent deep venous thrombosis and pulmonary embolism would lead to readmission for a full hospital stay. Assigned costs for these complications were based on average Medicare reimbursement for deep venous thrombophlebitis and pulmonary embolism [32]. By definition, major bleeding always occurred during the initial treatment period. We assumed that major bleeding complications were uniformly distributed over this period and that hospital length of stay increased from 0 days if bleeding occurred on the first hospital day to 5 days if bleeding occurred on the sixth hospital day. Therefore, major bleeding resulted in an average additional length of stay of 2.5 days. We assumed that outpatients who developed major bleeding incurred costs for a full hospitalization for gastrointestinal hemorrhage [32].
Cost of Late Complications Costs for late complications were derived from an observational study of long-term complications of deep venous thrombosis in a cohort of 257 Swedish patients, most of whom were probably treated with unfractionated heparin [25]. In this study, the average cost of the initial episode of deep venous thrombosis was based on reported unit prices and was approximately two times greater than our estimate based on Medicare reimbursement. To correct for this discrepancy, we recalculated reported yearly per-patient costs for long-term complications after adjusting for this factor. We assumed that per-patient costs were equal for patients who received low-molecular-weight heparin and those who received unfractionated heparin, but we included these costs because more patients receiving low-molecular-weight heparin were at risk for complications during the first 2 years of follow-up.
Future Health Care Costs Costs of future health care were also included because slightly more patients receiving low-molecular-weight heparin were alive during the first 2 years of follow-up, although the annual costs for each group were again assumed to be equal on a per-patient-at-risk basis. Our estimate for these costs was based on age-specific, average, annual health care expenditures in 1995 [37]. These costs were adjusted by subtracting yearly per-patient costs for long-term complications of deep venous thrombosis.
Time Preference To reflect individual patient preferences for having material goods sooner rather than later, we discounted all costs and health effects at an annual rate of 3% [9]. Discount rates between 0% and 5% were tested in the sensitivity analysis.
Calculation of Incremental Cost-Effectiveness Ratios For each treatment strategy, we calculated the expected value of total costs by multiplying the probability of each unique outcome with its associated costs and then adding these values for all possible outcomes. Life expectancy for each cohort was determined by calculating the area under the survival curves. Quality-adjusted life expectancy was calculated by multiplying the yearly probability of survival by its corresponding quality weight and summing these values over the entire life span. We then calculated the incremental cost-effectiveness of low-molecular-weight heparin relative to unfractionated heparin by dividing the difference in costs by the difference in life expectancy (or quality-adjusted life expectancy). For example, if low-molecular-weight heparin treatment was associated with a total cost of $20 000 and a life expectancy of 10 QALYs and unfractionated heparin was associated with a total cost of $18 000 and a life expectancy of 9.5 QALYs, the incremental cost-effectiveness of treatment with low-molecular-weight heparin would be $4000 per QALY gained ([$20 000 - $18 000]/[10 - 9.5] = $2000/0.5 = $4000).
Sensitivity Analysis We used sensitivity analysis to identify important model uncertainties. When possible, ranges for variables were based on reported or calculated 95% Cls from the data sources. Otherwise, we determined ranges by adding or subtracting 25% from the baseline estimate.
Results Base-Case Analysis Average total costs associated with inpatient treatment with low-molecular-weight heparin were $26 516, whereas costs associated with unfractionated heparin treatment were $26 361, resulting in a net difference of $155 per patient treated. Treatment with low-molecular-weight heparin resulted in 9.43 life-years or 8.00 QALYs, and treatment with unfractionated heparin resulted in 9.41 life-years or 7.98 QALYs. Thus, treatment with low-molecular-weight heparin resulted in a net gain of 0.02 life-years (or 0.02 QALYs). This corresponds to an increase in life expectancy of approximately 8 days. The incremental cost-effectiveness of low-molecular-weight heparin was calculated to be $6910 per life-year gained or $7820 per QALY gained. When compared with cost-effectiveness ratios for other widely accepted medical interventions, inpatient treatment of acute deep venous thrombosis with low-molecular-weight heparin seems to be highly cost-effective [38].
Disaggregated costs for patients who received low-molecular-weight heparin included $3638 for initial treatment, $520 for early complications, $2368 for late complications, and $19 990 for future health care. For patients who received unfractionated heparin, disaggregated costs included $3402 for initial treatment, $664 for early complications, $2346 for late complications, and $19 949 for future health care. These results are summarized in the upper portion of Table 4.
Table 4. Results of the Cost-Effectiveness Analysis*
When we modified our assumptions so that 100% of the low-molecular-weight heparin cohort received outpatient treatment, initial treatment costs were reduced to $1560 and total cost savings amounted to almost $1900 per patient.
Sensitivity Analysis As illustrated in Figure 2, the cost-effectiveness of low-molecular-weight heparin was sensitive to our baseline assumption that late complications occurred with equal frequency in the two treatment cohorts. When these complications were assumed to occur 25% less frequently in patients who received unfractionated heparin, the incremental cost-effectiveness ratio increased to almost $75 000 per QALY gained. Conversely, when we assumed that these complications occurred 25% less frequently in patients who received low-molecular-weight heparin, the latter treatment resulted in a net cost savings. When we tested other model variables over a wide range of values, the cost-effectiveness ratio for inpatient treatment with low-molecular-weight heparin was always less than $25 000 per QALY gained.
Figure 2. Tornado diagram showing the results of univariate sensitivity analyses. The solid vertical line represents the incremental cost-effectiveness of inpatient treatment with low-molecular-weight heparin relative to treatment with unfractionated heparin when all variables were set at their baseline value. Horizontal bars indicate the range in incremental cost-effectiveness ratios obtained by setting each variable at the lower and upper limit of its range and holding all other variables constant at their baseline value. Incremental cost-effectiveness ratios less than $0 (dashed vertical line) indicate that treatment with low-molecular-weight heparin is cost saving. The cost-effectiveness of inpatient treatment with low-molecular-weight heparin was sensitive to only one variable: the effectiveness in preventing late complications. When other model variables were tested over a wide range of values, the cost-effectiveness ratio for inpatient treatment with low-molecular-weight heparin was always less than $25 000 per quality-adjusted life-year (QALY) gained.
( Figure 3) illustrates the results of a sensitivity analysis that varied three model variables: pharmacy costs for low-molecular-weight heparin, treatment costs for early complications, and the effectiveness of low-molecular-weight heparins in preventing early complications. Because probabilities and costs for early complications represented bundled values for multiple different complications, these three variables encompassed most of the variables in the model and allowed us to examine the combined influence of as many potentially important variables as possible. Although we widely varied our baseline estimates, the cost-effectiveness ratio for inpatient treatment with low-molecular-weight heparin was almost always less than $25 000 per QALY except when it was assumed to be at the lower limit of effectiveness in preventing early complications and when the pharmacy cost was $105 per day or more.
Figure 3. Results of multivariate sensitivity analysis. Each solid line indicates the incremental cost-effectiveness of inpatient treatment with low-molecular-weight heparin relative to unfractionated heparin at various levels of pharmacy costs for low-molecular-weight heparin. The middle line (circles) represents baseline assumptions about the effectiveness of low-molecular-weight heparin in preventing early complications. The upper (diamonds) and lower (triangles) lines represent the incremental cost-effectiveness of low-molecular-weight heparin treatment at its lower and upper limits of effectiveness in preventing early complications. Vertical bars represent the effect of varying the cost of treating early complications by +/- 25%. A negative cost-effectiveness ratio indicates that low-molecular-weight heparin is a cost-saving strategy. The cost-effectiveness ratio for inpatient treatment with low-molecular-weight heparin was almost always less than $25 000 per quality-adjusted life-year (QALY) except when low-molecular-weight heparin was assumed to be at the lower limit of effectiveness in preventing early complications and the pharmacy cost was $105 (125% of the baseline estimate) or greater.
When we considered the possibility of outpatient management, we found that low-molecular-weight heparins provided substantial cost savings under a series of reasonable assumptions about patient eligibility and resource utilization. When just more than half of all patients were eligible for partial or complete outpatient management, treatment with low-molecular-weight heparin saved an average of $790 per patient treated. Our threshold analysis revealed that low-molecular-weight heparin treatment achieved dominance when as few as 8% of patients were treated as outpatients or when at least 13% were discharged after 3 days of hospitalization.
Sensitivity testing demonstrated that our conclusions about effectiveness were robust over a wide range of values for almost all important model uncertainties. One exception to this involved the relative effectiveness of low-molecular-weight heparin in preventing late complications. When we assumed that unfractionated heparin was 25% more effective than low-molecular-weight heparin for preventing late complications, the cost-effectiveness ratio approached $75 000 per QALY. However, we believe it is more likely that late complications would occur either with equal or lower frequency in patients receiving low-molecular-weight heparin; two studies have demonstrated superior thrombus resolution after treatment with low-molecular-weight heparin [13,19], whereas other studies have shown no difference between treatments in the degree of venographic improvement [14-16,21].
Our conclusions complement and extend the findings of other investigators. In an observational study of the feasibility of outpatient treatment with dalteparin, 35% of patients were discharged within 24 hours and more than half were discharged within 3 days [7]. Total treatment costs were reduced by almost 35% compared with costs for historical controls who had received unfractionated heparin in the inpatient setting. The findings of this study are limited by its use of historical controls and incompletely described methods for calculating costs. We found that costs for initial treatment and early complications were reduced by almost 25% when outpatient treatment with low-molecular-weight heparin was possible.
Hull and colleagues [39] performed an economic analysis by using data from a single multicenter randomized trial. These investigators reported that inpatient treatment with tinzaparin was less costly than treatment with unfractionated heparin and calculated a net savings of approximately $40 per patient treated. This analysis differed from ours in several respects. First, we assumed a societal perspective, whereas Hull and colleagues adopted the perspective of a third-party payer. Second, we pooled data from multiple sources, whereas these authors collected data on effectiveness and costs from collaborating centers. Third, because we used a modeling approach, we were able to extend the time horizon of our analysis to cover the entire life span of each patient, whereas their time horizon was necessarily restricted to the duration of the trial. Finally, our assigned pharmacy costs for low-molecular-weight heparin, which were based on the average wholesale price, were much higher than Hull and colleagues' hospital-derived costs. Our use of average wholesale prices was appropriate for the societal perspective of this analysis because they closely approximate true opportunity costs [40].
Our study has several limitations. Our probability estimates for early complications were based on studies that evaluated multiple, different low-molecular-weight heparin preparations. Because these preparations differ in their molecular weight, anti-factor Xa activity, and degree of protein binding, they may differ with respect to their safety and effectiveness [41]. By using results from multiple studies, we implicitly assumed that all preparations were equally safe and effective. Little evidence exists to support or refute this assumption. Of the five low-molecular-weight heparin preparations that have been studied for treating venous thrombosis, two are available for use in the United States: enoxaparin and dalteparin. We based our pharmacy costs on the average wholesale price of enoxaparin. Of note, the average wholesale price for dalteparin is less than that for enoxaparin but is not less than the cost-saving threshold of $58 per day.
An additional limitation involves our assumption that clinical effectiveness was independent of the treatment setting. Those who received outpatient treatment with low-molecular-weight heparin had the same risk for bleeding complications and recurrences as those who were treated as inpatients. This assumption has not been confirmed in clinical trials. In fact, meta-analysis results suggest that low-molecular-weight heparins may have been more effective in preventing major bleeding complications in inpatient treatment studies compared with studies in which outpatient treatment was possible [17]. However, these studies did not report bleeding outcomes separately for inpatients and outpatients; thus, reliable estimates of bleeding complications in outpatients are not available.
Some assumptions potentially bias our analysis in favor of unfractionated heparin. Low-molecular-weight heparin treatment would have been more strongly favored if we had considered nursing time costs for drug administration or if we had not assumed that inpatient and outpatient treatment had the same utility.
We conclude that low-molecular-weight heparins are highly cost-effective relative to unfractionated heparin for inpatient treatment of acute deep venous thrombosis. Outpatient treatment with low-molecular-weight heparin holds potential for substantial cost savings. Although decisions about resource utilization are always subject to budgetary constraints, it would be reasonable to treat hospitalized patients with low-molecular-weight heparin. Outpatient treatment with low-molecular-weight heparin in eligible patients not only is beneficial from the societal perspective but also is likely to be a highly attractive option for many individual patients.
Grant Support: By grant HS00028-11 from the Agency for Health Care Policy and Research, Rockville, Maryland.
Request for Reprints: Michael K. Gould, MD, MSc, Pulmonary and Critical Care Section, 111P, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304; e-mail, gould@stanford.edu.
Current Author Addresses: Dr. Gould: Pulmonary and Critical Care Section, 111P, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304.
Dr. Dembitzer: Department of Medicine, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, CA 94304.
Dr. Sanders: Department of Medicine, HRP Redwood Building T242, Stanford University Medical Center, Stanford, CA 94305. Dr. Garber: Center for Primary Care and Outcomes Research, Stanford University Medical Center, 30 Alta Road, Stanford, CA 94305.
REFERENCES 1. Hull RD, Raskob GE, Pineo GF, Green D, Trowbridge AA, Elliott CG, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med. 1992;326:975-82. [Medline Link] [Context Link]
2. Koopman MM, Prandoni P, Piovella F, Ockelford PA, Brandjes DP, van der Meer J, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. N Engl J Med. 1996;334:682-7. [Fulltext Link] [Medline Link] [Context Link]
3. Levine M, Gent M, Hirsh J, Leclerc J, Anderson D, Weitz J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med. 1996;334:677-81. [Fulltext Link] [Medline Link] [Context Link]
4. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. The Columbus Investigators. N Engl J Med. 1997;337:657-62. [Medline Link] [Context Link]
5. Menzin J, Colditz GA, Regan MM, Richner RE, Oster G. Cost-effectiveness of enoxaparin vs low-dose warfarin in the prevention of deep-vein thrombosis after total hip replacement surgery. Arch Intern Med. 1995;155:757-64. [Fulltext Link] [Medline Link] [Context Link]
6. Anderson DR, O'Brien BJ, Levine MN, Roberts R, Wells PS, Hirsh J. Efficacy and cost of low-molecular-weight heparin compared with standard heparin for the prevention of deep vein thrombosis after total hip replacement. Ann Intern Med. 1993;119:1105-12. [Medline Link] [Context Link]
7. Lindmarker P, Holmstrom M. Use of low molecular weight heparin (dalteparin), once daily, for the treatment of deep vein thrombosis. A feasibility and health economic study in an outpatient setting. Swedish Thrombosis Dalteparin Trial Group. J Intern Med. 1995;240:395-401. [Medline Link] [Context Link]
8. Russell LB, Gold MR, Siegel JE, Daniels N, Weinstein MC. The role of cost-effectiveness analysis in health and medicine. Panel on Cost-Effectiveness in Health and Medicine. JAMA. 1996;276:1172-7. [Context Link]
9. Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the Panel on Cost-effectiveness in Health and Medicine. JAMA. 1996;276:1253-8. [Fulltext Link] [Medline Link] [Context Link]
10. Drummond MF, Richardson WS, O'Brien BJ, Levine M, Heyland D. Users' guides to the medical literature. XIII. How to use an article on economic analysis of clinical practice. A. Are the results of the study valid? Evidence-Based Medicine Working Group. JAMA. 1997;277:1552-7. [Fulltext Link] [Medline Link] [Context Link]
11. Gold MR, Siegel JE, Russell LB, Weinstein MC, eds. Cost-Effectiveness in Health and Medicine. New York: Oxford Univ Pr; 1996. [Context Link]
12. Russell LB, Siegel JE, Daniels N, Gold MR, Luce BR, Mandelblatt JS. Cost-effectiveness analysis as a guide to resource allocation in health: roles and limitations. In: Gold MR, Siegel JE, Russell LB, Weinstein MC, eds. Cost-Effectiveness in Health and Medicine. New York: Oxford Univ Pr; 1996:3-24. [Context Link]
13. Simonneau G, Charbonnier B, Decousus H, Planchon B, Ninet J, Sie P, et al. Subcutaneous low-molecular-weight heparin compared with continuous intravenous unfractionated heparin in the treatment of proximal deep vein thrombosis. Arch Intern Med. 1993;153:1541-6. [Medline Link] [Context Link]
14. Lindmarker P, Holmstrom M, Granqvist S, Johnsson H, Lockner D. Comparison of once-daily subcutaneous Fragmin with continuous intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemost. 1994;72:186-90. [Medline Link] [Context Link]
15. Fiessinger J, Lopez-Fernandez M, Gatterer E, Granqvist S, Kher A, Olsson CG, et al. Once-daily subcutaneous dalteparin, a low molecular weight heparin, for the initial treatment of acute deep vein thrombosis. Thromb Haemost. 1996;76:195-9. [Medline Link] [Context Link]
16. Luomanmaki K, Granqvist S, Hallert C, Jauro I, Ketola K, Kim HC, et al. A multicentre comparison of once-daily subcutaneous dalteparin (low molecular weight heparin) and continuous intravenous heparin in the treatment of deep vein thrombosis. J Intern Med. 1996;240:85-92. [Medline Link] [Context Link]
17. Gould MK, Dembitzer AD, Doyle RL, Hastie TJ, Garber AM. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. Ann Intern Med. 1999;130:800-9. [Fulltext Link] [Medline Link] [CINAHL Link] [Context Link]
18. Prandoni P, Lensing AW, Cogo A, Cuppini S, Villalta S, Carta M, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125:1-7. [Fulltext Link] [Medline Link] [Context Link]
19. A randomised trial of subcutaneous low molecular weight heparin (CY 216) compared with intravenous unfractionated heparin in the treatment of deep vein thrombosis. A collaborative European multicentre study. Thromb Haemost. 1991;65:251-6. [Medline Link] [Context Link]
20. Prandoni P, Lensing AW, Buller HR, Carta M, Cogo A, Vigo M, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet. 1992;339:441-5. [Medline Link] [Context Link]
21. Lopaciuk S, Meissner AJ, Filipecki S, Zawilska K, Sowier J, Ciesielski L, et al. Subcutaneous low molecular weight heparin versus subcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicenter trial. Thromb Haemost. 1992;68:14-8. [Medline Link] [Context Link]
22. Philbrick JT, Becker DM. Calf deep venous thrombosis. A wolf in sheep's clothing? Arch Intern Med. 1988;148:2131-8. [Medline Link] [Context Link]
23. Passman MA, Moneta GL, Taylor LM Jr, Edwards JM, Yeager RA, McConnell DB, et al. Pulmonary embolism is associated with the combination of isolated calf vein thrombosis and respiratory symptoms. J Vasc Surg. 1997;25:39-45. [Medline Link] [Context Link]
24. Leizorovicz A. Efficacy and safety of low molecular weight heparin (enoxaparin) and unfractionated heparin in proximal deep vein thrombosis [Abstract]. Thromb Haemost. 1997;Suppl:290. [Context Link]
25. Bergqvist D, Jendteg S, Johansen L, Persson U, Odegaard K. Cost of long-term complications of deep venous thrombosis of the lower extremities: an analysis of a defined patient population in Sweden. Ann Intern Med. 1997;126:454-7. [Fulltext Link] [Medline Link] [Context Link]
26. National Center for Health Statistics. Abridged U.S. Life Tables. Hyattsville, MD: U.S. Department of Health and Human Services; 1994. Available at http://www.cdc.gov/nchswww. [Context Link]
27. Fryback D, Dasbach E, Klein R, Klein BE, Dorn N, Peterson K, et al. The Beaver Dam Health Outcomes Study: initial catalog of health-state quality factors. Med Decis Making. 1993;13:89-102. [Medline Link] [Context Link]
28. Lenert LA, Soetikno RM. Automated computer interviews to elicit utilities: potential applications in the treatment of deep venous thrombosis. J Am Med Inform Assoc. 1997;4:49-56. [Medline Link] [CINAHL Link] [Context Link]
29. HCIA, Inc. Length of Stay by Diagnosis, United States. Baltimore: HCIA; 1997. [Context Link]
30. Torrance G. Measurement of health state utilities for economic appraisal: a review. Journal of Health Economics. 1986;5:1-30. [Context Link]
31. Froberg D, Kane R. Methodology for measuring health-state preferences-II: Scaling methods. J Clin Epidemiol. 1989;42:459-71. [Medline Link] [Context Link]
32. Health Care Financing Administration. Medicare Provider Analysis and Review. Hyattsville, MD: U.S. Department of Health and Human Services; 1995. Available: http://www.hcfa.gov/stats/stats.htm. [Context Link]
33. Physicians' Current Procedural Terminology. Chicago: American Medical Assoc; 1996. [Context Link]
34. Drug Topics Red Book. Montvale, NJ: Medical Economics; 1997. [Context Link]
35. Health Care Financing Administration. 1997 adjusted average per capita cost (AAPCC) for Tax Equity and Fiscal Responsibility Act of 1982 (TERFA) risk contractors-information. Hyattsville, MD: U.S. Department of Health and Human Services; 1997. Available at http://www.hcfa.gov/stats/cover97.txt. [Context Link]
36. Bureau of Labor Statistics. National Current Employment Statistics. Washington, DC: U.S. Department of Labor; 1997. Available at http://stats.bls.gov/ceshome.htm. [Context Link]
37. Bureau of Labor Statistics. Consumer Expenditure Survey. Washington, DC: U.S. Department of Labor; 1995. Available at http://stats.bis.gov/csxhome.htm. [Context Link]
38. Siegel JE, Weinstein MC, Torrance GW. Reporting cost-effectiveness studies and results. In: Gold MR, Siegel JE, Russell LB, Weinstein MC, eds. Cost-Effectiveness in Health and Medicine. New York: Oxford Univ Pr; 1996:276-303. [Context Link]
39. Hull R, Raskob G, Rosenbloom D, Pineo GF, Lerner RG, Gafni A, et al. Treatment of proximal vein thrombosis with subcutaneous low-molecular-weight heparin vs intravenous heparin. An economic perspective. Arch Intern Med. 1997;157:289-94. [Fulltext Link] [Medline Link] [Context Link]
40. Luce BR, Manning WG, Siegel JE, Liscomb J. Estimating costs in cost-effectiveness analysis. In: Gold MR, Siegel JE, Russell LB, Weinstein MC, eds. Cost-Effectiveness in Health and Medicine. New York: Oxford Univ Pr; 1996:176-213. [Context Link]
41. Weitz J. Low-molecular-weight heparins. N Engl J Med. 1997;337:688-98. [Fulltext Link] [Medline Link] [CINAHL Link] [Context Link]