Low-Molecular-Weight Heparins Compared with Unfractionated Heparin for Treatment of Acute Deep Venous Thrombosis: A Cost-Effectiveness Analysis

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. DVT UFH LMWH PE Clinical Problem The target population for this analysis was all adult patients with a confirmed diagnosis of acute, proximal, lower-extremity deep venous thrombosis. We compared treatment costs and clinical outcomes in two hypothetical cohorts of 10 000 patients with acute deep venous thrombosis. In each cohort, the representative patient was a 60-year-old, 75-kg man. We selected this patient because in randomized trials of low-molecular-weight heparin, slightly more than half of all participants were men, and in most of these trials, the mean age of participants was 57 to 64 years (2-4, 13-16). 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 We used data from an observational study of the long-term course of acute deep venous thrombosis to estimate incidence rates for mild and severe postphlebitic syndrome (18). We assumed that incidence rates for these complications were equal for the two treatment cohorts, because this study did not compare rates in patients who received low-molecular-weight heparin and those who received unfractionated heparin. 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 for men (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 Cost of Initial Treatment To calculate the cost of inpatient treatment with heparin, we added costs for hospital care, physician services, and 6 days of treatment with either low-molecular-weight heparin or unfractionated heparin. Hospital costs were based on average Medicare reimbursement for deep venous thrombophlebitis in 1995 (32) minus the estimated pharmacy and supply cost