Cost-Effectiveness of Low-Molecular-Weight Heparin for Treatment of Pulmonary Embolism

Drahomir Aujesky; Kenneth J. Smith; Jacques Cornuz; Mark S. Roberts

doi:10.1378/chest.128.3.1601

September 2005, Vol 128, No. 3

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Clinical Investigations | September 2005

Cost-Effectiveness of Low-Molecular-Weight Heparin for Treatment of Pulmonary Embolism^* FREE TO VIEW

Drahomir Aujesky, MD, MSc; Kenneth J. Smith, MD; Jacques Cornuz, MD, MPH; Mark S. Roberts, MD, MPP

Author and Funding Information

^*From the Division of General Internal Medicine (Drs. Aujesky, Smith, and Roberts), Department of Medicine, University of Pittsburgh, Pittsburgh, PA; and the University Outpatient Clinic (Dr. Cornuz), University of Lausanne, Lausanne, Switzerland.

Correspondence to: Drahomir Aujesky, MD, MSc, Center for Health Equity Research and Promotion, VA Pittsburgh Healthcare System, University Drive C, Building 28, Suite 1A129, Pittsburgh, PA 15240; e-mail: aujesky@swissonline.ch

Chest. 2005; 128(3):1601-1610. doi:10.1378/chest.128.3.1601

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Acknowledgment

Abstract

Background: Low-molecular-weight heparin (LMWH) appears to be safe and effective for treating pulmonary embolism (PE), but its cost-effectiveness has not been assessed.

Methods: We built a Markov state-transition model to evaluate the medical and economic outcomes of a 6-day course with fixed-dose LMWH or adjusted-dose unfractionated heparin (UFH) in a hypothetical cohort of 60-year-old patients with acute submassive PE. Probabilities for clinical outcomes were obtained from a metaanalysis of clinical trials. Cost estimates were derived from Medicare reimbursement data and other sources. The base-case analysis used an inpatient setting, whereas secondary analyses examined early discharge and outpatient treatment with LMWH. Using a societal perspective, strategies were compared based on lifetime costs, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio.

Results: Inpatient treatment costs were higher for LMWH treatment than for UFH ($13,001 vs $12,780), but LMWH yielded a greater number of QALYs than did UFH (7.677 QALYs vs 7.493 QALYs). The incremental costs of $221 and the corresponding incremental effectiveness of 0.184 QALYs resulted in an incremental cost-effectiveness ratio of $1,209/QALY. Our results were highly robust in sensitivity analyses. LMWH became cost-saving if the daily pharmacy costs for LMWH were <$51, if ≥ 8% of patients were eligible for early discharge, or if ≥ 5% of patients could be treated entirely as outpatients.

Conclusion: For inpatient treatment of PE, the use of LMWH is cost-effective compared to UFH. Early discharge or outpatient treatment in suitable patients with PE would lead to substantial cost savings.

Figures in this Article

Low-molecular-weight heparin (LMWH) preparations are as safe, effective, and more cost-effective than unfractionated heparin (UFH) for the initial treatment of deep vein thrombosis (DVT), and currently represent the standard of care for this illness.¹ The safety, efficacy, and economic consequences of LMWH for treating pulmonary embolism (PE), a pathophysiologically related disease, are less well documented. While LMWH appeared to be as safe and effective as UFH for treatment of PE in a recent metaanalysis,² its cost-effectiveness for treating PE was never evaluated. We therefore constructed a decision analytic model comparing medical and economic outcomes for PE treatment with either LMWH or UFH. In our base-case analysis, we assumed that all patients were treated in the hospital. To fully evaluate the potential economic impact of LMWH treatment for PE, we performed a secondary analysis in which different proportions of patients receiving LMWH were discharged early or treated entirely as outpatients.

Materials and Methods

Overview of the Model

We built a Markov state-transition model (Fig 1 ) to evaluate the cost-effectiveness of LMWH vs UFH in a hypothetical cohort of 60-year-old patients with acute submassive PE.³ We selected this age because the mean age in most clinical trials of LMWH was 56 to 66 years.² As recommended by the Panel on Cost-Effectiveness in Health and Medicine,⁴ we took the societal perspective when we considered direct medical costs and indirect costs of obtaining care. We discounted future costs and benefits at an annual rate of 3%. We constructed our model using DATA Professional software (TreeAge; Williamstown, MA).

Major Model Assumptions

Patients with acute PE who entered the model were treated for a total of 6 days either with enoxaparin in a fixed dosage of 1 mg/kg subcutaneously bid (the LMWH strategy) or with adjusted-dose IV UFH at 30,000 U/d (the UFH strategy). We chose enoxaparin over other LMWH preparations because enoxaparin is widely used in the United States and appears to be as safe and effective for submassive PE treatment as other LMWH preparations.² In both treatment strategies, conventional-intensity anticoagulation with warfarin (target international normalized ratio [INR] of 2 to 3) was commenced during heparin treatment and continued for 3 months. During the first 3 months after the initial PE, patients in either treatment strategy were at risk for early complications: death, heparin-induced thrombocytopenia (during the initial hospital stay only), recurrent venous thromboembolism (VTE) [PE or DVT], minor bleeding, and major bleeding.⁵ Probabilities for early complications depended on the type of treatment received. Patients who survived the first 3 months remained at risk for death, recurrent VTE, minor bleeding, and major bleeding (late complications). Late complication risks were assumed to be equal for the two treatment strategies.

We made several additional assumptions. First, heparin-induced thrombocytopenia during the initial hospitalization for PE led to 1 additional day in the hospital.⁵ Second, the patients with recurrent VTE received unlimited-duration, conventional-intensity anticoagulation with warfarin to prevent future VTE events.⁶ Third, the patients had a constant baseline risk of minor and major bleeding. The magnitude of this bleeding risk increased if they received treatment with anticoagulants.⁷ Fourth, major bleeding always led to the discontinuation of anticoagulation. While the discontinuation was permanent for patients who had experienced hemorrhagic stroke, those with noncerebral major bleeding remained eligible for future treatment with anticoagulants (ie, if recurrent VTE developed). A minor bleeding episode led only to one outpatient office visit. Fifth, patients with hemorrhagic stroke remained permanently disabled and died at high rates.⁸ Finally, if VTE recurred despite treatment with anticoagulants or if both VTE and major bleeding recurred during the same month, a permanent inferior vena cava filter was implanted to prevent PE.¹

Base-Case Estimates

The base-case estimates and ranges of all clinical probabilities, quality-of-life measures (utilities), and costs used in the model are displayed in Table 1 .

Clinical Probabilities

We derived probabilities for early complications (mortality, VTE events, minor and major bleeding episodes) from a meta-analysis² of clinical trials comparing the efficacy and safety of LMWH with the efficacy and safety of UFH in the treatment of patients with submassive PE. Since the risk for heparin-induced thrombocytopenia was not reported in the metaanalysis,² we pooled data derived from the individual trials included in the metaanalysis to estimate the risk of thrombocytopenia associated with LMWH or UFH.²⁹¹⁰¹¹¹²¹³¹⁴¹⁵¹⁶¹⁷ Importantly, although this meta-analysis combined trials using six different LMWH preparations, there was no evidence that any LMWH preparation was better or worse than another in terms of efficacy or safety outcomes.²

We obtained estimates for late complications from various clinical trials and cohort studies of patients with PE. We abstracted mortality rates for up to 8 years following PE from a US observational study.¹⁸ To model mortality rates after this time, we used data from US standard life tables for the year 2000.¹⁹ Based on evidence that the risk of death is higher in patients who have PE and either have recurrent VTE or receive a vena cava filter,²⁰²¹ we modeled a higher baseline mortality rate in these patient subgroups. We used the placebo group of a PE trial to estimate long-term recurrence rates for VTE.²² We assumed these recurrence rates to be constant over time.

Preliminary data suggest that the ability of vena cava filters to prevent PE is only transitory and that the long-term risk of recurrent VTE (mostly DVT) is higher in patients who have PE and who receive a vena cava filter.¹⁵²³ Based on this evidence, we modeled a higher baseline risk for DVT and slightly higher baseline risk for recurrent PE in filter-treated patients. We assumed that one third of filter-treated patients received concomitant therapy with warfarin.²⁴

We obtained data concerning anticoagulation efficacy in preventing recurrent VTE from two clinical trials of patients receiving long-term conventional-intensity anticoagulation with warfarin.⁶²⁵²⁶ We used a large metaanalysis²⁷ and the placebo groups of VTE trials to estimate the baseline risk of minor and major bleeding with and without anticoagulants and to estimate the frequency of hemorrhagic stroke.²²²⁶ The risk of bleeding was assumed to be constant over time.

Quality-of-Life Measures (Utilities)

Utilities represent preferences for a given health state and are scaled from 0 to 1, where 0 denotes death and 1 denotes perfect health. We adjusted life expectancy for quality of life by multiplying the time spent in each health state and its associated health state utility.

For acute transient complications, we expressed disutilities in terms of days lost from quality-adjusted life expectancy because of hospitalization or disease,²⁸ a commonly used method in cost-effectiveness studies of VTE.⁵²⁹ To estimate the number of days lost because of noncerebral major bleeding, recurrent PE, and DVT, we used the mean length of hospital stay for each illness, based on national average length of stay data for each diagnosis-related group.³⁰ Patients who acquired heparin-induced thrombocytopenia or minor bleeding incurred the disutility of 1 day lost because of hospitalization or disease.⁵ We assumed that patients with PE had the same disutility regardless of whether the PE episode was treated in the hospital or at home.⁵ For patients without complications, we used age-adjusted mean utility values based on the National Health Interview Survey.³¹

Costs

Pharmacy costs for enoxaparin, UFH, and warfarin were the average wholesale prices based on the 2002 Red Book.³² Costs for supplies associated with UFH treatment, such as an IV catheter, tubing, and automatic pump, were abstracted from an earlier US cost-effectiveness analysis.⁵ We used 2002 average Medicare reimbursement data to estimate costs for hospitalization, physician visits, home nursing, laboratory tests, and medical procedures.³⁰³³ Patients with recurrent PE, DVT, noncerebral major bleeding, or hemorrhagic stroke incurred the full costs of hospitalization for these complications, including costs for physician visits, medical procedures, and rehabilitation after the stroke.³⁰³³ We assumed that patients with noncerebral major bleeding incurred the full costs of hospitalization for upper-GI bleeding.³⁰ Heparin-induced thrombocytopenia resulted in costs for an additional day of hospitalization.⁵³⁰³³ The annual costs of care after stroke were abstracted from an earlier US cost-effectiveness analysis.³⁴

Costs for outpatient treatment of PE and administration of warfarin, including emergency department visits, physician office visits, home nursing, and radiographic and laboratory tests, were based on 2002 average Medicare reimbursement data.³³ Indirect costs included patient transportation expenses for physician visits and anticoagulation monitoring, estimated at $15 per visit, and the costs for patient and caregiver time based on the average hourly wage of a US non-farm production worker in 2002.³⁵ We assumed that patients needed a daily visit by a visiting nurse and 4 h of home care by a family member per outpatient day.⁵ Patients with minor bleeding incurred the costs of a physician visit. All costs were adjusted to 2002 US dollars by using the medical care component of the consumer price index.³⁵

Analysis

For each treatment strategy, our model calculated lifetime benefits expressed in terms of unadjusted life expectancy and quality-adjusted life expectancy (quality-adjusted life-years [QALYs]) and costs.⁴ We compared the performance of the two treatment strategies using the incremental cost-effectiveness ratio, defined as the extra cost of the more expensive strategy divided by its extra clinical benefit in unadjusted life-years or in QALYs.⁴

We conducted one-way sensitivity analyses to assess the effect of varying baseline estimates within plausible ranges on cost-effectiveness.⁴ Variables that changed the incremental cost-effectiveness ratio by > 10% were selected for Monte Carlo (probabilistic) sensitivity analysis in which parameters were varied simultaneously over predefined probability distributions.³⁶ Clinical probabilities were approximated by β-distributions, and costs were approximated by triangular distributions.³⁷ Values from each probability distribution were randomly selected during each of 1,000 Monte Carlo iterations. We reported the median value and the 2.5th and 97.5th percentile values of the incremental cost-effectiveness ratio between the competing strategies, and we also reported the percentage of Monte Carlo iterations for which a given strategy resulted in a net monetary benefit at various willingness-to-pay ceilings.³⁸ The willingness-to-pay ceiling is a cost-effectiveness ratio that denotes the most that society is willing to pay for an incremental gain in health.³⁸

Our base-case analysis assumed that all patients incurred a full hospital stay for PE of 6.6 days. In a secondary analysis, we assessed the potential economic impact of LMWH treatment if different proportions of patients receiving LMWH were discharged early (ie, after a 3-day inpatient stay) or received all of their care in an outpatient setting.⁵ We established the proportion of patients with PE who had to be discharged early or treated entirely as outpatients before LMWH treatment became cost-saving.

Because our base-case model used point estimates of risk parameter values from a metaanalysis² in which differences for early complications between UFH and LMWH were not statistically significant, we performed another secondary analysis, assuming that patients receiving LMWH had the same risk for early mortality, recurrent VTE, and major bleeding as patients receiving UFH.

Results

While the lifetime cost of UFH was lower than that of LMWH ($12,780 vs $13,001), the mean life expectancy of UFH-treated patients was also lower than that of LMWH-treated patients both in terms of unadjusted years (10.138 life-years vs 10.381 life-years) and quality-adjusted years (7.493 QALYs vs 7.677 QALYs) [Table 2] . The resulting incremental cost-effectiveness ratio was $914 per unadjusted life-year or $1,209/QALY.

In one-way sensitivity analyses (Fig 2 ), the incremental cost-effectiveness ratio of LMWH always remained < $3,000/QALY. Due to the lower recurrence and major bleeding rates associated with LMWH, the incremental cost-effectiveness remained < $3,000/QALY even if the early mortality with LMWH was slightly higher than with UFH (6.2% vs 6.1%). If the daily LMWH pharmacy costs were < $51 (59% of the average wholesale price for enoxaparin), LMWH use became cost-saving. When these model parameters were varied simultaneously over 1,000 Monte Carlo iterations, the median incremental cost-effectiveness ratio of LMWH was $1,196/QALY, while the 2.5th and 97.5th percentile values were $– 553 and $5,522, respectively (a negative incremental cost-effectiveness ratio indicates that LMWH is cost-saving). At willingness-to-pay ceilings of $5,000/QALY and $50,000/QALY gained, the LMWH strategy was cost-effective in 96% and 99% of Monte Carlo iterations, respectively, and was cost-saving in 7%.

Our secondary analyses showed that if ≥ 8% of patients receiving LMWH were discharged early or if ≥ 5% of patients were treated entirely as outpatients, LMWH use was cost-saving. If each treatment had the same early mortality, major bleeding, and recurrent VTE risks, then LMWH cost $1,360,411/QALY. However, if the likelihood of early discharge was ≥ 13% or if ≥ 8% of patients were treated as outpatients, LMWH became cost-saving.

Discussion

Our results demonstrate that, based on the best available evidence, treatment with LMWH is cost-effective for inpatient management of acute PE compared to conventional treatment with UFH. The incremental cost-effectiveness ratio of $1,209/QALY gained represents a modest additional cost of $221 per patient treated and a corresponding increase of 0.184 QALYs. The initially greater treatment costs for patients receiving LMWH were partly offset by reduced costs for treating early complications.

In sensitivity analyses, our results are highly robust over a wide range of values for all important model parameters. LMWH use became cost-saving if the daily pharmacy costs for enoxaparin were <$51 or < 59% of the 2002 US wholesale price of the drug. Since favored buyers, such as large health plans or the Veterans Affairs Healthcare System, may purchase LMWH at prices that are significantly below the average wholesale price, LMWH treatment for PE is likely to be cost-saving in these settings.

We found LMWH treatment to be cost-saving if ≥ 8% of patients were eligible for early discharge, or if ≥ 5% of patients could be treated as outpatients. Although outpatient treatment for PE not currently the standard of care, there is growing evidence that early discharge or outpatient management is safe and feasible in many patients with submassive PE.³⁹⁴⁰⁴¹⁴²⁴³ Based on these data, some professional organizations such as British Thoracic Society recommend consideration of outpatient treatment for clinically stable patients with PE.⁴⁴ However, the safety of this approach needs to be evaluated in further studies. Due to its increased risk of major bleeding in patients with severe renal insufficiency, the use of LMWH is not recommended in these patients.⁴⁵

Some assumptions potentially bias our analysis in favor of UFH. We based our pharmacy costs on the average wholesale price for enoxaparin at a dosage of 1 mg/kg bid. The average wholesale price for another validated dosing scheme—such as enoxaparin, 1.5 mg/kg qd; dalteparin, 120 IU/kg bid; or tinzaparin, 175 IU/kg qd—is less than the price for the enoxaparin dosage we used, but it is not less than the cost-saving threshold of $51/d. Similarly, LMWH treatment would have been more favored if we had not assumed that inpatient and outpatient treatment had the same disutility or that patients incurred the costs for a home nursing visit per outpatient day. Prospective studies³⁹⁴⁰ demonstrate a preference by many patients for outpatient care and safety in LMWH administration by the patient or family members without home nursing. We made the simplifying assumption that heparin-induced thrombocytopenia, which occurs more frequently with UFH, resulted in 1 additional hospital day. If we had considered more complex management options, such as the use of relatively expensive direct thrombin inhibitors, LMWH would have been more favored. Fondaparinux has also been shown to be as effective and safe as UFH in the initial treatment of PE⁴⁶; however, fondaparinux and LMWH have not been compared in terms of their efficacy and safety in the treatment of PE.

Our findings complement and extend the findings of studies⁵⁴⁷⁴⁸⁴⁹ that examined the cost-effectiveness of LMWH treatment for DVT. In one US study,⁵ the incremental cost-effectiveness ratio for inpatient LMWH treatment was $7,820/QALY gained compared with UFH treatment, with LMWH treatment becoming cost-saving when ≥ 13% of patients receiving LMWH were eligible for early discharge or ≥ 8% of patients were treated as outpatients. Thus, LMWH treatment appears to be not only highly cost-effective for DVT but also for PE, the more severe form of VTE.

Our analysis has several limitations. First, the model does not consider uncommon complications of PE, such as chronic pulmonary hypertension.⁵⁰ Second, early complication rates were based on a metaanalysis² that included six different LMWH preparations. Although this metaanalysis² found no evidence that any LMWH preparation is better or worse than another, the safety and efficacy of individual LMWH preparations (eg, enoxaparin) for treating PE must be further evaluated. Third, we used different early recurrence and complication likelihoods for each therapy, although these differences were not statistically significant.² If these likelihoods were assumed to be equal, then LMWH was expensive at baseline (>$1,000,000/QALY) but became cost-saving if hospitalization could be shortened or avoided in clinically plausible proportions of patients (early discharge ≥ 13% or outpatient therapy ≥ 8%). Fourth, the model assumes the risk for late complications to be equal for the two treatment strategies. Although no study reported late complication rates for LMWH treatment vs UFH treatment, there is no biological, pharmacologic, or clinical reason to expect that long-term complication rates of the two treatments will differ. Fifth, we assumed that the effectiveness of LMWH treatment was independent of the treatment setting. Although this assumption has not been confirmed in clinical trials, evidence from prospective studies³⁹⁴⁰⁴¹⁴² suggests that the complication rate in selected patients who have a PE and receive outpatient care with LMWH is low. Sixth, since directly measured utility values from patients with PE were not available, we modeled the decrease of quality of life due to acute complications as days of utility lost because of hospitalization. This is only a minor limitation because the variation of quality-of-life measures in sensitivity analysis did not influence our cost-effectiveness results. Finally, our model was based on a meta-analysis² of clinical trials of submassive PE. Thus, our results are not applicable to patients who have massive PE who require different interventions such as thrombolysis and intensive care.

In conclusion, our model shows that LMWH for inpatient treatment of PE is cost-effective compared to UFH. In suitable patients with PE, early discharge or outpatient treatment with LMWH offers potential cost-savings.

Abbreviations: DVT = deep vein thrombosis; INR = international normalized ratio; LMWH = low-molecular-weight heparin; PE = pulmonary embolism; QALY = quality-adjusted life-year; UFH = unfractionated heparin; VTE = venous thromboembolism

Dr. Aujesky was supported by the Swiss Foundation for Grants in Medicine and Biology and the Swiss Medical Association.

Figure Jump LinkFigure 1. Markov model. Patients remain in a health state (circular arrows) or move from one health state to another (straight or curved arrows) on the basis of transition probabilities. As patients cycle through the model, they accumulate costs and utilities expressed as QALYs. The Markov cycle length is 1 month. Patients with acute PE enter the model in the “well” state and receive a 6-day course either of fixed-dose LMWH or dose-adjusted UFH, followed by a 3-month course of warfarin. During each cycle, patients are at risk for death from any cause and are at risk for bleeding, recurrent VTE, or both. Hemorrhagic stroke leads to permanent disability. During the initial hospitalization for PE, patients are also at risk for heparin-induced thrombocytopenia (not shown).Grahic Jump Location

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Table 1. Base-Case Estimates and Ranges Used in Sensitivity Analysis^*

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Variables	Base-Case Estimate	Range	References	Notes
Clinical probabilities
Early complications (months 0 to 3)
Overall mortality, %
LMWH strategy	4.7	3.4–6.2	²
UFH strategy	6.1	4.7–7.9	²
Heparin-induced thrombocytopenia, %
LMWH strategy	1.1	0.7–1.8	², ⁹¹⁰¹¹¹²¹³¹⁴¹⁵¹⁶¹⁷
UFH strategy	1.7	1.0–2.5	², ⁹¹⁰¹¹¹²¹³¹⁴¹⁵¹⁶¹⁷
Minor bleeding, %
LMWH strategy	11.3	9.3–13.6	²
UFH strategy	8.2	6.4–10.3	²
Major bleeding, %
LMWH strategy	2.3	1.4–3.4	²
UFH strategy	4.1	2.9–5.7	²
Recurrent PE, %
LMWH strategy	1.8	1.0–2.9	²
UFH strategy	2.5	1.5–3.9	²
DVT, %
LMWH strategy	1.7	0.9–2.8	²
UFH strategy	2.4	1.5–3.7	²
Late complications (> 3 mo)
Overall mortality
Risk during months 3 to 12 after PE, %/yr	11.7	8.8–15.2	¹⁸
Risk during years 1 to 8 after PE, %/yr	4.6	3.9–5.4	¹⁸
Relative risk after recurrent VTE	2.0	1.4–2.9	²⁰
Relative risk with vena cava filter	1.9	1.2–3.1	²¹
Minor bleeding
Risk without anticoagulation, %/yr	1.4	0.0–7.8	²⁶
Risk with warfarin (INR, 2 to 3), %/yr	7.7	2.8–16.8	²⁶
Major bleeding
Risk without anticoagulation, %/yr	0.6	0.0–1.0	²²	Range estimated
Risk with warfarin (INR, 2 to 3), %/yr	2.7	1.0–5.0	²⁷	Range estimated
Frequency of hemorrhagic stroke, %	8.7	5.7–12.7	²⁷
Mortality after hemorrhagic stroke, %/yr	41.0	39–43	⁸
Recurrent PE
Risk without anticoagulation, %/yr	2.5	1.0–4.0	²²
Relative risk with vena cava filter DVT	1.4	0.9–2.3	²³
Risk without anticoagulation, %/yr	1.6	0.6–3.3	²²
Relative risk with vena cava filter	2.4	1.7–3.4	²³
Efficacy of warfarin to prevent recurrent VTE, %	90.0	87–95	⁶, ²⁵, ²⁶
Patients with filter receiving warfarin, %	33.0	24–43	²⁴
Quality-of-life measures (utilities)
Hemorrhagic stroke	0.60	0.02–1.00	⁵¹	Median standard-gamble utility for physicians and healthy volunteers
Disutility for warfarin therapy	0.01	0.00–0.08	⁵², ⁵³	Based on mean time-tradeoff utility for patients who either had a history of atrial fibrillation or were treated at an anticoagulation clinic; range based on the literature
Disutility for vena cava filter	0.02	0.00–0.10	⁵¹	Based on mean standard-gamble utility for mild postthrombotic syndrome for physicians and healthy volunteers
Disutilities for acute complications, d†				Ranges ± 50% of base-case estimates
Noncerebral major bleeding‡	4.8	2.4–7.2	³⁰	Assumes 4.8 d lost because of hospitalization
Recurrent PE	6.6	3.3–9.9	³⁰	Assumes 6.6 d lost because of hospitalization
DVT	5.4	2.7–8.1	³⁰	Assumes 5.4 d lost because of hospitalization
Heparin-induced thrombocytopenia	1.0	0.5–1.5	⁵	Assumes 1 additional day lost because of hospitalization
Minor bleeding	1.0	0.5–1.5	Estimate	Assumes 1 outpatient day lost because of disease
				(continues)

Table 1A. Continued^*

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Variables	Base-Case Estimate	Range	References	Notes
Costs (2002 US dollars)				Ranges ± 50% of base-case estimates
Initial PE episode, inpatient treatment
6.6-d hospitalization, excluding costs for UFH	6,156	3,078–9,234	⁵, ³⁰, ³³	Average Medicare reimbursement for diagnosis-related group 078 (PE) minus estimated costs for UFH therapy for 6 d
Physician services	293	147–440	³³	Average Medicare reimbursement for initial physician visit and 5.6 follow-up visits.
UFH therapy
Daily pharmacy costs	6	3–9	³²	Includes average wholesale price for heparin (30,000 U/d).
Daily costs for supplies/ancillary resources	24	12–36	⁵, ³³	Costs for supplies (IV catheter, tubing, and automatic pump); average Medicare reimbursement for nine venipunctures, nine partial thromboplastin times, and one automated hemogram over 6 d
LMWH therapy
Daily pharmacy costs	87	44–131	³²	Includes average wholesale price for enoxaparin, 1 mg/kg bid, for a 75-kg patient
Daily costs for supplies/ancillary resources	5	3–8	³³	Costs for syringes and needles; average Medicare reimbursement for two venipunctures, one creatinine measurement, and one automated hemogram over 6 d
Initial PE episode, outpatient treatment
Initial evaluation in the emergency department	768	384–1152	³³	Average Medicare reimbursement for evaluation and management services, one helical CT with interpretation, one chest radiograph, one ECG with interpretation and report, one arterial puncture with blood gas determination, one venipuncture, one hemogram, one creatinine measurement, and one INR; costs for 6 h of patient time§
Physician office visits per outpatient day	33	17–50	³³	Average Medicare reimbursement for office visits; costs for 1 h of patient time§ and patient transportation (estimated at $15); assumes 0.5 office visits per outpatient day over 6.6 d
Home care by visiting nurse per outpatient day	45	23–68	³³	Medicare reimbursement for one visit per day for all outpatients over 6.6 d
Home care by family member per outpatient day	60	30–90	⁵	Assumes 4 h of the care-giver’s time per day over 6.6 d§
Miscellaneous
Daily costs for oral anticoagulation with warfarin	3	2–5	³², ³³	Average wholesale price for 5 mg of warfarin per day and costs for anticoagulation monitoring (Medicare reimbursement for 1 venipuncture and one INR; costs for 1 h of patient time§ and patient transportation [estimated at $15]); assumes 0.067 anticoagulation checks per day
Costs of vena cava filter placement	482	241–723	³³	Average Medicare reimbursement
Costs of complications
Heparin-induced thrombocytopenia	966	483–1449	⁵, ³⁰, ³³	Costs for 1 additional hospital day ($6,156/6.6) plus one additional follow-up physician visit
Minor bleeding	98	49–147	³³	Average Medicare reimbursement for one office visit, one venipuncture, one INR, and one automated hemogram; costs for 2 h of patient time§ and costs for patient transportation (estimated at $15)
Noncerebral major bleeding	5137	2,569–7,706	³⁰,³³	Average Medicare reimbursement for diagnosis-related group 174 (upper-GI bleeding), one initial physician visit, 3.8 follow-up visits, and one upper endoscopy with control of bleeding

Table 1B. Continued^*

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Variables	Base-Case Estimate	Range	References	Notes
Acute hemorrhagic stroke	13,781	6,891–20,672	³⁰, ³³	Average Medicare reimbursement for diagnosis-related group 014 (intracerebral hemorrhage), one initial physician visit, 4.9 follow-up visits, and physician fees for interpretation of one cerebral CT without contrast; average Medicare reimbursement for diagnosis-related group 462 (rehabilitation)
Care after hemorrhagic stroke, per year	15,950	7,975–23,925	³⁴
Recurrent PE	6,728	3,364–10,092	³⁰, ³³	Average Medicare reimbursement for diagnosis-related group 078 (PE), one initial physician visit, 5.6 follow-up visits, and physician fees for interpretation of one helical CT.
DVT	3,483	1,742–5,225	³⁰, ³³	Average Medicare reimbursement for diagnosis-related group 128 (DVT), one initial physician visit, 4.4 follow-up visits, and physician fees for one duplex ultrasonography
Annual discount rate, %	3	0–5	⁴

* The base-case estimates represent the best estimate for each value. Unless otherwise noted, ranges are defined by 95% confidence intervals.

† Disutilities for acute complications were expressed as days lost from quality-adjusted life expectancy because of hospitalization or disease. For noncerebral major bleeding, recurrent PE, and DVT, the number of days lost because of hospitalization is equal to the average length of hospital stay based on data from the 2002 Medicare Provider Analysis and Review.³⁰

‡ The number of days lost for noncerebral major bleeding is based on the mean length of stay for upper-GI bleeding.

§ Based on the average hourly wage of a US nonfarm production worker in 2002 ($15), as reported by the US Bureau of Labor Statistics.³⁵

Table 2. Results of Base-Case Analysis^*

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Variables	LMWH Strategy	UFH Strategy	Difference
Unadjusted life expectancy, yr	10.381	10.138	0.243
Quality-adjusted life expectancy, QALYs	7.677	7.493	0.184
Total costs, $	13,001	12,780	221
Costs for initial treatment^†	7363	7070	293
Costs for early complications	349	441	− 92
Costs for late complications	5289	5269	20
Incremental cost-effectiveness ratio, $/life-yr			914
Incremental cost-effectiveness ratio, $/QALY			1,209

* Costs and QALYs are discounted at 3%/yr.

† Includes costs for oral anticoagulation with warfarin.

Figure Jump LinkFigure 2. Results of one-way sensitivity analyses. Only variables whose variation caused the incremental cost-effectiveness ratio (x-axis) to change by > 10% are shown. Ranges of one-way sensitivity analyses are shown next to each bar. The vertical line denotes the base-case incremental cost-effectiveness ratio ($1,209/QALY gained). An incremental cost-effectiveness ratio < $0/QALY gained indicates that LMWH is cost-saving.Grahic Jump Location

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We thank Daniel J. Quinlan, MBBS, and John W. Eikelboom, MBBS, for providing unpublished data from their meta-analysis.

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Figures

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Tables

Table 1. Base-Case Estimates and Ranges Used in Sensitivity Analysis^*

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Variables	Base-Case Estimate	Range	References	Notes
Clinical probabilities
Early complications (months 0 to 3)
Overall mortality, %
LMWH strategy	4.7	3.4–6.2	²
UFH strategy	6.1	4.7–7.9	²
Heparin-induced thrombocytopenia, %
LMWH strategy	1.1	0.7–1.8	², ⁹¹⁰¹¹¹²¹³¹⁴¹⁵¹⁶¹⁷
UFH strategy	1.7	1.0–2.5	², ⁹¹⁰¹¹¹²¹³¹⁴¹⁵¹⁶¹⁷
Minor bleeding, %
LMWH strategy	11.3	9.3–13.6	²
UFH strategy	8.2	6.4–10.3	²
Major bleeding, %
LMWH strategy	2.3	1.4–3.4	²
UFH strategy	4.1	2.9–5.7	²
Recurrent PE, %
LMWH strategy	1.8	1.0–2.9	²
UFH strategy	2.5	1.5–3.9	²
DVT, %
LMWH strategy	1.7	0.9–2.8	²
UFH strategy	2.4	1.5–3.7	²
Late complications (> 3 mo)
Overall mortality
Risk during months 3 to 12 after PE, %/yr	11.7	8.8–15.2	¹⁸
Risk during years 1 to 8 after PE, %/yr	4.6	3.9–5.4	¹⁸
Relative risk after recurrent VTE	2.0	1.4–2.9	²⁰
Relative risk with vena cava filter	1.9	1.2–3.1	²¹
Minor bleeding
Risk without anticoagulation, %/yr	1.4	0.0–7.8	²⁶
Risk with warfarin (INR, 2 to 3), %/yr	7.7	2.8–16.8	²⁶
Major bleeding
Risk without anticoagulation, %/yr	0.6	0.0–1.0	²²	Range estimated
Risk with warfarin (INR, 2 to 3), %/yr	2.7	1.0–5.0	²⁷	Range estimated
Frequency of hemorrhagic stroke, %	8.7	5.7–12.7	²⁷
Mortality after hemorrhagic stroke, %/yr	41.0	39–43	⁸
Recurrent PE
Risk without anticoagulation, %/yr	2.5	1.0–4.0	²²
Relative risk with vena cava filter DVT	1.4	0.9–2.3	²³
Risk without anticoagulation, %/yr	1.6	0.6–3.3	²²
Relative risk with vena cava filter	2.4	1.7–3.4	²³
Efficacy of warfarin to prevent recurrent VTE, %	90.0	87–95	⁶, ²⁵, ²⁶
Patients with filter receiving warfarin, %	33.0	24–43	²⁴
Quality-of-life measures (utilities)
Hemorrhagic stroke	0.60	0.02–1.00	⁵¹	Median standard-gamble utility for physicians and healthy volunteers
Disutility for warfarin therapy	0.01	0.00–0.08	⁵², ⁵³	Based on mean time-tradeoff utility for patients who either had a history of atrial fibrillation or were treated at an anticoagulation clinic; range based on the literature
Disutility for vena cava filter	0.02	0.00–0.10	⁵¹	Based on mean standard-gamble utility for mild postthrombotic syndrome for physicians and healthy volunteers
Disutilities for acute complications, d†				Ranges ± 50% of base-case estimates
Noncerebral major bleeding‡	4.8	2.4–7.2	³⁰	Assumes 4.8 d lost because of hospitalization
Recurrent PE	6.6	3.3–9.9	³⁰	Assumes 6.6 d lost because of hospitalization
DVT	5.4	2.7–8.1	³⁰	Assumes 5.4 d lost because of hospitalization
Heparin-induced thrombocytopenia	1.0	0.5–1.5	⁵	Assumes 1 additional day lost because of hospitalization
Minor bleeding	1.0	0.5–1.5	Estimate	Assumes 1 outpatient day lost because of disease
				(continues)

Table 1A. Continued^*

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Variables	Base-Case Estimate	Range	References	Notes
Costs (2002 US dollars)				Ranges ± 50% of base-case estimates
Initial PE episode, inpatient treatment
6.6-d hospitalization, excluding costs for UFH	6,156	3,078–9,234	⁵, ³⁰, ³³	Average Medicare reimbursement for diagnosis-related group 078 (PE) minus estimated costs for UFH therapy for 6 d
Physician services	293	147–440	³³	Average Medicare reimbursement for initial physician visit and 5.6 follow-up visits.
UFH therapy
Daily pharmacy costs	6	3–9	³²	Includes average wholesale price for heparin (30,000 U/d).
Daily costs for supplies/ancillary resources	24	12–36	⁵, ³³	Costs for supplies (IV catheter, tubing, and automatic pump); average Medicare reimbursement for nine venipunctures, nine partial thromboplastin times, and one automated hemogram over 6 d
LMWH therapy
Daily pharmacy costs	87	44–131	³²	Includes average wholesale price for enoxaparin, 1 mg/kg bid, for a 75-kg patient
Daily costs for supplies/ancillary resources	5	3–8	³³	Costs for syringes and needles; average Medicare reimbursement for two venipunctures, one creatinine measurement, and one automated hemogram over 6 d
Initial PE episode, outpatient treatment
Initial evaluation in the emergency department	768	384–1152	³³	Average Medicare reimbursement for evaluation and management services, one helical CT with interpretation, one chest radiograph, one ECG with interpretation and report, one arterial puncture with blood gas determination, one venipuncture, one hemogram, one creatinine measurement, and one INR; costs for 6 h of patient time§
Physician office visits per outpatient day	33	17–50	³³	Average Medicare reimbursement for office visits; costs for 1 h of patient time§ and patient transportation (estimated at $15); assumes 0.5 office visits per outpatient day over 6.6 d
Home care by visiting nurse per outpatient day	45	23–68	³³	Medicare reimbursement for one visit per day for all outpatients over 6.6 d
Home care by family member per outpatient day	60	30–90	⁵	Assumes 4 h of the care-giver’s time per day over 6.6 d§
Miscellaneous
Daily costs for oral anticoagulation with warfarin	3	2–5	³², ³³	Average wholesale price for 5 mg of warfarin per day and costs for anticoagulation monitoring (Medicare reimbursement for 1 venipuncture and one INR; costs for 1 h of patient time§ and patient transportation [estimated at $15]); assumes 0.067 anticoagulation checks per day
Costs of vena cava filter placement	482	241–723	³³	Average Medicare reimbursement
Costs of complications
Heparin-induced thrombocytopenia	966	483–1449	⁵, ³⁰, ³³	Costs for 1 additional hospital day ($6,156/6.6) plus one additional follow-up physician visit
Minor bleeding	98	49–147	³³	Average Medicare reimbursement for one office visit, one venipuncture, one INR, and one automated hemogram; costs for 2 h of patient time§ and costs for patient transportation (estimated at $15)
Noncerebral major bleeding	5137	2,569–7,706	³⁰,³³	Average Medicare reimbursement for diagnosis-related group 174 (upper-GI bleeding), one initial physician visit, 3.8 follow-up visits, and one upper endoscopy with control of bleeding

Table 1B. Continued^*

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Variables	Base-Case Estimate	Range	References	Notes
Acute hemorrhagic stroke	13,781	6,891–20,672	³⁰, ³³	Average Medicare reimbursement for diagnosis-related group 014 (intracerebral hemorrhage), one initial physician visit, 4.9 follow-up visits, and physician fees for interpretation of one cerebral CT without contrast; average Medicare reimbursement for diagnosis-related group 462 (rehabilitation)
Care after hemorrhagic stroke, per year	15,950	7,975–23,925	³⁴
Recurrent PE	6,728	3,364–10,092	³⁰, ³³	Average Medicare reimbursement for diagnosis-related group 078 (PE), one initial physician visit, 5.6 follow-up visits, and physician fees for interpretation of one helical CT.
DVT	3,483	1,742–5,225	³⁰, ³³	Average Medicare reimbursement for diagnosis-related group 128 (DVT), one initial physician visit, 4.4 follow-up visits, and physician fees for one duplex ultrasonography
Annual discount rate, %	3	0–5	⁴

* The base-case estimates represent the best estimate for each value. Unless otherwise noted, ranges are defined by 95% confidence intervals.

‡ The number of days lost for noncerebral major bleeding is based on the mean length of stay for upper-GI bleeding.

§ Based on the average hourly wage of a US nonfarm production worker in 2002 ($15), as reported by the US Bureau of Labor Statistics.³⁵

Table 2. Results of Base-Case Analysis^*

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Variables	LMWH Strategy	UFH Strategy	Difference
Unadjusted life expectancy, yr	10.381	10.138	0.243
Quality-adjusted life expectancy, QALYs	7.677	7.493	0.184
Total costs, $	13,001	12,780	221
Costs for initial treatment^†	7363	7070	293
Costs for early complications	349	441	− 92
Costs for late complications	5289	5269	20
Incremental cost-effectiveness ratio, $/life-yr			914
Incremental cost-effectiveness ratio, $/QALY			1,209