Cost Effectiveness of Thromboprophylaxis With a Low-Molecular-Weight Heparin Versus Unfractionated Heparin in Acutely Ill Medical Inpatients

Objective: To compare the cost effectiveness of prophylaxiswith a low-molecular-weight heparin with that of prophylaxis withunfractionated heparin for the prevention of venous thromboembolismin acutely ill medical inpatients.

Study Design: Cost-effectiveness analysis based on decision-treemodel.

Participants and Methods: A hypothetical cohort of 10 000patients was assumed to receive either (1) prophylaxis with enoxaparin,a low-molecular-weight heparin, 40 mg daily; (2) prophylaxiswith unfractionated heparin, 5000 IU twice daily; or (3) noprophylaxis. We developed a decision-analytic model with parameterestimates derived from published clinical trials and other secondarysources. Then, for each strategy, we estimated the risks ofvenous thromboembolism, complications of prophylaxis and treatment(heparin-induced thrombocytopenia and bleeding), mortality,and costs of prophylaxis and treatment within a 30-day period.

Results: In a hypothetical cohort of 10 000 inpatients, expectednumbers of deaths attributable to venous thromboembolism ordrug complications related to both prophylaxis for and treatment ofVTE over a 30-day period were 37 with enoxaparin prophylaxis, 53with unfractionated heparin prophylaxis, and 81 with no prophylaxis.In 2001, corresponding expected costs of prevention, diagnosis,and management of VTE were $3 502 000 for enoxaparin,$3 772 000 for unfractionated heparin, and $3 105 000 for no prophylaxis.The incremental cost per death averted with enoxaparinprophylaxis versus no prophylaxis was $9100. Enoxaparin dominatedunfractionated heparin by being both more effective and lesscostly in the base-case analysis, as well as in sensitivity analyses inwhich equal efficacy and equal risks of bleeding were assumed.

Conclusions: Thromboprophylaxis with this low-molecular-weightheparin represents a cost-effective use of healthcare resourcesin acutely ill medical inpatients and dominatesthromboprophylaxis with unfractionated heparin.

(Am J Manag Care. 2004;10:632-642)

Venous thromboembolism (VTE) is a life-threateningvascular disease common among hospitalizedpatients. It is estimated that more than 170000 incident cases of VTE are diagnosed in hospitalizedpatients in the United States each year, and morethan 20 000 of these patients die of the condition beforedischarge.¹ Because many cases of incident thromboembolismgo undetected and untreated, primary preventionin at-risk patients is of critical importance.

Several subgroups of hospitalized patients are at elevatedrisk for VTE, including those undergoing orthopedicor other major surgery, as well as those with acutecirculatory conditions such as myocardial infarction,atrial fibrillation, angina, or thrombotic stroke. TheSixth ACCP Guidelines for Antithrombotic Therapy forPrevention and Treatment of Thrombosis recommendthromboprophylaxis as standard practice for thesepatients.² In recent years, the substantial risk of VTE inthe general medical population has emerged as animportant clinical concern also.³ Acutely ill medicalinpatients, such as those hospitalized for congestiveheart failure, chronic obstructive pulmonary disease, oracute infections, often have hypercoagulability andperiods of prolonged immobility that may place them atincreased risk of VTE.^2,4 Because these patients are likelyto have one or more additional risk factors (eg, historyof VTE, advanced age, obesity, varicose veins,estrogen use),² the potential benefits of thromboprophylaxisin this population may be substantial.

As the risk of VTE among general medical patientshas gained recognition, the introduction of low-molecular-weight heparin (LMWH) has provided an alternativeto thromboprophylaxis with unfractionated heparin(UFH), the previous standard. The efficacy of bothLMWH and UFH as thromboprophylaxis in selectedgroups of medical inpatients has been demonstrated inclinical trials,^5-11 and there is evidence that LMWH mayhave a better safety profile than UFH with regard to bothhemorrhage^6-8 and heparin-induced thrombocytopenia(HIT).^6-7,11 Because LMWH is more costly, however,the question remains whether its use can be justified interms of reduced risk ofdrug-related adverseevents and, possibly,improved efficacy. Toaddress this question,we examined the costeffectiveness of prophylaxiswith an LMWH,specifically enoxaparin,versus prophylaxis withUFH in acutely ill generalmedical inpatients.

METHODS

Study Design

We used techniquesof decision analysis anddata from secondarysources to develop a model of the prevention, detection,treatment, and outcomes of VTE in generalmedical patients. A hypothetical cohort of 10 000acutely ill medical inpatients was assumed to receiveone of three methods of thromboprophylaxis:(1) enoxaparin, a representative LMWH (Lovenox;Aventis Pharmaceuticals; Bridgewater, NJ), 40 mgadministered subcutaneously once daily; (2) UFH,5000 IU administered subcutaneously twice daily; or(3) no prophylaxis. Our choice of dosing and frequencyof administration reflects current recommendationsfor thromboprophylaxis in medical patients.² For eachstrategy, we estimated the 30-day risks of VTE,including deep vein thrombosis (DVT) and/or pulmonaryembolism (PE); complications of prophylaxisand therapy, such as HIT and bleeding; mortality; andthe costs of prophylaxis, diagnostic testing, and treatment.We used these estimates to examine the incrementalcost effectiveness of thromboprophylaxis,expressed in terms of the cost per death averted.

Treatment patterns and outcomes of care were modeledfor 30 days from the time of hospital admission.This time period was chosen to capture DVT and PEoccurring both in the hospital and during the periodimmediately following discharge, during which time patientsmay continue to be at elevated risk of VTE. Ouranalysis was conducted from the perspective of a thirdpartyhealth insurer and therefore considered only directmedical costs.

Model Structure

The structure of the decision-tree model is illustratedin Figures 1 through 3. The clinical starting point forthe model is admission to an acute-care facility fortreatment of a serious medical condition. For thesepatients, the clinical decision of interest is the methodof thromboprophylaxis administered, either enoxaparin,UFH, or no prophylaxis (Figure 1). Patientsreceiving enoxaparin or UFH are assumed to be at riskfor drug-related adverse events, including hemorrhage("bleed") and HIT. Bleeds may be either minor or major,while HIT is classified as asymptomatic or symptomaticaccording to the presence or absences of overtclinical symptoms. Major bleeds and symptomaticHIT may lead to death, though for modeling conveniencewe assumed that patients who survive one of theseadverse events are not at risk of additional adverseevents or VTE.

Patients who do not experience HIT or hemorrhageare at risk of DVT (Figure 2). Because clinical diagnosisof DVT is imperfect, the tree reflects this uncertaintyby allowing patients to receive a true- orfalse-positive or negative clinical diagnosis. Patientswith a positive clinical diagnosis (whether true or false)are referred for duplex ultrasound and, if confirmed, fortreatment. Those with a negative clinical diagnosisreceive no confirmatory diagnostic procedures ortreatment. This model assumes that all patientswhose DVT diagnosis is confirmed by ultrasoundundergo anticoagulation therapy with enoxaparin;such patients are at risk for bleeds and HIT. Patients whosurvive treatment-related adverse events, such as bleedsor HIT, finish treatment and are not at risk of furtheradverse events or PE.

or

Patients who have DVT and do not experience anadverse event from its treatment are at risk for PE(Figure 3). Patients who experience PE and survive theperiod immediately after the acute event may be giveneither a true-positive or a false-negative clinical diagnosisof PE. Patients with apositive clinical diagnosis(whether true or false) arereferred for a confirmatoryventilation—perfusion (V/Q)scan or computed tomography(CT) scan and, if positive,for treatment of PE.Patients may die fromtreated untreated PE orfrom other underlyingmedical conditions.

Model Estimation

Model estimation involvesassigning probabilityestimates to each of themodel's chance nodes andcost estimates to each pathway.Base-case transitionprobabilities and datasources are summarized inTable 1.

Risks of failure and theoccurrence of adverseevents for each prophylaxismethod were obtained from the published literature. Weused data from MEDENOX,¹⁰ a recent placebo-controlledclinical trial, in our model, evaluating 40 mgenoxaparin once daily as thromboprophylaxis in medicalpatients to estimate the risk of DVT with enoxaparinprophylaxis and the baseline risk of DVT amonguntreated patients. MEDENOX is the only publishedplacebo-controlled trial of an LMWH that enrolled generalmedical patients, administered a dose of enoxaparinconsistent with current recommendations,² and diagnosedDVT using venography. We were unable to identifyany published studies that compared an LMWH toeither UFH or placebo and met these criteria. Therefore,to estimate the risk of prophylaxis failure among patientsreceiving UFH, we used the results of a recent meta-analysisof trials that compared LMWH to UFH in medicalpatients¹² and applied the summary risk-ratio of 0.83 tothe risk of prophylaxis failure in the LMWH arm of theMEDENOX trial.

Because HIT and bleeds occurred infrequently in thepublished trials of thromboprophylaxis in medical inpatientsand because their detection does not depend onvenography, estimates of the rates of occurrence andseverity of these events were drawn from a wider rangeof clinical trials than those used for the efficacy estimates.^6-8,11 Published estimates of "symptomatic" or"severe" HIT^10,15-18 were assumed to include thrombocytopenialeading to thromboembolism. The other transitionprobabilities in the model are uniform across alltreatment arms, and most were estimated from the publishedliterature. The estimate of the probability of false-negativeclinical diagnosis of DVT was derived fromstudies examining the prevalence of DVT in asymptomaticpatients.^29-30 For the base—case analysis, the riskof death due to the underlying medical condition wasassumed to be 10%, which is consistent with the rates ofdeath reported in published clinical trials focusing onacutely ill medical inpatients.^6-10,12 Finally, because weassumed that one half of the patients with suspected PEwould undergo CT scans and one half V/Q scans, weused the average sensitivity and specificity of these 2diagnostic techniques in the model. Where multipledata sources were used, estimates were combinedacross studies by direct pooling.

Costs

The model's cost parameters include (1) study medicationsand ancillary resources, (2) laboratory procedures,(3) hospital inpatient days, (4) physician inpatientvisits, and (5) physician office/outpatient visits. All costestimates employed in the analysis are summarized inTable 2.

Drug acquisition costs were estimated from averagewholesale prices⁴²; for the weight-based doses, the totalamount of drug used was estimated assuming a 75-kgpatient. Cost estimates associated with the suppliesused to administer drugs were obtained from publisheddata.⁴³ The costs of laboratory procedures for monitoringanticoagulation therapy were estimated using datafrom the Centers for Medicare & Medicaid Services⁴⁴;and the costs of physician inpatient and office/outpatientvisits were estimated using the Medicare Resource-Based Relative Value Scale payment rates.⁴⁵ Mean dailyinpatient costs attributable to adverse drug reactionsand VTE were estimated by dividing the unadjustedpayment for deep vein thrombophlebitis (DiagnosisRelated Group 128) by the average length of stay forthis diagnosis.⁴⁶

Although our primary focus was on costs incurredwithin 30 days of hospital admission, we included costsafter 30 days if they were incurred as a direct consequenceof events within the first 30 days (eg, 6 monthsof warfarin therapy following DVT). All costs weremeasured in 2001 US dollars; where necessary, costswere updated to 2001 using the medical-care componentof the Consumer Price Index.⁴⁷ Because of the brieftime horizon of the model, discounting was notrequired.

Analyses

dominated

For each of the 3 prophylaxis methods being evaluated,we used our model to estimate the total costs of prevention,detection, treatment, and outcomes of VTE in acohort of 10 000 acutely ill medical inpatients over a 30-day period. Cost effectiveness is expressed in terms ofthe cost per death averted. To compare treatment strategieswe first rank-ordered regimens by increasing costand eliminated those strategies that were found bothmore costly and less effective than ( by) others.For each remaining strategy we then calculated theadditional cost and additional deaths averted versus thenext lowest cost strategy. The ratio of these 2 numbers(ie, the incremental cost per death averted) is the incrementalcost-effectiveness ratio.

Sensitivity analyses were performed to assess therobustness of key model parameters and to evaluatethe effect of alternative assumptions on model outcomes.To explore the cost effectiveness of thromboprophylaxisin patients with different comorbidity andrisk profiles, we analyzed subgroups of patients fromthe MEDENOX trial with heart failure, respiratory disease,or infectious disease.⁴⁸ We varied the backgrounddeath rate and the underlying risk of DVT in patientsreceiving no prophylaxis, as well as the relative safetyand efficacy of the 2 active prophylaxis arms. Lastly,we examined the effect on our findings of changingassumptions about the cost of drug therapy, risk ofbleeding due to prophylaxis, progression from DVT toPE, and death from PE.

RESULTS

Outcomes of Thromboprophylaxis

Base-case estimates of the occurrence of DVT, PE, andVTE-related death in a cohort of 10 000 acutely ill generalmedical inpatients are presented in Figure 4. The riskof each of these outcomes is lowest among patientsreceiving thromboprophylaxis with enoxaparin and highestamong those receiving no prophylaxis. Compared tono thromboprophylaxis, enoxaparin prophylaxis isexpected to prevent 860 cases of DVT, 171 cases ofPE, and 44 deaths, while UFH is expected to prevent776 cases of DVT, 155 cases of PE, and 28 deaths.

Costs of Thromboprophylaxis

The total costs of thromboprophylaxis, adverseevents (related to both prophylaxis and treatment ofVTE), and diagnosis and management of DVT andPE are presented in Figure 5. Patients receiving nothromboprophylaxis had the lowest total costs, followedby those receiving enoxaparinand UFH.

Cost Effectiveness ofThromboprophylaxis

Results of the incremental analysiscomparing a strategy of no prophylaxiswith the 2 active prophylactic strategiesare presented in Table 3. Whencompared with no prophylaxis, prophylaxiswith enoxaparin was the morecost-effective strategy, at a cost of$9100 per death averted. Unfractionatedheparin prophylaxis was dominatedby enoxaparin prophylaxis, whichwas both less costly and more effectivein preventing deaths.

Sensitivity Analyses

Subgroup Analysis

. Results for thesubgroups of patients with heart failure,respiratory disease, or infectious disease were similarto those for all acutely ill medical patients (Table 4).For each subgroup, thromboprophylaxis with enoxaparindominated that with UFH, and costs per deathaverted for enoxaparin versus no prophylaxis were evenmore favorable than in the base case.

Underlying Risks in Patient Population.

Our findingsalso were relatively insensitive to variations in theassumed competing risk of death (10% in the base-caseanalysis). Eliminating the competing risk of deathmade the results slightly more favorable forenoxaparin. Increasing the underlying risk ofdeath to 20% increased the cost per deathaverted with enoxaparin versus no prophylaxisby only about $1000 and did not changethe dominance of enoxaparin over UFH. Themodel was more sensitive to changes in theassumed risk of DVT. When we reduced therisk of DVT in all groups by one half (ie, to2.8% with enoxaparin, 3.3% with UFH, and7.1% with no prophylaxis), the cost per deathaverted for enoxaparin versus no prophylaxisincreased to $56 300, and enoxaparin continuedto dominate UFH. In contrast, when weincreased the risk of DVT by one half (ie, to8.3% with enoxaparin, 9.9% with UFH, and21.3% with no prophylaxis), both activemethods of prophylaxis were less costly andmore effective than no prophylaxis, withenoxaparin continuing to dominate UFH.When we conducted a similar analysis inwhich we simultaneously varied the risk ofbleeds with both enoxaparin and UFH from 50% to 150%of the base-case estimates, we found that enoxaparindominated UFH under both the high-risk and low-riskscenarios, with cost per death averted versus no prophylaxisranging from about $5000 assuming lower riskof bleeds to $14 000 assuming higher risk of bleeds.

Effectiveness and Side Effects of Enoxaparin vsUFH.

and

To determine if our results depended on theassumption that enoxaparin had an efficacy advantageover UFH, we assumed equal efficacy (ie, 5.5% probabilityof DVT) for both methods of prophylaxis. Under thisassumption, enoxaparin remained both less costly andmore effective than UFH because of the reduced risk ofHIT and hemorrhage. Similarly, enoxaparin continuedto dominate UFH when equal rates of hemorrhage wereassumed for the 2 prophylactic strategies. When bothequal efficacy equal rates of hemorrhage wereassumed, we found that UFH was no longer dominatedby enoxaparin, and the incremental cost effectiveness ofenoxaparin versus UFH was $43 256 per death averted.

Other Key Model Parameters

. To examine the sensitivityof our results to changes in drug costs, we calculatedthe drug price at which enoxaparin would nolonger dominate UFH. We found that, up to a per-doseprice of $37.42 for enoxaparin (vs the base-case of$24.46), the cost per death averted with enoxaparin islower than with UFH. We also examined the sensitivityof our results to the assumed risk of progressionfrom DVT to PE, both with and without treatment, andthe probability of death due to treated or untreated PE.Varying each of these parameters from 50% to 150%of the base-case estimate, we found that our resultswere relatively insensitive to these assumptions. Foreach of these scenarios, thromboprophylaxis withenoxaparin was both less costly and more effectivethan UFH, and the incremental cost effectiveness ofenoxaparin versus no prophylaxis was less than$21 000 per death averted.

DISCUSSION

Our analysis highlights a number of important issuesrelated to the choice of thromboprophylactic strategyfor medical inpatients. First, the results of our base-caseanalysis indicate that, given the limitations andassumptions of the model, if the societal value of preventinga VTE-related death among acutely-ill medicalpatients is at least $9100, then the use of thromboprophylaxiswith LMWH among these patients can be consideredcost effective. If each death averted results ina gain of just one quality-adjusted life-year, this marginalcost is well below the often-cited threshold of$50 000 per quality-adjusted life-year gained.⁴⁹ Moreover,despite higher drug acquisition costs, thromboprophylaxiswith enoxaparin dominates UFH by beingboth less costly and more effective.

and

In sensitivity analyses, enoxaparin remained costeffective in all scenarios examined. The cost-effectivenessadvantage of enoxaparin in our model may be seenas due to our assumptions that this drug has greaterefficacy as well as a more favorable adverse-event profilethan UFH, especially with respect to HIT. But sensitivityanalyses showed that even without an efficacyadvantage a lower risk of bleeding complications,the incremental cost per death averted with enoxaparinversus UFH is less than $50 000. This suggeststhat the reduction in the risk of HIT alone may warrantthe use of this LMWH.

Our sensitivity analyses also indicate that, althoughthe incremental cost effectiveness of thromboprophylaxiswith a LMWH versus no thromboprophylaxis issomewhat sensitive to changes in the assumed underlyingrisk of VTE in untreated patients, the incrementalcost effectiveness of enoxaparin exceeds $50 000only slightly, even when this risk is halved. This suggeststhat thromboprophylaxis with enoxaparin may bea cost-effective strategy even among medical inpatientsat relatively low risk of VTE.

Our findings are qualitatively similar to those of 4recently published studies that evaluated the cost effectivenessof thromboprophylaxis with LMWH versusplacebo in medical patients from Canada,⁵⁰ Italy,⁵¹Spain,⁵² and the United States.⁵³ Our findings are alsogenerally consistent with the published studies in thesurgical population. A number of studies have examinedthe cost effectiveness of LMWH prophylaxis aftertotal hip replacement surgery and have found it to becost effective versus both warfarin^54-56 and UFH.^57,58Studies in the general surgery⁵⁹ and trauma⁶⁰ populationsreported similar results, while a study comparingthromboprophylaxis with LMWH versus UFH after colorectalsurgery⁶¹ found UFH to be the more cost-effectivestrategy. Although most of these studies did notreport cost per death averted in US currency, the onestudy that did⁵⁵ reported a cost-effectiveness ratio of$12 000 per death averted for enoxaparin versus warfarinin total hip replacement surgery, which is in linewith our finding of $9100 per death averted.

Our study is subject to a number of limitations.First, the decision-tree model is necessarily a simplifiedrepresentation of the disease and treatment processand cannot include all possible strategies and outcomes.Moreover, although our study followed patientsfor 30 days after admission in order to include thromboembolicevents occurring even after hospital discharge,this time period may not capture all of thelonger-term consequences of VTE, including post-thromboticsyndrome and increased risk of recurrentDVT. We also recognize that acutely ill medicalpatients are a heterogeneous group, and estimating costeffectiveness for medical patients as a whole may maskimportant underlying differences in risks and outcomesbetween groups.

In addition, we note that probabilities and costs foreach of the pathways were estimated by gathering andcombining data from a variety of sources. Because, inthis population of acutely ill medical patients, no studieshave been conducted that compare an LMWHsimultaneously to both UFH and placebo, it was necessaryto synthesize data on efficacy and adverse eventsfrom different studies. In applying the risk-ratio for anLMWH versus UFH from a meta-analysis to the observedrisk of DVT with enoxaparin in the MEDENOX trial,we assumed that the risk of DVT with UFH is a constantmultiple of the risk with enoxaparin and is independentof the underlying risk of DVT or other patient characteristics.This assumption could not be verified. Inaddition, because the incidence of adverse events isrelatively low for all strategies examined, it was necessaryto combine data from a number of studies thatused different study designs and populations. Thevalidity and precision of the estimates derived by thisprocess are unknown. We also note that the MEDENOXtrial and the trials synthesized in the meta-analysiswere conducted on selected groups of medicalpatients and excluded subgroups such as women ofchildbearing potential, patients with recent strokes,and those requiring chronic anticoagulation; therefore, extrapolation of our finding to these populationsmay not be appropriate.

The majority of costs used in this analysis were takenfrom standard sources; the extent to which they reflectthe true costs of administering medical care isunknown. In particular, the use of average wholesaleprices to estimate drug acquisition costs likely overstatesthe actual cost of drugs to hospital pharmacies.However, even if the cost of the LMWH used in thisanalysis was underestimated, sensitivity analyses indicatethat an increase of more than 50% in its cost wouldbe required to alter the dominance of enoxaparin overUFH. Finally, this study was conducted from the perspectiveof the third-party payer and as such does notinclude such costs of VTE as lost productivity, caregivertime, transportation, and other unreimbursedexpenses. Because inclusion of these costs would haveincreased the costs of thromboembolism, however, thecost-effectiveness argument for enoxaparin thromboprophylaxiswould have been strengthened.

In conclusion, when compared with UFH, thromboprophylaxiswith enoxaparin is both less costly andmore effective. Although prophylaxis with this LMWH inacutely ill medical inpatients is associated with highermedical costs than no thromboprophylaxis, its costeffectiveness compares favorably to other generallyaccepted medical interventions.⁶²

Acknowledgments

The authors would like to thank Michael Stokes, MPH,and Mark Comanducci, BA, for their work on the datasynthesis and analysis, and Ronald Preblick, PharmD, forhis contributions to the study concept and manuscriptrevisions.

From Innovus Research Inc, Medford, Mass (LJM, DT, and MCW); Center for RiskAnalysis, Harvard School of Public Health, Boston, Mass (MCW); and CardiovascularDivision, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (SZG).

Funding for this research was provided by Aventis Pharmaceuticals, Bridgewater, NJ.A poster of the results was presented in May 20, 2002 at the annual meeting of theInternational Society for Pharmacoeconomics and Outcomes Research (ISPOR) in CrystalCity, Va.

Address correspondence to: David Thompson, PhD, Innovus Research Inc, 10 CabotRoad, Suite 102, Medford, MA 02155. E-mail: dthompson@innovus.com.

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