REVIEWS

Outpatient Therapy with Low Molecular WeightHeparin for the Treatment of Venous

Thromboembolism: A Review of Efficacy,Safety, and Costs

Jodi B. Segal, MD, MPH, Dennis T. Bolger, MD, MPH, Mollie W. Jenckes, MHSc,Jerry A. Krishnan, MD, Michael B. Streiff, MD, John Eng, MD, Leonardo J. Tamariz, MD, MPH,

Eric B. Bass, MD, MPH

PURPOSE: To summarize the evidence comparing the effi-cacy, safety, and costs of outpatient and inpatient treatment ofvenous thromboembolism.METHODS: We searched the literature through March 2002for studies comparing outpatient and inpatient treatment ofvenous thromboembolism with low molecular weight heparinor unfractionated heparin, and for studies addressing the costsof low molecular weight heparin use in any setting. We includedstudies with comparison groups or decision analyses.RESULTS: Eight studies (three randomized trials and five cohortstudies) compared outpatient use of low molecular weight heparinwith inpatient use of unfractionated heparin in 3762 patients. Theincidence of recurrent deep venous thrombosis was similar in thetwo groups (median, 4% [range, 0% to 7%] vs. 6% [range, 0% to

9%]), as was major bleeding (median, 0.5% [range, 0% to 2%] vs.1% [range, 0% to 2%]). Use of low molecular weight heparin wasassociated with shorter hospitalization (median, 2.7 days [range,0.03 to 5.1 days] vs. 6.5 days [range, 4 to 9.6 days]) and lower costs(median difference, $1600). Comparisons of outpatient and in-hospital use of low molecular weight heparin reported no differ-ence in outcomes, but there were savings in hospitalization costs.Low molecular weight heparin was also found to be more costsaving and cost-effective than unfractionated heparin, with savingsof 0% to 64% (median, 57%).CONCLUSION: The evidence indicates that outpatient treat-ment of deep venous thrombosis with low molecular weightheparin is likely to be efficacious, safe, and cost-effective. Am JMed. 2003;115:298 –308. ©2003 by Excerpta Medica Inc.

High-quality systematic reviews have concludedthat low molecular weight heparin, adminis-tered subcutaneously, is as efficacious as intra-

venous unfractionated heparin for the treatment of deepvenous thrombosis and does not increase the likelihoodof major hemorrhagic complications (1). However, mosttrials in these reviews compared the two agents in an in-patient setting (2–14).

Because low molecular weight heparin does not re-

quire intravenous administration, it is being used in-creasingly in an outpatient setting or at home. The safetyand efficacy of this practice is not known, although theFood and Drug Administration approved enoxaparin foroutpatient use in 1998. Furthermore, the costs associatedwith this practice need to be determined before it can berecommended widely.

This situation calls for better understanding of thebenefits and cost implications to be expected with use oflow molecular weight heparin in an outpatient setting.Such information is important to clinicians choosing thebest therapy for patient care, to insurers making decisionsabout reimbursement levels, to case managers appealingto insurers for coverage of outpatient therapy, to hospitaland managed care administrators optimizing the use ofhospital resources, and to researchers requiring evidencewith which to design future studies.

We therefore sought to review the evidence on the ef-ficacy and safety of treating deep venous thrombosis in anoutpatient as compared with an inpatient setting, and onthe cost-effectiveness of treatment with low molecularweight heparin or unfractionated heparin, regardless ofthe setting.

From the Departments of Medicine (JBS, DTB, MWJ, JAK, MBS, LJT,EBB), and Radiology (JE), Johns Hopkins University School of Medi-cine, and the Bloomberg School of Public Health of the Johns HopkinsUniversity (EBB), Baltimore, Maryland.

This study was conducted by the Johns Hopkins Evidence-BasedPractice Center under Contract No. 290-97-0006 to the Agency forHealthcare Research and Quality, Rockville, Maryland. The authors areresponsible for the content of this article, including any treatment rec-ommendations. No statement in this article should be construed as anofficial position of the Agency for Healthcare Research and Quality orthe U.S. Department of Health and Human Services.

Requests for reprints should be addressed to Jodi B. Segal, MD, MPH,Department of Medicine, Johns Hopkins University School of Medi-cine, 720 Rutland Avenue, Ross Building #1025, Baltimore, Maryland21205, or jsegal@jhmi.edu.

Manuscript submitted December 10, 2002, and accepted in revisedform May 9, 2003.

298 © 2003 by Excerpta Medica Inc. 0002-9343/03/$–see front matterAll rights reserved. doi:10.1016/S0002-9343(03)00326-7

METHODS

Literature SearchWe identified studies through March 2002 usingMEDLINE (which includes articles since 1966) as wellas the Cochrane Database of Systematic Reviews and theCochrane Controlled Trials Register (15). We then exam-ined reference lists from retrieved articles and referenceliterature, queried experts in the field, and reviewed thetables of contents (October 2001 through March 2002)from journals cited most frequently in the literaturesearches.

Abstract ReviewTwo researchers independently reviewed abstracts to ex-clude those that were not relevant to the research ques-tions, reported on prevention but not treatment of ve-nous thromboembolism, were not written in English, didnot include human data, or were published only as anabstract. Articles that did not include a comparison groupfor the evaluation of outpatient versus inpatient therapywere also excluded. We included analyses that modeledthe costs associated with use of the two heparins, as well ascost-effectiveness (i.e., reported results as costs associatedwith some unit of benefit) and cost-minimization (i.e.,reported overall benefits in monetary terms) studies.

Data AbstractionWe developed and pilot tested article review forms, whichincluded a quality assessment and a content abstractionform. The quality assessment forms for the treatmentstudies included items in the following categories: de-scription and representativeness of the study sample,likelihood of bias and confounding, adequacy of descrip-tion of therapy, completeness of outcomes reporting, andquality of the statistical analyses. These items were de-rived from study quality forms used in previous projects(16,17) and are available for review (15). Each item wasscored as 0 (criteria not met), 1 (criteria partially met), or2 (criteria fully met). The score for each category was thepercentage of the total points available in each category(0% to 100%). The overall quality score was the averageof the five categorical scores.

We created a separate quality assessment form for thecost-effectiveness studies using information suggested bythe Evidence-Based Medicine Working Group (18). Thiscomprised nine items (scored from 0 to 2) particular tomodeled analyses, including the perspective taken, sourceof parameter estimates, use of sensitivity analyses, andappropriate reporting of results (19). The overall qualityscore was the average of the scores from these nine items.

The content abstraction form included items describ-ing the type of study; geographical location; definition ofstudy groups; specific aims; inclusion and exclusion cri-teria; demographic, social, and clinical characteristics of

subjects; sources of data for the decision analyses; andoutcomes or results relevant to each question.

Article Review ProcessTwo investigators reviewed each article and came to con-sensus by discussion. They were not blinded to author orjournal names because previous work has shown thatblinding is unlikely to affect the results of the data ab-straction (20).

We developed a database for the quality assessmentand content abstraction data. The evidence tables werebuilt using Microsoft Access 2000 (Microsoft Corpora-tion, Redmond, Washington), with a data-entry frontend developed with Delphi (Borland Delphi, Scotts Val-ley, California).

Summary of EvidenceAbstracted information was put into evidence tables. Thequalitative heterogeneity among the outpatient versus in-patient studies (including differences in enrolled popula-tion, study design, duration of therapy) precluded aquantitative pooling of the results. No standard method-ology exists for pooling the results of decision analyses,and the qualitative heterogeneity in these studies alsomade pooling the results unsuitable. For trials that re-ported monetary outcomes, we converted all costs to2001 U.S. dollars by using year-specific conversion ratesand inflating the estimates to 2001 dollars.

Evidence GradesFive investigators independently graded the strength ofthe evidence on the two questions addressed in this re-view. If there was disagreement, the final grade was basedon the majority decision. The grading system was as fol-lows (16,21): A (strong)—appropriate data are available,including one well-designed randomized controlled trial;study sample is sufficiently large; adequate controls; dataare consistent across studies; one intervention is clearlysuperior, equivalent, or inferior to another strategy; B(moderate)—appropriate data are available; study sam-ple is sufficiently large; adequate controls; data are rea-sonably consistent across studies; one intervention islikely to be superior, equivalent, or inferior to another,but not enough evidence to conclude definitively; C(weak)—some data are available; study sample is reason-ably large; data indicate a trend supporting benefit (orequivalence) of one intervention compared with another,but not enough evidence to conclude that intervention islikely to be superior, equivalent, or inferior to another;and I (insufficient)—appropriate data are not availableor insufficient number of patients studied.

RESULTS

Our search identified 1786 potential citations. Weexcluded citations of articles that did not address the

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Table 1. Description of Studies Comparing Outpatient and Inpatient Treatment of Venous Thromboembolism

First Author(Reference), Study

Design Study Aims Exclusion Criteria Intervention

Demographic/Clinical Characteristics

MeanAge

(years)MaleSex

PriorThrombus or

ThrombophiliaRecentSurgery

TemporaryRisk Factor

Percentage

LMWH at home vs. unfractionated heparin in hospitalKoopman (25),

randomizedTo show equivalence in efficacy

and safety and evaluate useof resources in patients withDVT and 6-month follow-up

Pregnancy; likely noncompliance;life expectancy �6 months;treatment with heparin for 24hours; age �18 years; previousthrombus, thrombophilia,malignancy

Nadroparin in/outpatient, 250IU/kg twice daily, 6 days

59 53 20 49 69

Unfractionated heparin, 5000U then 1250 U/h, 6 days

62 48 19 52 68

Levine (26),randomized

Comparison in patients as DVTtreatment with 3-monthfollow-up

Likely noncompliance, hereditarybleeding, contraindication toanticoagulation, venousthromboembolism inpreceding 6 months, calf veinthrombus only

Enoxaparin in/outpatient, 1mg/kg twice daily, 5 days

57 62 21 29 100

Unfractionated heparin, 5000U then 1280 U/h, 5 days

59 58 14 28 100

Belcaro (22),randomized

Comparison including oralanticoagulant for proximalDVT with 3-month follow-up

Pregnancy, likely noncompliance,hereditary bleeding,thrombocytopenia

Nadroparin in/outpatient, 100IU/kg twice daily, 14 days

54 55 7 20 100

Unfractionated heparin, 5000U then 1300 U/h, unknownduration

53 59 7 22 100

Unfractionated heparin,12,500 IU twice dailysubcutaneously, 90 days

54 53 9 22 100

Pearson (27),retrospective

To examine short-termoutcomes in patients withDVT treated in an outpatientprogram compared withbefore programimplementation

No pulmonary embolism Enoxaparin in/outpatient, 1mg/kg twice daily, 5 days

57 42 NR NR NR

Unfractionated heparin, doseand duration unknown

56 43 NR NR NR

Grau (23),retrospective

To compare incidence ofrecurrent venousthromboembolism inpatients with DVT

Pregnancy, oral contraceptives,hormone replacement therapy,recent fracture or cast,thrombophilia

Nadroparin outpatient, 175U/kg twice daily, 5 days

68 58 2.3 30 81

Unfractionated heparin, doseunknown, 5 days

59 58 3.4 37 79

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Table 1. Continued

First Author(Reference), Study

Design Study Aims Exclusion Criteria Intervention

Demographic/Clinical Characteristics

MeanAge

(years)MaleSex

PriorThrombus or

ThrombophiliaRecentSurgery

TemporaryRisk Factor

Percentage

Vinson (29),prospective

To evaluate effectiveness andsafety of outpatient carepathway with LMWH forDVT with 2-week follow-up

Pregnancy, allergy, likelynoncompliance, hereditarybleeding, contraindication toanticoagulation, stroke,anemia, calf vein thrombusonly, upper extremity DVT

Enoxaparin outpatient, 1 mg/kg twice daily, 7 days

63 46 14 25 100

Unfractionated heparin, doseand duration unknown

63 46 20 32 100

Huse (24),retrospective

To quantify economic benefitsof treatment with LMWHwith early discharge usingdata from managed healthcare plans

Likely noncompliance,thrombophilia, surgery,previous venousthromboembolism, positivefamily history

Enoxaparin in/outpatient,duration unknown

48 46 NR NR NR

Unfractionated heparin, doseand duration unknown

54 44 NR NR NR

Smith (28),retrospective

To evaluate costs andsatisfaction

Pregnancy, life expectancy �2years, allergy, likelynoncompliance, hereditarybleeding, contraindication toanticoagulation, malignancy,recent fracture or cast,previous venousthromboembolism

Enoxaparin outpatient, 1 mg/kg twice daily, 5 days

57 61 0 NR NR

Unfractionated heparin, doseunknown, 5 days

57 61 0 NR NR

LWMH at home vs. in hospitalBoccalon (30),

randomizedTo compare efficacy and cost in

inpatients and outpatientswith DVT with 6-monthfollow-up

Pregnancy, likely noncompliance,contraindication toanticoagulation, previousvenous thromboembolism, calfvein thrombus only

Dalteparin, enoxaparin, ornadroparin outpatient, doseand duration unknown

65 54 NR NR NR

Dalteparin, enoxaparin, ornadroparin inpatient, doseand duration unknown

63 59 NR NR NR

Kovacs (31),prospective

To evaluate use of LMWH inoutpatients with pulmonaryembolism with 3-monthfollow-up

Likely noncompliance, unstable(oxygen requirements,hemodynamic instability, pain)

Dalteparin outpatient, 200U/kg/d, 5 days

NR 56 12 NR NR

Dalteparin in/outpatient, 200U/kg/d, 5 days

NR 59 7 NR NR

DVT � deep venous thrombosis; LMWH � low molecular weight heparin; NR � not reported.

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study questions (n � 1122 studies), contained nooriginal data or analyses (n � 354), were not in English(n � 99), had no human data (n � 18), were limited toprevention of venous thromboembolism (n � 126),were case reports (n � 29), or presented data reportedin other publications (n � 2), as well as excluded ab-stracts that had no accompanying published article(n � 3). Another 14 articles were excluded during thearticle review process for not containing original data,lacking a comparison group, involving only outpatients,or lacking relevance. Thus, 19 studies remained eligiblefor review.

Clinical Outcomes of Outpatient and InpatientTherapyDescription of studies. Eight studies compared the clin-ical outcomes of patients with deep venous thrombosiswho were treated with either low molecular weight hep-arin at home or unfractionated heparin in the hospital(Table 1) (22–29). Three were randomized trials(22,25,26) and five were cohort studies. Two other stud-ies (30,31) compared the clinical outcomes of and costsfor patients who received low molecular weight heparinat home or in the hospital (Table 1).

The smallest of these 10 studies enrolled 28 patients ineach arm (28), whereas the largest comprised 1850 pa-tients (164 of whom had received low molecular weightheparin and the remainder had received unfractionatedheparin) (24). All of the studies used enoxaparin, na-droparin, or dalteparin, administered subcutaneously,during the intervention, and an oral anticoagulant duringthe follow-up (Table 1). Enoxaparin was always given at adosage of 1 mg/kg two times daily; the dosages of theother low molecular weight heparins varied. Unfraction-

ated heparin was always given intravenously in the hos-pital, except for one trial in which a group of patientstreated at home received unfractionated heparin subcu-taneously (22). Six studies allowed a brief inpatient ad-mission before completion of therapy at home for thepatients who had been randomly assigned to the outpa-tient therapy group (22,24 –27,31).

All but one study (31) excluded patients with pul-monary embolism. This study, however, excluded pa-tients who required oxygen, had severe pain, or werehemodynamically unstable, leaving only patients withgood cardiopulmonary reserve or small clot burden. Theexclusion criteria in the other studies were moderatelyrestrictive; most excluded patients with known throm-bophilic conditions, including prior venous thrombo-embolism. More than half of the studies excluded pa-tients who were considered likely to be noncompliantwith outpatient therapy. Only three studies used sched-uled radiological surveillance to detect recurrences(22,26,30).

Quality of studies. The studies had strong descriptionsof the patient samples but weaker descriptions of the in-terventions, particularly interventions involving unfrac-tionated heparin (Table 2). There was also little informa-tion on the adequacy of anticoagulation during the acuteintervention or follow-up period.

Results of studies. There were minimal differences in therate of recurrent deep venous thrombosis (0% to 9%) bytreatment group (Table 3). Pulmonary embolism wasrare. Similarly, the incidence of major bleeding was low(0% to 2%). Mortality during follow-up ranged from 0%to 11%, again with no difference between groups. Thestudy that exclusively enrolled patients with pulmonary

Table 2. Quality of Studies Comparing Outpatient and Inpatient Treatment of Venous Thromboembolism

First Author(Reference)

OverallQuality*

Representativenessof Study

Population

Minimizationof Bias and

Confounding

Descriptionof

Treatment

Reporting onOutcomes and

Follow-up

StatisticalQuality and

Interpretation

Percentage

LMWH at home vs. unfractionated heparin in hospitalKoopman (25) 79 88 88 50 85 83Levine (26) 78 100 81 50 75 83Belcaro (22) 67 100 75 50 60 50Pearson (27) 38 88 31 25 10 38Grau (23) 47 88 31 25 30 63Vinson (29) 57 100 38 50 30 67Huse (24) 41 50 13 0 65 75Smith (28) 41 75 31 25 10 63

LMWH at home vs. in hospitalBoccalon (30) 64 63 63 75 80 38Kovacs (31) 54 75 44 50 70 33

* Average of the five categorical scores.LMWH � low molecular weight heparin.

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Table 3. Results of Studies Comparing Outpatient and Inpatient Treatment of Venous Thromboembolism

First Author(Reference) Groups

Number ofPatients

Follow-up(months)

Outcomes

Costs PerPatient*

Costs Included inTabulations

Deep VenousThrombosis

PulmonaryEmbolism

MajorBleeding

MinorBleeding Deaths

InpatientDays

Number (%)

Koopman (25) Outpatient 202 NR 10 (5) 4 (2) 1 (0.5) 27 (13) 14 (7) 2.7Inpatient 190 NR 12 (6) 5 (3) 4 (2) 15 (8) 16 (8) 8.1

Levine (26) Outpatient 247 3 11 (4) 2 (1) 5 (2) 6 (2) 11 (4) 1.1Inpatient 253 3 15 (6) 2 (1) 3 (1) 6 (2) 17 (7) 6.5

Belcaro (22) Outpatient 98 NR 6 (6) 0 0 3 (3) 5.1 $ 889 Hospital treatmentand monitoring

Inpatient 97 NR 6 (6) 0 0 4 (4) 5.4 $3174Outpatient

(unfractionated)99 NR 7 (7) 0 0 1 (1) 0 $ 253

Pearson (27) Outpatient 40 0.5 1 (2.5) 0 0 0 $4053 Hospital, drug, homecare, and clinicvisit

Inpatient 67 NR $5956

Grau (23) Outpatient 130 21.6 5 (4) 1 (1) 3 (2) 1 (1) 11 (8)Inpatient 149 35 13 (9) 9 (6) 1 (1) 4 (3) 17 (11)

Vinson (29) Outpatient 178 0.5 0 1 (1) 0 2 (1) 0 0.03Inpatient 96 0.5 0 1 (1) 1 (1) 1 (1) 0 4

Huse (24) Outpatient 164 12 11 (7) 1 (1) 4.2 $1886 Outpatient onlyInpatient 1696 12 153 (9) 14 (1) 6.8 $ 986

Smith (28) Outpatient 28 NR $ 653 Ultrasound, clinicvisit, drugs,monitoring, staff,discharge planning

Inpatient 28 NR $1462

Boccalon (30) Outpatient 99 NR 1 (1) 2 (2) 17 (17) 0 1 $1995 Ultrasound, doctors,nurse visits,monitoring,

Inpatient 102 NR 2 (2) 2 (2) 11 (11) 2 (2) 9.6 $4524

Kovacs (31) Outpatient 81 NR 0 5 (6) 1 (1) 3 (4) 4 (5)Inpatient 27 NR 1 (4)

* All costs converted to 2001 U.S. dollars.NR � not reported.

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Table 4. Methods of the Cost Analyses Comparing Low Molecular Weight Heparin with Unfractionated Heparin for Treatment of Venous Thromboembolism

First Author(Reference) Study Design Comparisons

Sources of CostEstimates/Sources ofEvent Rate Estimates

IncrementalCost-effectiveness Cost Savings* Sensitivity Analysis Comments

Hull (34) Cost-effectivenessanalysis, third-party payerperspective, 3-month horizon

Inpatient tinzaparin(175 IU/kg/d)

Inpatient unfractionatedheparin

Direct medical costs inpatients enrolled (1992Canadian and U.S.dollars)/observed intrial

Tinzaparindominates

$501 per person withtinzaparin vs.inpatientunfractionatedheparin (11%savings)

Robust to all one-wayanalyses; not costsaving whentinzaparin is 5.8 timesbase cost

If 37% are treated asoutpatients, costsavings of $1141 perperson

Rodger (37) Cost-effectivenessanalysis, third-party payerperspective, 3-month horizon

Outpatient LMWH ifeligible, inpatientLMWH if not

Outpatient LMWH ifeligible, inpatientunfractionatedheparin if not

Inpatient LMWH

Case-costing usingonline resource-utilization-basedpatient-specific costaccounting system(1995 Canadiandollars)/systematicliterature review

LMWH dominateswhether used inoutpatients orinpatients

$641 per person withLMWH outpatient/inpatient relativeto unfractionatedheparin (23%savings)

Using “worst-case”estimates, cost-effectiveness ofinpatient LMWHrelative to inpatientunfractionatedheparin is $21,459 perlife saved at 3 months

If equivalent efficacyand safety in allarms assumed,LMWH is cheaperto deliver in anysetting anddominates

Inpatient unfractionatedheparin

Gould (3) Cost-effectivenessanalysis, societalperspective, untildeath or age 99years

Inpatient enoxaparin (1mg/kg twice daily)

Inpatient unfractionatedheparin (includessecondary analyses ofoutpatientenoxaparin)

Medicare reimbursementrates, prescriptioncosts, wholesale prices(1997 U.S. dollars withdiscounting)/literatureand U.S. life tables

$7532 per life-year or$8524 per quality-adjusted life-yearwith enoxaparin vs.unfractionatedheparin

None in base case Cost saving when 8%of enoxaparin-treatedpatients areoutpatients, or when13% have earlydischarge; sensitive tofrequency of latecomplications, robustto other variables

Robustlycost-effective;becomes cost savingif LMWH-treatedpatients areoutpatients

Estrada (33) Cost-effectivenessanalysis, third-party payerperspective, 3-month horizon

Outpatient LMWH ifeligible, inpatientLMWH if not

Outpatient LMWH ifeligible, inpatientunfractionatedheparin if not

Inpatient unfractionatedheparin

Direct costs fromliterature review,institutionalaccounting, and coststo Medicare (1996 U.S.dollars)/literature

$10,752 perrecurrence averted;$89,600 per deathaverted withoutpatient/inpatientLMWH relative tooutpatient LMWH/inpatientunfractionatedheparin

$347 per person forLMWHoutpatient/inpatientrelative toinpatientunfractionatedheparin (10%savings)

Sensitive to the % ofpatients eligible foroutpatient treatment,if fewer than 14%,unfractionatedheparin is lowest cost;model sensitive tocosts ofunfractionatedheparin

Lower costs primarilydue to savings inhospitalization costs

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Table 4. Continued

First Author(Reference) Study Design Comparisons

Sources of CostEstimates/Sources ofEvent Rate Estimates

IncrementalCost-effectiveness Cost Savings* Sensitivity Analysis Comments

Lloyd (35) Cost-minimizationanalysis, third-party payerperspective, 5-dayhorizon

Inpatient nadroparin(weight based twicedaily)

Inpatient unfractionatedheparin (two routes)

Direct costs measured ashospital charges topayer (Swiss sicknessfund), list prices ofdrugs/rates assumedequivalent in all arms

NA $171 per personwith nadroparinrelative to inpatientunfractionatedheparin (57%savings)

Robust to all one-wayanalyses; cost savingsless if nadroparin-treated patients arerequired to havepartial thrombo-plastin time measured

van den Belt(13)

Cost-minimizationanalysis, third-party payerperspective, 6-month horizon

Outpatient fraxiparine(weight adjusted)

Inpatient unfractionatedheparin

Direct medical costsmeasured at one site ofa multicenter clinicaltrial (1993 Dutchguilders)/ratesobserved in trial sitesand considered equalin both groups

NA $3933 per person withfraxiparine relativeto inpatientunfractionatedheparin (64%savings)

Fraxiparine is costsaving even if 50% ofpatients require homecare visits; cost savingeven if 50% requireinpatient care

O’Brien(36)

Cost-minimizationanalysis, societalperspective, 3-month horizon

Outpatient enoxaparin(1 mg/kg twice daily)

Inpatient unfractionatedheparin

Canadian national datasystems, local labor,and treatment costs(1997 Canadiandollars)/observed intrial and measuredhealth-related qualityof life

NA $2422 per person withenoxaparin relativeto inpatientunfractionatedheparin (57%savings)

Robust to all one-wayanalyses

Higher socialfunctioning withenoxaparin,otherwise nodifference in health-related quality of lifemeasures or events

de Lissovoy(32)

Cost-minimizationanalysis, third-party payerperspective, 3-month horizon

Inpatient enoxaparin(1.5 mg/kg/d or 1.0mg/kg twice daily)

Inpatient unfractionatedheparin

Direct medical costsfrom 33 U.S. sitesparticipating in amulticenter trial (1997U.S. dollars)/observedin the 33 U.S. trial sites

NA None Robust to all one-wayanalyses

Blood testing and costsof medication offsetby fewerreadmissions withenoxaparin

Tillman(38)

Decision analysis,third-party payerperspective, 3-month horizon

Outpatient enoxaparin(1 mg/kg twice daily)

Inpatient unfractionatedheparin

Direct medical costsmeasured inoutpatients in HMO;source of inpatientcosts unclear (1998U.S. dollars)/measuredin outpatients

NA $3025 per person withenoxaparin relativeto inpatientunfractionatedheparin (60%savings)

Enoxaparin not costsaving if drug costincreases by 750% orhospitalization costsdecline by 77%

Rates of events in theunfractionatedheparin arm notexplicitly stated

* All costs in 2001 U.S. dollars.HMO � health maintenance organization; LMWH � low molecular weight heparin; NA � not available.

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embolism also reported no significant difference in eventrates (31).

There were fewer inpatient days in the treatment armsthat used low molecular weight heparin either entirely athome or after a brief inpatient stay than in the arms thatused unfractionated heparin in the hospital. Few studiesreported the statistical significance of these differences.The duration of hospitalization depended strongly on thestudy design.

Four (22,27,28,30) of the five cost studies suggestedcost savings with outpatient therapy. The study (24) thatreported higher costs with low molecular weight heparin,however, included only outpatient costs in the estimates.The authors did state that if 2.5 hospital days were elim-inated per patient treated as an outpatient, a savings of$1911 per patient might be seen. Only two studies (27,30)reported a statistically significant difference in costs be-tween the study arms, although cost differences also ap-peared to be substantial in other studies. As each studyincluded different items in the tabulations of costs, thecost savings between studies cannot be compared easily.

Based on these studies (Evidence grade B), we con-cluded that outpatient treatment of deep venous throm-bosis with low molecular weight heparin is likely to beefficacious, safe, and economically favorable.

Analyses of Costs and Cost-effectivenessDescription of studies. Nine studies used decision anal-ysis to address the costs of treatment with low molecularweight heparin or unfractionated heparin, regardless ofinpatient or outpatient setting (Table 4). Four were cost-effectiveness analyses (3,33,34,37), four were cost-mini-mization studies (13,32,35,36), and one used a decisionmodel that could not be classified as either (38). A societalperspective was used in quantifying costs in two studies(3,36), whereas the other seven took the perspective of athird-party payer.

The comparisons fell into two categories: the use of lowmolecular weight heparin compared with unfractionatedheparin, with all drugs administered in the hospital(3,32,34,35); and the use of low molecular weight heparinat home compared with unfractionated heparin in thehospital (13,33,36 –38). Two of these latter studies(33,37) modeled the use of low molecular weight heparinin patients at home if they were considered medically el-igible to be treated as outpatients, and in the hospital ifthey were not. The estimates for the costs in the modelsvaried; half used actual costs measured in the setting of aclinical trial and others used costs obtained from data-bases maintained by the government or a payer, or costsabstracted from literature review. Similarly, the rates ofevents included in the models came from actual data ob-served in trials or from the literature. Two studies (13,35)assumed on the basis of earlier work that the rates ofrecurrent thrombosis and adverse events were similar for

low molecular weight heparin and unfractionatedheparin.

Quality of studies. The quality scores for studies oncost-effectiveness or cost minimization were high (67%to 100%; median, 89%), with the studies by Hull et al (34)and Gould et al (3) ranking the highest. Studies wereweakest in their descriptions of the sensitivity analysesand of the samples to which the results were expected toapply.

Results of studies. Of the four studies that compared lowmolecular weight heparin with unfractionated heparin ininpatients, two were cost-minimization studies (32,35).One projected a cost savings of 57% with nadroparin in-stead of with unfractionated heparin (35) (Table 4),whereas the other found no difference in costs betweentreatment with enoxaparin and unfractionated heparin(32). The authors concluded that because these costs wereaccrued in the setting of a clinical trial, some of the labo-ratory tests were protocol driven, thus raising the costsabove what would be seen in usual practice, particularlyin the enoxaparin arm (32). One (34) of the two cost-effectiveness studies comparing inpatient treatment ofthe two heparins found that tinzaparin was both lesscostly and more efficacious than unfractionated heparin.This study predicted a cost savings of 11% with the use oftinzaparin in the hospital in place of unfractionated hep-arin. Gould et al (3) found that although inpatient enox-aparin treatment was more expensive, it was more cost-effective than inpatient unfractionated heparin becauseof the increase in quality-adjusted life-years. Further-more, if 8% of the patients taking enoxaparin weretreated as outpatients, treatment with low molecularweight heparin would be both cost-effective and costsaving.

Outpatient treatment with low molecular weight hep-arin was less costly than hospitalization for treatmentwith unfractionated heparin (Table 4). One cost-effec-tiveness study (33) found that use of low molecularweight heparin, at home for clinically stable patients andin the hospital for unstable patients, yielded a cost savingsof 10% as compared with use of unfractionated heparinin the hospital for all patients, largely due to savings oninpatient costs. Another study (37) found a cost savingsof 23% in a similar comparison. The two cost-minimiza-tion studies found outpatient low molecular weight hep-arin to be associated with a cost savings of 57% (36) and64% (13) as compared with inpatient unfractionatedheparin. The study by Tillman et al (38) provided littledata on event rates in the unfractionated heparin arm;however, the authors reported a cost savings of 60% withenoxaparin at home as compared with unfractionatedheparin in the hospital, and suggested that this treatmentwould be cost saving even if hospitalization costs were77% lower.

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The cost-effectiveness studies were consistent in sug-gesting that low molecular weight heparin is either costsaving or cost-effective as compared with unfractionatedheparin (Evidence grade A).

DISCUSSION

The randomized trials that compared treatment with lowmolecular weight heparin in outpatients (or in patientswith early discharge) with unfractionated heparin in in-patients demonstrated no difference in adverse outcomesbetween groups (including recurrent deep venousthrombosis, pulmonary embolism, major bleeding, ordeath), but showed that use of low molecular weight hep-arin reduced the duration of hospitalization and associ-ated costs substantially. Similarly, comparisons of use oflow molecular weight heparin in the hospital or at homerevealed no difference in outcomes but demonstrated amajor savings in hospitalization costs.

No study was adequately powered to detect small dif-ferences in the rates of adverse events between groups.Thus, although a difference in outcomes between groupswas not demonstrated, equivalency cannot be definitivelyclaimed. Nonetheless, the direction of the results wasconsistent and suggested that it is very unlikely that at-home use of low molecular weight heparin will be less safethan unfractionated heparin in appropriately selected pa-tients.

Cost studies were consistent in showing that low mo-lecular weight heparin was either cost saving or cost-ef-fective as compared with unfractionated heparin, regard-less of whether it was administered in the hospital or athome, although the cost savings would be greater if hos-pitalization were avoided. A retrospective analysis pub-lished after completion of our literature search reportedcost savings with enoxaparin that was similar to thoseseen in the trials we reviewed (39).

This review has several limitations. Most of the studieswere small with infrequent adverse events and thus wereunderpowered to look at the designated outcomes. Coststudies often did not include all relevant costs (e.g., timelost from work, cost of outpatient visits). The trials hadstrict criteria for patients considered for outpatient ther-apy; consequently, the results may not apply to all pa-tients seen in usual clinical practice. In particular, moststudies excluded patients who were thought to be un-likely to comply with therapy. Furthermore, some pa-tients in the outpatient groups were initially treated in thehospital before early discharge, raising the possibility thatinitial inpatient treatment contributed to the safety dem-onstrated in these studies. Additionally, the use of onlyEnglish-language literature, the possible exclusion ofsome primary literature by our search strategy, and the

use of quality assessment instruments that have not beenvalidated in other settings may have affected results.

In conclusion, the evidence suggests that outpatienttreatment of deep venous thrombosis with low molecularweight heparin is likely to be efficacious, safe, and costbeneficial. Still, additional studies are needed to evaluatethe use of outpatient treatment among a less restrictedgroup of patients or in patients at high risk of adverseevents, such as those with pulmonary embolism, malig-nancies, or hereditary thrombophilias. High-qualityequivalency studies are needed to confirm that the use oflow molecular weight heparin in outpatients is as effica-cious and safe as unfractionated heparin in the hospital inless select patients. Studies are also needed to evaluate theshort-term and long-term efficacy of low molecularweight heparin as outpatient therapy for symptomaticcalf vein thrombosis.

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