Alex C. Spyropoulos, MD; Judith S. Hurley, MS, RD; Gabrielle N. Ciesla, MS; and Gregory de Lissovoy, PhD, MPH

Management of Acute Proximal Deep Vein Thrombosis* Pharmacoeconomic Evaluation of Outpatient Treatment With Enoxaparin vs Inpatient Treatment With Unfractionated Heparin Alex C. Spyropoulos, MD; Judith S. Hurley, MS, RD; Gabrielle N. Ciesla, MS; and Gregory de Lissovoy, PhD, MPH Objectives: A landmark Canadian randomized controlled clinical trial compared treatment of acute proximal vein thrombosis via low-molecular-weight heparin (LMWH) [enoxaparin] administered primarily at home with IV unfractionated heparin (UH) in the hospital. Results demonstrated equivalent safety and efficacy for home care with enoxaparin with a reduction in cost. Our objective was to validate these findings in the routine practice setting of a US health maintenance organization. Design: Retrospective analysis of medical and administrative records of health-plan members meeting inclusion-exclusion criteria of the Canadian trial during the period from 1995 to 1998. Setting: Staff-model health maintenance organization serving New Mexico. Patients: Persons presenting as outpatients from 1995 to 1996 or from 1997 to 1998 with acute, proximal deep vein thrombosis (DVT) diagnosed by duplex ultrasonography. Interventions: Initial anticoagulant therapy of IV UH administered in the hospital (from 1995 to 1996 group, n 64) or subcutaneous LMWH (enoxaparin) administered primarily at home (from 1997 to 1998 group, n 65), followed by warfarin therapy. Results: No statistically significant differences were observed in the number of recurrent venous thromboembolic events (p 0.36) or bleeding events (p 1.0). Mean SD cost per patient was $9,347 8,469 in the enoxaparin group compared with $11,930 10,892 in the UH group, a difference of $2,583 (95% bootstrap-adjusted asymmetrical confidence interval, $ 6,147, $650). Conclusions: Retrospective replication of the Canadian study in a US routine (managed) care setting found similar clinical and economic outcomes. Treatment of acute proximal DVT with enoxaparin in a primarily outpatient setting can be accomplished safely and yields savings through avoidance or minimization of inpatient stays. (CHEST 2002; 122:108 114) Key words: economics; enoxaparin; low-molecular-weight heparin; managed care; outpatient treatment; pharmacoeconomic evaluation; proximal deep vein thrombosis; utilization Abbreviations: DVT deep venous thrombosis; HMO health maintenance organization; INR international normalized ratio; LMWH low-molecular-weight heparin; UH unfractionated heparin Venous thromboembolism is a potentially lifethreatening disease with 200,000 first lifetime cases reported each year in the United States. 1 *From the Clinical Thrombosis Center (Dr. Spyropoulos), Lovelace Health Systems, Albuquerque, NM; Center for Pharmacoeconomic and Outcomes Research (Ms. Hurley), Lovelace Respiratory Research Institute, Albuquerque, NM; and MED- TAP International (Ms. Ciesla and Dr. Lissovoy), Bethesda, MD. Partially supported by an unrestricted grant from Aventis. Manuscript received June 18, 2001; revision accepted January 11, 2002. Correspondence to: Alex C. Spyropoulos, MD, Medical Director, Clinical Thrombosis Center, Lovelace Health Systems, 5400 Gibson Blvd SE, Albuquerque, NM 87108; e-mail: acspyr@ lovelace.com Fatalities in the United States from pulmonary embolism are estimated at 100,000 to 200,000 persons per year. 2 Standard treatment for proximal deep vein thrombosis (DVT) has been infusion of unfractionated heparin (UH) administered during a hospital admission of approximately 5 to 7 days. With the advent of low-molecular-weight heparin (LMWH), outpatient heparin treatment has become feasible because of more predictable anticoagulant response and administration via subcutaneous injection. 3 A landmark Canadian randomized clinical trial established the safety and efficacy of treating acute proximal DVT with enoxaparin, a LMWH, adminis- 108 Clinical Investigations

tered primarily at home (n 247) relative to UH administered in the hospital (n 253). 4 Economic analysis of a subset of trial subjects (n 300) who presented as outpatients and were followed up for 3 months demonstrated a substantially lower average cost of treatment for the enoxaparin/outpatient group relative to the UH inpatient group ($2,278 vs $5,323 [Canadian dollars]). 5 Authors of the Canadian study attempted to generalize their economic findings to the United States by substituting a US national average hospital per diem for the Canadian rate, and applying a US-Canadian exchange rate conversion to other costs. On this basis, average savings of $2,750 (US dollars) were predicted for the enoxaparin/outpatient approach relative to UH inpatient care. These findings offer useful information to US health-care decision makers evaluating optimal approaches to managing acute venous thrombosis. However, several factors could limit generalizability of results to a US routine care setting. Simple currency conversion may not reflect differences in practice patterns between Canada and the United States, or the relative prices of specific medical resources. The Canadian results reflect a course of treatment observed in a protocol-based clinical trial as opposed to a routine clinical care setting. For these reasons, we designed a study to replicate the Canadian trial in the setting of a US managed care organization. The principal objective was to determine treatment costs for patients presenting with acute proximal venous thrombosis who were treated on an outpatient basis with enoxaparin and compare these to costs of similar patients receiving UH inpatient care. Study Site Materials and Methods Our study was conducted at Lovelace Health Systems, an integrated health-care delivery system and staff/network model health maintenance organization (HMO) serving New Mexico. During the study time frame (from 1995 to 1998), enrollment in the Lovelace Health Plan grew from approximately 152,000 to 190,000 members. Prior to 1997, all patients with DVT requiring anticoagulation therapy were hospitalized and received UH (initiation phase) followed by warfarin (maintenance phase). Beginning in 1997, an outpatient DVT treatment program was established in conjunction with a pharmacist-managed anticoagulation clinic. Patients meeting eligibility criteria were offered an outpatient-based treatment with the LMWH enoxaparin. Patients who did not meet exclusionary criteria but whose treating physician felt uncomfortable with initiation of therapy in the outpatient setting received initial therapy in the hospital and were then switched to outpatient therapy. An internal medicine physician with expertise in thromboembolic management directed the program. Study Design In this retrospective study, we compared the health-care costs and outcomes of patients treated with UH while hospitalized during from 1995 to 1996 (UH group) with patients who received enoxaparin primarily on an outpatient basis during from 1997 to 1998 (enoxaparin group). The study protocol was approved by the Lovelace Institutional Review Board. Patients were selected for the study based on the inclusion and exclusion criteria defined in the Canadian clinical trial protocol. 4 These criteria were either explicitly stated in that protocol or implicit and confirmed as applied criteria. 4,6 We also applied additional exclusionary criteria that reflected treatment protocols used by the Lovelace outpatient DVT treatment program (Table 1). Study Population We identified a pool of patients potentially eligible for the UH group and the enoxaparin group through search of health-plan enrollment and administrative claims records. For the UH group, we identified all patients hospitalized during from 1995 to 1996 with a diagnosis of DVT (International Classification of Diseases code 453.8). For the enoxaparin group, we identified all from 1997 to 1998 patients who had an outpatient diagnosis of DVT, and one or more outpatient prescriptions for warfarin. We also searched anticoagulation clinic records for from 1997 to 1998 to identify additional potentially eligible enoxaparin patients not identified through claims data. Patients identified in this manner (n 354) represented the pool of subjects potentially eligible for the analysis. Medical record reviewers examined patient charts to verify that the DVT was acute, proximal, and diagnosed by duplex ultrasonography, and that oral anticoagulant therapy was planned for at least 3 months with an intended target international normalized ratio (INR) of 2.0 to 3.0. These criteria also permitted exclusion of patients whose claims records contained a diagnosis code for DVT that was a rule-out code rather than a true diagnosis. Concordance with other study inclusion and exclusion criteria was also assessed. Clinical Data Information describing clinical status at presentation, diagnoses related to venous thromboembolism, course of treatment, and clinical events during the episode of care was extracted from medical records according to a standardized chart abstraction protocol. Primary clinical events included: death from thromboembolic causes, recurrent DVT (confirmed by Doppler duplex ultrasound), recurrent pulmonary embolism, and major bleed during the heparin or warfarin phase (defined as retroperitoneal bleeding, intracranial bleeding, drop in hemoglobin 2 g/dl, or bleeding necessitating transfusion of 2 U of packed RBCs). Secondary clinical events included minor bleeding during the heparin or warfarin phase (defined as epistaxis, hematuria, ecchymoses, or nonspecific bleeding), and heparin-induced thrombocytopenia. Health-Care Administrative Data The study episode of care was segmented into two phases, initiation and maintenance, The initiation phase began on the first day of heparin treatment and ended on the last day of heparin treatment; duration of this phase could vary across patients. The maintenance phase was a follow-up period that started the day after the last heparin treatment and ended at 90 days. Administrative data were extracted in three categories: enrollment data (sex, age, dates of enrollment, and disenrollment www.chestjournal.org CHEST / 122 / 1/ JULY, 2002 109

Table 1 Inclusion and Exclusion Criteria in the Canadian Trial as Adapted for the Lovelace Study Inclusion criteria Proximal, acute, lower-extremity DVT* DVT was diagnosed by duplex ultrasonography* Oral anticoagulation treatment planned for at least 3 mo at an intended target INR of 2.0 to 3.0 Age 18 yr* Exclusion criteria Platelet count 100,000 Presence of active bleeding/hemorrhage from any source* History of GI bleed within previous 6 mo History of heparin hypersensitivity or heparin-induced thromboytopenia or thrombocytopenia* Underlying liver disorder (INR 1.5) Familial bleed disorder* Pregnant or lactating woman* Severe hypertension (systolic BP 220 mm Hg and/or diastolic BP 120 mm Hg) Renal insufficiency (serum creatinine 2.5 mg dl) Catheter-associated DVT Clinically unstable pulmonary embolus* Morbid obesity (absolute weight, 150 kg 330 lb) Underlying congenital or acquired hypercoaguable state* Comorbidity possibly increasing risk of home treatment (congestive heart failure, COPD, diabetes, cancer, recent myocardial infarction or stroke, or any other condition increasing risk to the patient treated at home vs in the hospital)* Other condition possibly increasing risk of home treatment (such as no phone, unsuitable home environment, lack of social support)* *Exclusion criterion explicit or implicit in Canadian clinical trial protocol. 4 Additional exclusion criterion based on Lovelace outpatient DVT treatment guidelines. from health plan); medical services (inpatient and outpatient dates of service, diagnoses, procedures, and charges); and prescription drugs (drug fill dates, national drug code, quantity, days supply, and average wholesale price). Resource use and costs (based on procedure and drug charges) were tabulated and assigned to either the initiation phase or maintenance phase based on the service date. Each cost was assigned to a category: (1) inpatient care, (2) outpatient care, (3) home health care, (4) hospice-related care, or (5) outpatient pharmacy. As is typical in analysis of health-care administrative databases, discrepancies were resolved in a data cleaning process. Services were sometimes listed without a corresponding charge; in such cases, a value was imputed based on the mean amount recorded for the identical service in other records. All medical resources and costs were included in the analysis; no attempt was made to exclude non-dvt related care. Statistical Analysis Data were analyzed with commercially available statistical software (SAS version 6.12; SAS Institute; Cary, NC; and S-Plus 2000; Insightful Corporation; Seattle, WA). For each treatment group (UH or enoxaparin) patient-level costs were summed by category of service, phase of episode, and total episode cost. The arithmetic mean and 95% confidence interval were computed for each cost component. Difference between group means was assessed using a Student t test and confirmed with a bootstrap bias-corrected 95% confidence interval. Further examination of the association of treatment group and total cost of the episode of care was performed using multiple regression analysis. Results Review of the medical charts of the 354 potential subjects identified from claims data resulted in 225 subjects being disqualified for the following reasons: the DVT was not proximal (n 46); the DVT was not acute (n 44); the DVT was not lower extremity (n 9); insufficient DVT documentation existed (n 5); a disqualifying comorbid condition or inappropriate target INR level was documented (n 42); heparin therapy had been initiated for a condition other than DVT (n 61); and in the 1997 1998 group, patient did not have heparin administered at least partially on an outpatient basis (n 18). The final study groups consisted of 64 patients in the UH group and 65 in the enoxaparin group (Table 2). All patients in the UH group were hospitalized for the full course of heparin administration. The enoxaparin group included 32 patients managed entirely on an outpatient (home care) basis, 22 moderate-risk patients hospitalized for observation during initiation of therapy (mean number of inpatient days, 2.3; range 1 to 6 days) but who completed heparin treatment on an outpatient basis, Table 2 Lovelace Study Patient Demographic Characteristics Characteristics Primarily Outpatient (Enoxaparin) Inpatient (UH) Enrollees, No. 65 64 Male gender, No. (%) 29 (44.6) 29 (45.3) Mean (SD) age, yr Male subjects 61.9 (15.1) 64.0 (15.6) Female subjects 66.4 (16.1) 64.7 (19.5) 110 Clinical Investigations

and 11 patients treated initially as outpatients but hospitalized at some point during the course of treatment. Clinical Events Clinical outcomes are shown in Table 3. No deaths from thromboembolic causes occurred during the study episode. Three primary clinical events occurred in the UH group vs two events in the enoxaparin group, a difference that was not statistically significant (p 0.67). There were three cases of recurrent DVT in the UH group and one case in the enoxaparin group. Major bleeding was rare with one case occurring in an enoxaparin patient during the heparin phase. Secondary clinical events included five cases of minor bleeding during the heparin period (three cases in the enoxaparin group and two cases in the UH group), and five cases of minor bleeding in the warfarin period (four cases in the enoxaparin group and one case in the UH group). No cases of heparin-induced thrombocytopenia were observed. Treatment Costs Initiation Phase: During the heparin administration phase, the mean ( SD) cost of care for patients in the UH group was $5,582 1,897, while cost for patients in the enoxaparin group was $3,366 2,998. Costs for the enoxaparin group were lower by $2,216 (p 0.0001). Inpatient care accounted for 99% ($5,538) of costs incurred by the UH group; no costs were incurred for ambulatory care, home health care, or hospice care. This was expected since these patients were hospitalized during heparin administration. By comparison, costs for the enoxaparin group were divided across inpatient care (49.2%, $1,657), ambulatory care (19.6%, $658), home health care (15.1%, $508), hospice care (9.5%, $319), and outpatient pharmacy (6.6%, $224; Table 4). Table 4 Distribution of Costs by Study Group and Phase of Treatment* Treatment Phases Study Group Enoxaparin (n 65) UH (n 64) Initiation Inpatient care Hospital facility $1,532 $4,945 Professional fees (consultations) $125 $593 Outpatient care Ambulatory care $162 Laboratory and diagnostic procedures $423 Professional fees (consultations) $73 Home health care $508 Pharmacy LMWH $141 Warfarin $24 $16 Other prescription drugs $59 $28 Hospice $319 Total cost for initiation phase $3,366 $5,582 Maintenance Inpatient care Hospital facility $1,397 $2,776 Professional fees (consultations) $86 $143 Outpatient care Ambulatory care $1,394 $1,287 Outpatient surgery $138 $60 Laboratory and diagnostic procedures $1,442 $705 Professional fees (consultations) $294 $232 Home health care $358 $659 Pharmacy Warfarin $43 $71 Other prescription drugs $271 $304 Hospice $560 $111 Total cost for maintenance phase $5,981 $6,348 *In US dollars. Maintenance Phase: Costs for the two groups were similar during the warfarin phase. Mean cost for the UH group was $6,448 10,023 vs $5,981 7,896 for the enoxaparin group. While mean cost was lower by $366 for the enoxaparin group, the difference was not significant (p 0.8173). Total cost for the war- Table 3 Confirmed Primary Clinical Events (Lovelace Study vs Canadian Trial)* Lovelace Health Plan Cohorts Canadian Trial Cohorts Clinical Events Primarily Outpatient (Enoxaparin), n 65 Inpatient (UH), n 64 Primarily Outpatient (Enoxaparin), n 149 Inpatient (UH), n 151 Recurrent DVT 1 (1.5) 3 (4.7) 8 (5.4) 10 (6.6) Recurrent pulmonary embolism 0 (0) 0 (0) 2 (1.3) 1 (0.7) Major bleeding in heparin period 1 (1.5) 0 (0) 4 (2.7) 1 (0.7) Major bleeding in warfarin period 0 (0) 0 (0) 1 (0.7) 0 (0) *Data are presented as No. (%). Confirmed clinical events reported; adapted from Table 1. 6 www.chestjournal.org CHEST / 122 / 1/ JULY, 2002 111

farin phase in the UH group encompassed inpatient care (46.0%, $2,919), ambulatory care (36.0%, $2,284), home health care (10.4%, $659), outpatient pharmacy (5.9%, $375), and hospice care (1.74%, $111). For the enoxaparin group, costs were incurred for ambulatory care (54.6%, $3,268), inpatient care (24.8%, $1,483), hospice care (9.4%, $560), home health care (6.0%, $358), and outpatient pharmacy (5.2%, $314; Tables 3, 4). Total Episode of Care: The mean total episode of care cost was $9,347 8,469 for the enoxaparin group vs $11,930 10,892 for the UH group (Table 5). For the enoxaparin group, 36.0% of the costs were incurred during the initiation phase and 64% during the maintenance phase. In the UH group, 46.8% of the costs were incurred during the initiation phase and 53.2% during the maintenance phase. Mean difference in cost was $2,583 favoring the enoxaparin group (p 0.1349; bootstrap adjusted 95% confidence interval, $6,147, $650). These results were confirmed in multiple regression analysis controlling for age and sex (data not shown). Predicted cost savings with the enoxaparin regimen ranged from $2,894 to $3,534 for the mean age male and female patients, respectively (p 0.01). Discussion Our study assessed whether results of a Canadian randomized controlled trial of outpatient therapy for acute proximal DVT can be generalized to the routine care environment of a US managed care organization. Based on the Canadian inclusion-exclusion criteria, we assembled a similar cohort of patients treated in our health plan over the same time period. Clinical outcomes were established through medical chart review while resource use and costs were documented by means of an administrative database. Results of our study are remarkably similar to the Canadian findings. Both studies demonstrate the efficacy and safety of home treatment with enoxaparin. Adverse clinical outcomes such as recurrence of DVT and major bleeding were rare in both studies, while the event rates were nearly identical. Extrapolating economic findings to the US, the Canadian researchers predicted average savings of $2,750 per patient for the enoxaparin/primarily home treatment regimen relative to UH inpatient care (1997 US dollars). Our study yielded a remarkably similar figure, with actual cost savings averaging $2,583 per patient. The economic impact of outpatient DVT treatment using enoxaparin has been evaluated in randomized controlled trials, decision-model analyses, and observational studies. 6 16 The clinical trials included extremely restrictive exclusionary criteria for outpatient therapy that excluded 30 to 92% of screened patients. Modeling studies have included assumptions on superiority of enoxaparin therapy in terms of mortality benefit and reduction in late complication rates, as well as equivalence of various forms of enoxaparin. Treatment costs in most studies are based on estimates rather than documented resource use or billing data. Economic analyses from observational studies in European tax-financed national health-care systems may not be applicable to the US insurance-funded health-care system. 14 16 Several observational studies 8 10 evaluated the economic impact of outpatient DVT management with enoxaparin in the United States, reporting estimated cost savings of $547 to $2,471 per patient. A study 7 in a group-model HMO estimated $2,828 in cost savings from the program based on estimated hospital costs. These studies provide useful information for US health-care policy decision makers and to some degree validate the generalizability of the cost savings reported by the Canadian clinical trial. However, limitations of these studies include lack of a control group and reliance on estimated costs. 7,8 Two major characteristics distinguish our study from previous work. First, we applied inclusionexclusion criteria from a published clinical trial to Table 5 Comparison of Costs in US Dollars by Phase of Treatment* Costs of Treatment Inference Treatment Phases Primarily Outpatient (Enoxaparin), n 65 Inpatient (UH), n 64 Cost Difference (Enoxaparin, UH) p Value Initiation 3,366 (2,998), 36% 5,582 (1,897), 47% 2,216 ( 2,983, 1,290) 0.0001 Maintenance 5,981 (7,896), 64% 6,448 (10,023), 53% 366 ( 3,207, 2,789) 0.8173 Total episode cost 9,347 (8,469), 100% 11,930 (10,892), 100% 2,583 ( 6,147, 650) 0.1349 *Data are presented as mean (SD), % or No. (95% bootstrap-adjusted asymmetrical confidence interval). t test of group mean differences. 112 Clinical Investigations

select parallel treatment and control groups. Second, we included actual costs and all costs incurred by patients over the period based on administrative records, whereas most previous studies are based on estimated costs and only those related to treatment of DVT. Study limitations stem from the retrospective design. Despite careful application of inclusion-exclusion criteria, unmeasured clinical or social factors may have introduced selection bias, resulting in a less resource-intensive, and therefore less expensive, outpatient cohort. The inclusion of hospice patients may have introduced a downward cost bias in favor of the enoxaparin group by avoiding hospitalization. However, the same inclusionary criteria were applied to outpatient and inpatient subjects, and hospice costs occurred to both groups. In addition, the Lovelace outpatient DVT program, unlike the Canadian study protocol, stipulates that patients who are eligible for enoxaparin therapy but whose treating physician is uncomfortable with outpatient initiation of anticoagulant therapy be hospitalized while enoxaparin therapy is initiated, followed by completion of therapy in the outpatient setting. This cautious treatment approach, by adding inpatient costs for some enoxaparin patients (22 of 65 patients in our study), increased the costs in the enoxaparin group, thus biasing against cost savings in this group. In other words, our estimate of the cost savings from enoxaparin treatment are conservative; US clinical practices using a LMWH protocol that permits more extensive treatment of patients on an outpatient basis might realize greater savings than were seen here. Patients observed in the study received treatment at different points over a 4-year time span. Our cost results might have been different if all patients had been treated contemporaneously. We therefore tested for but did not detect cost inflation that would require year-to-year price adjustment. Hospital admissions in the UH group the single most expensive component of care reflect prices during the early part of the study period (from 1995 to 1996), when prices were presumably lowest. If inflation did occur over the study period, that would bias results against cost savings in the enoxaparin group (from 1997 to 1998). In 1997, there were 122,000 hospital discharges in the United States with a diagnosis of DVT. 17 Based on the $11,930 cost per episode observed in our study, national expenditures associated with these events may have been in the range of $1.5 billion. Shifting 50% of these patients to the enoxaparin regimen could potentially have saved $150 million in direct medical expenditure. Conclusion Our study has shown that outpatient treatment of DVT with enoxaparin in a routine clinical practice setting of a US HMO reduces costs compared to standard inpatient therapy using IV UH, even when a proportion of those patients require initial hospitalization. Avoidance or minimization of inpatient treatment more than offsets a substantial shift of resources to outpatient care, pharmacy, and home health services. In addition, this treatment strategy is safe and efficacious, as shown by comparable clinical outcomes between the enoxaparin and UH groups. References 1 Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158:585 593 2 Anderson FA, Wheeler HB, Goldberg RJ, et al. A populationbased perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism: the Worcester DVT Study. Arch Intern Med 1991; 151:933 938 3 Ginsberg JS. Management of venous thromboembolism. N Engl J Med 1996; 335:1816 1828 4 Levine M, Gent M, Hirsh J, et al. A comparison of lowmolecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334: 677 681 5O Brien B, Levine M, William A, et al. Economic evaluation of outpatient treatment with low-molecular-weight heparin for proximal vein thrombosis. Arch Intern Med 1999; 159: 2298 2304 6 Yusen RD, Brennan MH, Gage BF, et al. Criteria for outpatient management of proximal lower extremity deep venous thrombosis. Chest 1999; 115:972 979 7 Tillman DJ, Charland SL, Witt DM, et al. Effectiveness and economic impact associated with a program for outpatient management of acute deep vein thrombosis in a group model health maintenance organization. Arch Intern Med 2000; 160:2926 2932 8 Dedden P, Chang B, Negal D, et al. Pharmacy-managed program for home treatment of deep vein thrombosis with enoxaparin. Am J Health Syst Pharm 1997; 54:1968 1972 9 Groce JB III. Patient outcomes and cost analysis associated with an outpatient deep venous thrombosis treatment program. Pharmacotherapy 1998; 18:175S 180S 10 Pearson SD, Blair R, Halpert A, et al. An outpatient program to treat deep venous thrombosis with low-molecular-weight heparin. Eff Clin Pract 1999; 2:210 217 11 Hull RD, Raskob GE, Rosenbloom D, et al. Treatment of proximal vein thrombosis with subcutaneous low-molecular weight heparin vs intravenous heparin: an economic perspective. Arch Intern Med 1997; 157:289 294 12 Gould MK, Dembitzer AD, Sanders GD, et al. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a costeffectiveness analysis. Ann Intern Med 1999; 130:789 799 13 Rodger M, Bredeson C, Wells PS, et al. Cost-effectiveness of low-molecular-weight heparin and unfractionated heparin in treatment of deep vein thrombosis. Can Med Assoc J 1998; 159:931 938 www.chestjournal.org CHEST / 122 / 1/ JULY, 2002 113

14 Boccalon H, Elias A, Chale JJ, et al. Clinical outcome and cost of hospital vs home treatment of proximal deep vein thrombosis with a low-molecular-weight heparin: the Vascular Midi-Pyrenees study. Arch Intern Med 2000; 160:1769 1773 15 Ting SB, Ziegenbein RW, Gan TE, et al. Dalteparin for deep venous thrombosis: a hospital-in-the-home program. Med J Aust 1998; 168:272 276 16 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. J Intern Med 1996; 240:395 401 17 Healthcare Cost and Utilization Project. Nationwide Inpatient Sample (NIS): release 6, 1997 data. Rockville MD: Agency for Healthcare Research and Quality, PB 2000 500006 114 Clinical Investigations