Estimated total cost of the 3-month episode of care (mean and 95% confidence interval).
de Lissovoy G, Yusen RD, Spiro TE, Krupski WC, Champion AH, Sorensen SV. Cost for Inpatient Care of Venous ThrombosisA Trial of Enoxaparin vs Standard Heparin. Arch Intern Med. 2000;160(20):3160-3165. doi:10.1001/archinte.160.20.3160
Copyright 2000 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2000
Enoxaparin, a low-molecular-weight heparin administered to hospitalized patients once or twice daily, has shown efficacy and safety equivalent to unfractionated heparin in the treatment of acute venous thromboembolic disease. Although the cost of either enoxaparin regimen is greater than that of unfractionated heparin, the overall cost of care for each of these 3 treatment strategies is unknown.
A cost minimization analysis of a 3-month, partially blinded, randomized, controlled efficacy and safety trial of anticoagulant therapy for deep vein thrombosis. Three hundred thirty-nine hospitalized patients with symptomatic lower extremity deep vein thrombosis were randomly assigned to initial therapy with subcutaneous enoxaparin either once (n = 112) or twice (n = 123) daily, or with dose-adjusted intravenous unfractionated heparin (n = 104), followed by long-term oral anticoagulant therapy. Estimated 1997 total cost from a third-party payer perspective for the 3-month episode of care was calculated by assigning standard unit costs to counts of medical resources used by each patient in the clinical trial.
Average total cost for the 3-month episode of care was similar across all 3 treatment regimens: once-daily dose of enoxaparin, $12,166 (95% confidence interval [CI], $10,744–$13,588); twice-daily dose of enoxaparin, $11,558 (95% CI, $10,201–$12,915); and unfractionated heparin, $12,146 (95% CI, $10,670–$12,622). Bootstrapped estimates and sensitivity analyses did not significantly change findings.
There was no significant difference in the overall cost for the 3-month episode of care for patients treated with either enoxaparin or unfractionated heparin. Additional acquisition costs for anticoagulant medication among patients treated with enoxaparin were offset by savings associated with lower incidence of hospital readmission and shorter duration of venous thromboembolism-related readmissions.
DEEP VEIN thrombosis and pulmonary embolism are causes of significant morbidity and mortality. A Swedish longitudinal study of men estimated that the cumulative probability for venous thromboembolism was 0.5% by age 50 and 10.7% by age 80.1 Extrapolation of data from a study in the United States suggests that some 170,000 patients are treated annually in acute care general hospitals for recognized initial episodes of venous thromboembolism while an additional 90,000 cases are hospitalized for recurrent disease.2
Heparin has been the standard for initial treatment of venous thromboembolism for more than 30 years and is included on the World Health Organization list of essential drugs.3 Enoxaparin, a low-molecular-weight heparin administered to hospitalized patients once or twice daily, has shown efficacy and safety equivalent to unfractionated heparin in the treatment of acute venous thromboembolic disease. Although the cost of either enoxaparin regimen is substantially greater than that of unfractionated heparin, the overall cost of care for each of these 3 treatment strategies in a hospital setting is unknown. To address that issue, we performed a retrospective cost analysis of a randomized clinical trial comparing enoxaparin with unfractionated heparin for treatment of acute venous thromboembolism.
The efficacy and safety of subcutaneous enoxaparin (Aventis SA, Inc [formerly Rhône-Poulenc Rorer Pharmaceuticals, Inc], Bridgewater, NJ, and Antony, France) vs continuous infusion of unfractionated heparin in the treatment of patients with deep vein thrombosis with or without pulmonary embolism were evaluated in a partially blinded, parallel group, multicenter international randomized controlled clinical trial. Double-blinding was used in the once-daily and twice-daily enoxaparin treatment arms. The use of unfractionated heparin was open label. A complete description of the efficacy and safety trial has been submitted for publication.2
The trial was conducted at 74 sites in Europe, the United States, Australia, and Israel from May 19, 1994, to July 17, 1996. The protocol was approved by the ethics committee or review board at each participating site. Persons enrolled had a diagnosis of symptomatic deep vein thrombosis of the proximal or distal lower extremity with or without pulmonary embolism, confirmed by venography or ultrasonography. All patients gave written informed consent. Exclusion criteria included previous treatment with anticoagulant agents or need for thrombolytic therapy, increased risk of hemorrhage or active hemorrhage, hypersensitivity to heparin, and other factors related to patient safety.
Patients were randomized to 1 of 3 treatment groups: (1) once-daily subcutaneous dose of enoxaparin (1.5 mg/kg), (2) twice-daily subcutaneous dose of enoxaparin (1.0 mg/kg), and (3) unfractionated heparin (nomogram-dosed, typically an intravenous bolus dose of 5000 U of unfractionated heparin followed by a continuous intravenous infusion of heparin at a rate of 1250 U/h).
All patients were to receive at least 5 days of the study drug. Patients also received an oral anticoagulant agent (warfarin sodium) initiated within 72 hours after administration of the initial study drug and continued for at least 3 months. Enoxaparin and unfractionated heparin therapy was to be discontinued when the international normalized ratio was between 2.0 and 3.0 on 2 consecutive measurements performed on consecutive days; patients could be discharged from the hospital at this point. All patients were hospitalized during the initial phase of therapy and followed up for 3 months from the date of randomization. All primary clinical analyses were conducted on an intent-to-treat basis.
A total of 900 patients were enrolled in the multinational clinical study (298 were assigned to receive a once-daily dose of enoxaparin; 312, twice-daily dose of enoxaparin; and 290, unfractionated heparin). The primary analysis of efficacy revealed that the 3 treatment regimens were equivalent in terms of the incidence of symptomatic, recurrent deep vein thrombosis and pulmonary embolism during the 3-month study.
The economic study included all patients enrolled at the participating sites in the United States to represent national practice patterns, and was performed on an intent-to-treat basis. The objective of the cost minimization analysis was to compare the direct medical cost of the 3-month episode of care across the 3 treatment regimens from the perspective of a third-party payer. The cost for each patient was calculated in a 3-stage process: (1) medical resources used by each patient during the episode of care were tabulated; (2) a standard unit cost was assigned to each type of resource; and (3) the quantity of each resource used by a patient was multiplied by the cost of that resource.
Treatment costs reported herein are based on data from 33 of 40 United States trial sites, which enrolled a total of 339 patients (112 to the once-daily enoxaparin treatment arm; 123 to the twice-daily enoxaparin treatment arm; and 104 to unfractionated heparin). Seven sites in the United States did not enroll any patients and were excluded from the economic analysis. Demographic and clinical features of these persons at enrollment are presented in Table 1. No significant differences were observed across treatment groups, except for a somewhat greater proportion of males in the enoxaparin groups (58.7% vs 50.0%). At the end of the 3-month study period, data were available for 107 (95.5%) patients in the once-daily enoxaparin group, 120 (97.6%) in the twice-daily enoxaparin group, and 101 (97.1%) in the heparin group.
Clinical trial case reports provided a detailed record of the procedures and services used by each patient. Based on daily observation during the initial treatment period and monthly patient visits during the 3-month follow-up, site coordinators documented the following information: length of hospital stay (measured from date of randomization to date of discharge), type and frequency of laboratory tests and diagnostic procedures, dose and quantity of study medications and concomitant medications, number of physician encounters by specialty, and number of encounters with other health care providers (home care nurse or physical therapist). The initial length of hospitalization was not recorded for 2 patients, both in the once-daily enoxaparin group. For each readmission, the investigator categorized the event as either venous thromboembolic disease-related or non–venous thromboembolic disease-related. All hospital readmissions, regardless of cause, were considered in this cost minimization study.
A unit cost was assigned to each type of resource, reflecting 1997 cost levels. Hospital admissions were valued using the Disease-Drug Audit, Inpatient database3 and reflect detailed billing data from 59 United States acute care general hospitals. The average daily charge for patients discharged in diagnostic-related group 128 (principal diagnosis of thrombophlebitis)4 was converted to cost using hospital-specific Medicare cost-to-charge ratios.2 Charges for laboratory, pharmacy, and diagnostic services were excluded as these were separately calculated. This yielded a hospital per diem cost of $496, which was applied to the number of hospital days recorded for each patient.
Each type of laboratory test, diagnostic procedure, and professional service (physician and nonphysician) was categorized using Current Procedural Terminology (CPT) coding.5 Costs for laboratory tests were based on the average charge for the test as reflected in the Disease-Drug Audit, Inpatient database, converted to cost using hospital-specific cost-to-charge ratios. Professional services were assigned a unit cost based on the midpoint of the reported national fee range paid by private third-party payers for the particular CPT code.6 Representative unit costs are shown in Table 2.
Study medications and concomitant medications were valued using the lowest average wholesale price as listed in the 1997 Redbook.7 The cost for enoxaparin was set at $0.56 per milligram, based on an average wholesale price of $168 for 10 injections of 0.3 mL (10 mg/0.1 mL). The cost for unfractionated heparin was $0.00018 per unit based on an average wholesale price of $17.77 per 10 mL, with 10,000 U/mL. Actual dosage of enoxaparin was determined by a patient's weight; the once-daily group received 1.5 mg/kg subcutaneously, and the twice-daily group, 1.0 mg/kg. Due to the extensive number of different concomitant medications recorded during the study, a drug-specific cost was established only for drugs that appeared 10 or more times. This accounted for 80% of all concomitant medications.
Economic analyses were conducted in the 3 treatment groups. The total cost of resources used by each patient was computed by multiplying the quantity of each item by the assigned unit cost and summing across all types of resources. The arithmetic mean and 95% confidence interval (CI) were calculated for the cost of each category of resource and for the total cost for the 3-month episode of care. As a confirmatory procedure, means and CIs for the total cost for the episode of care were also compared using a bootstrapping technique that compensates for the non-normal distribution that is typical of medical expenditure data.8 Samples were generated 1000 times for each treatment group. Statistical analysis was performed using commercially available software (SAS, version 6.12; SAS Institute, Cary, NC).
Sensitivity analysis was performed to determine whether findings were robust to variation in the standard unit prices assigned to treatment resources. Each unit cost parameter was individually varied by 50% above and below the base case level (1-way sensitivity analysis). This spanned the underlying range of costs used to derive the point estimate unit costs used in the analysis. Mean cost and the 95% CI were calculated for each low and high unit cost value.
On average, total hospital days were lower for patients in the 2 enoxaparin groups than for those treated with heparin (Table 3). Average length of hospital stay for the initial admission was similar across all 3 treatment groups (range, 8.2-8.5 days). Approximately one quarter of patients were readmitted during the 3-month follow-up. The overall rate of readmission for any reason in the unfractionated heparin group (26.0%) was somewhat greater than that for patients receiving once- and twice-daily doses of enoxaparin (20.5% and 17.1%, respectively). Average length of stay for readmission was similar (range, 13.0-14.9 days) across treatment groups. Admissions classified as venous thromboembolic disease-related were more frequent in the heparin group (17.3%) than in the once- and twice-daily enoxaparin groups (10.7% and 8.9%, respectively). In addition, the average length of hospitalization was appreciably longer among readmitted patients treated with standard heparin (14.3 days) relative to those receiving once- and twice-daily enoxaparin treatment (7.8 days and 9.2 days, respectively).
The mean daily dose of study medication was 126.9 mg for the once-daily enoxaparin group, 171.3 mg for the twice-daily enoxaparin group, and 24,780 U for patients receiving unfractionated heparin. Mean duration of treatment varied from 6.3 days for unfractionated heparin recipients to 6.7 days for both enoxaparin groups. Other medical resources used are presented in Table 4.
Costs for components of care are presented in Table 5. Average cost by component was similar across all 3 treatment groups. Initial inpatient hospital costs accounted for the largest share of total cost (approximately one third), with average cost ranging from $4061 to $4234. Professional fees for diagnostic procedures (range, $2304–$2398), laboratory tests (range, $1383–$1635), and nonphysician encounters (range, $798–$1140) were similar in magnitude across the 3 groups. The most notable relative cost difference among treatment groups involved study medication. While the average cost for the full course of unfractionated heparin was only $28, the average cost for enoxaparin ranged from $476 (once daily) to $645 (twice daily).
Mean total costs and 95% CIs for the complete episode of care are depicted in Figure 1. Mean total cost across the 3 regimens was similar: once-daily dose of enoxaparin, $12,166; twice-daily dose of enoxaparin, $11,558; and unfractionated heparin, $12,146. Each mean falls within the 95% CIs surrounding the 3 groups. Means and 95% CIs calculated using the bootstrap procedure were $12,124 ($10,723–$13,569) for enoxaparin (once daily); $11,574 ($10,419–$12,834) for enoxaparin (twice daily); and $12,117 ($10,647–$13,913) for unfractionated heparin.
Results were robust in 1-way sensitivity analysis. Reducing the cost of enoxaparin from $168 to $84 for 10 injections of 0.3 mL (10 mg/0.1 mL) decreased the expected total cost for the episode of care to $11,930 for once-daily dose of enoxaparin and $11,238 for twice-daily dose of enoxaparin. When other unit costs were increased or decreased by 50%, the relative total cost for the episode of care remained similar across the 3 treatment regimens. For example, when hospital daily cost was increased by 50% to $744, the projected total cost for the episode of care was $15,025 for patients in the once-daily enoxaparin treatment arm, $14,139 for those in the twice-daily enoxaparin treatment arm, and $15,139 for patients receiving unfractionated heparin.
Venous thromboembolic disease is a common and costly health problem in the United States. The annual incidence may be greater than 500,000 cases.9 Low-molecular-weight heparin therapy has been proposed to offer economic advantages over unfractionated heparin therapy because of a lack of need for anticoagulant monitoring, as well as its facilitating outpatient therapy.10- 12
In this study, we estimated total direct medical costs incurred by persons hospitalized and followed up for 3 months for treatment of deep vein thrombosis. The data reflected the experience of the subset of patients enrolled in centers in the United States that participated in a multinational efficacy and safety study of enoxaparin (once daily or twice daily) vs standard unfractionated heparin. Using a third-party payer perspective, we estimated the total cost for the 3-month episode of care by applying a standard unit cost to counts of medical resources used.
Clinical equivalence of the 3 treatment arms was demonstrated in the international study. Results of this cost minimization analysis revealed statistical equivalence in the average total cost of care incurred by the 3 treatment groups. A lower rate of all-cause readmission and shorter duration of venous thromboembolism-related readmissions among patients treated with enoxaparin offset this drug's substantially greater acquisition cost relative to unfractionated heparin.
The cost findings may actually underrepresent the potential economic benefits of enoxaparin relative to unfractionated heparin. Avoidance of initial hospitalization or reduction in the length of hospitalization represent the greatest potential cost savings for patients treated with low-molecular-weight heparin.13 However, that treatment strategy could not be explored in the present study because the trial design required that all patients receive the full course of initial anticoagulant therapy while hospitalized. Other studies have suggested that 18% to 66% of patients with deep vein thrombosis could receive initial anticoagulant treatment as an outpatient.11,12,14,15
Another potential source of savings associated with enoxaparin therapy is reduction in diagnostic testing. Compared with unfractionated heparin, enoxaparin's more predictable pharmacokinetic profile lessens the need for monitoring the status of anticoagulation effect.16 Because the clinical trial was primarily a safety and efficacy trial, the frequency of anticoagulation monitoring was dictated by protocol. This may have imposed additional costs on patients treated with enoxaparin that would not have occurred in actual practice.
This study had several limitations. The 3-month period of observation, dictated by the clinical trial protocol, may not have fully captured the impact of anticoagulant therapy on resource use. Protocol-driven costs may have inflated cost of care for all patients, particularly those in the enoxaparin groups. Therapy was administered in the environment of a controlled clinical trial. Outcomes may be different in routine practice. A societal perspective, rather than the third-party payer perspective adopted in this study, might have identified additional costs related to lost productivity of patients while undergoing treatment. However, differences in lost productivity attributable to choice of anticoagulant therapy would have been small because the duration of initial hospitalization was dictated by protocol.
This randomized trial demonstrated that enoxaparin administered subcutaneously once or twice daily was as effective and safe as unfractionated heparin in preventing recurrence of venous thromboembolic disease. The cost analysis component of the trial showed that, despite the substantially greater acquisition cost for enoxaparin relative to unfractionated heparin, there was no difference in the overall cost of care. The additional cost for anticoagulant medication among patients treated with enoxaparin compared with patients treated with unfractionated heparin was offset by the savings from a lower incidence of hospital readmissions. Subcutaneous administration and reduced need for monitoring anticoagulant effect offer additional economic advantages for enoxaparin.
Accepted for publication April 4, 2000.
This study was sponsored by Aventis SA (formerly Rhône-Poulenc Rorer Pharmaceuticals, Inc), Bridgewater, NJ, and Rhône-Poulenc Rorer SA, Antony, France.
This study was funded in part by National Research Service Award F32 HS000124 from the Agency for Health Care Policy and Research, Rockville, Md (Dr Yusen).
Reprints: Gregory de Lissovoy, PhD, MEDTAP International, Inc, 7101 Wisconsin Ave, Suite 600, Bethesda, MD 20814 (e-mail: firstname.lastname@example.org).