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rd j . Friedman, M D , Guest Editor

Early discharge from the hospital after total joint arthro-

plasty has increased the need for extended outpatient

thrombop rophylaxis. Mu ltiple controlled clinical trials and

several meta-analyses of these data have examined vari-

ous agents in different regimens. These data indicate that

extended prophylaxis with a low-molecular-weight

heparin after knee or h ip arthroplasty sign ificantly reduces

the number of venous thromboembolic episodes with no

increases in major bleeding. The data also show that

> 9 8 % of patients given long-term low-molecular-weight

heparin prophylaxis remain free from symptomatic deep

venous thrombosis and pulmonary embolism. Therefore,

to minim ize patient risk safely and cost-effectively, extend-

ed prophylaxis with low-molecular-weight heparin once-

daily for 4 weeks after surgery should be considered for

patients undergoing total joint arthroplasty.

of patients who have undergone

of patients who have had total

sis.' U p to 30% of

ficant morbidity; the postoperative

or a low-tnolecular-weight heparin,

was typically administered through the

5- to 14-day period of hospitalization.

However, lengths of stay are decreasing

dramatically at most institutions.

Patients who have undergone TKR are

now released from the hospital after

3-4 days, and patients who have had

THR are discharged 4-5 days after

surgery. As hospital stays decrease, so

too does the opportunity for appropriate

prophylaxis.

This reduction in hospitalization

invokes a significant risk for throm-

boembolism in the outpatient environ-

ment. Results of prospective clinical

trials using objective venography indi-

cate a 19%-39% incidence of deep

venous thrombosis 3 weeks after THR

in patients who have received conven-

tional inpatient prophylaxis after

surgery.-^"* Venous thromboembolism isthe most common cause of emergency

continues throughout the postoperative

period. In a survey of approximately

8000 patients who had received

thromboprophylaxis during THR,

the mortality rate from pulmonary

emboHsm was 1.04%. More than 50%

of these patients died during the second

postoperative week, almost 75% during

the third week, 8% during the fourth

week, and 5% five weeks after surgery.^

A strategy of extended prophylaxis

(ie, prophylactic therapy administered

daily for several weeks after dis-

charge) has evolved in response to the

changing institutional environment.

Increasing awareness of other throm-

botic risks has also stimulated interest

in extended outpatient prophylaxis.

These risks include the possibility

of persistent activation of coagulation

in certain patients,^ the presence of

deep venous thrombosis of uncertainclinical significance at discharge, and

the risk of postthrombotic syndrome,



ORTHOPEDICS FEBRUARY 2003 V O L 26 NO 2 / S U P P L

Incidence (

4 0 - 1 • Placeoo

• Enoiapann

Atl DVT Pro i ima l DV T

Incidence (%)

2 0 - , P=01B

1 5 -

1 0 -

5 -

0 -

All

••LJDVT

2n Paceoo

• Enoxapatin

PromnalDvr

Figure 1: Incidence of thromboembolic events detected on venography in 233 evaluable patients receiving extended prophyla

enoxaparin versus placebo. (Data from Bergqvist et al.") Figure 2: Incidence of thromboembol ic events detected on venography

evaluable patients receiving extended prophylaxis w ith enoxaparin versus placebo followin g hiparthroplasty. (Data from Planes et al.^

3: Incidence of thromboembolic events detected onvenography: enoxaparin versus placebo following hip or knee arthroplasty. (Da

Comp et al ." ) A bbreviations: DVT^deep venous thrombosis and PE=pulmonary embolism.

First Autho r, Year

Bergqvist, 1996

Planes, 1996Dahl, 1997Lassen, 1998Manganell i , 1998

Haentjens, 2000Heit, 2000

Hull, 2000Comp, 2001

TABLE 1

Overview of Nine Trials Included in a

Procedure

THRTHRTHRTHRTHRTHRTHR or TKR

THRTHR or TKR

Agent

Enoxaparin

EnoxaparinDalteparinDalteparinUFHNadroparinArdeparin

DalteparinEnoxaparin

Abbreviations: THR=totaI hip replacement TKR = total knee reptacmenentAdapted from Eilcelboom JW, et alJ- Copyright 2001. with permission fron

Meta-Analysis of Thromboprophylaxis

In-hospital

N

288

21030 830 080346

1320

99196 8

Duration (d'

10-11

13-157U )71516-174-10

6(2)7-10

and VFH-unfractionated heparin.Elsevier Science.

Out-of-hospital

N

26 2

17926528 179296

1195

56 9873

Duration

30(2)

35(2)35(2)353037-382

35(2)27-29

can compromise functional improve-

This review will examine efficacy

and safety data from multiple controlled

clinical trials, explore pharmaco-

economic analyses of extended throm-

boprophylaxis, and apply these findings

to clinical recommendations. Because

enoxaparin is the only low-molecular-

weight heparin that is approved for

extended prophylaxis after THR. we

emphasize data emerging from an array

of controlled clinical trials that focus on

this indication.

CLINICAL TRIALS WITHENOXAPARIN

Three prospective, randomized,double-blind, placebo-controlled stud-

have evaluated the efficacy and safety

of extended prophylaxis with enoxa-

parin in preventing deep venous throm-

bosis."*••*" The three trials featured sim-

ilar study designs, although specific

dosage andduration varied slightly.

Bergqvist et al"^ treated 262 patients

undergoing THR with enoxaparin

(40 mg per day subcutaneously) for

10-11 days (range, 6-12 days) of hospi-

talization. Upon discharge, 131 patients

received 40 mgof enoxaparin subcuta-

neously once a day and 131 patients

received daily subcutaneous injections

of placebo. The protocol dictated that

on day 21 (range, day 19-23) postdis-

charge, prophylaxis would be stopped

and patients would undergo bilateralvenography to screen for deep venous

thrombosis. Patients treated with

is remained >98% free of symp

deep venous thrombosis."^ Th

(P<.CK)1) of deep venous thro

and proximal deep venous thro

in patients whoreceived proph

enoxaparin were significantly

than the rates in patients who re

placebo (Figure 1)."^

Other investigators reported

fmdings.^ One hundred seven

patients undergoing THR r

40 mg of enoxaparin subcutan

once-daily for 13-15 days of h

ization. After bilateral venograp

performed todetect patients wit

venous thrombosis, patients w

charged and randomly assigned t

extended prophylaxis with enoor placebo. Injections continue

until the next venographic evalu



DMAN EXTENDED THROMBOPROPHYLAXIS

in patients given placebo

The rate of proximal deep

was comparable intwo groups.•*

who underwent THR or

All patients received 30 mg of

urs for the 7-10 days of hospital-

873 patients

to receive daily sub-

of either enoxa-

(40 mg) or placebo until the

ay 21 ±2 days. The results of thisa significantly lower

in the THR patients treated

(8%) than in patients

to a relative risk reduction of

(Figure 3 )." Also, rates of prox-

in the enoxaparin group

e 3 )."

of patients in

c events, whereas > 96 % of patients

did not require rebospitalization

of enoxaparin in

in

in comparison with

Tbe

of hemorrhagic orother drug-

was similar

in the

the prevalence of deep venous

in patients undergoing

META-ANALYSESet al'- analyzed data

com-

TABLE 2

Incidence of Out-of-Hospital Asymptomatic VenousThromboembolism in a Meta-Analysis of Thromboprophylaxis

OutcomeLMWH or

UFHPlacebo or

Untreated Control OR (95 % Cl)

No.Neededto Treat

Distal DVTProximal DVTAny DVT

6.8% (71/1047)2.9% (30/1047)9.6% (101/1047)

10.4% (89/854)

9.1% (78/854)

19.6% (167/854)

0.69 (0.49-0.96) 28

0.33 (0.21-0.51) 16

0.48(0.36-0.63) 10

Abbreviations: Cl=confidence interval. DVT=dL'ep venous thrombosis, LMWH=low-molecutar-weight heparin. OR=odds ratio, andUFH=unfracfionated heparin.Adapted from Eikeiboom JW. et al.'- Copyright 2001. with permission from Elsevier Science.

Study Heparin Control OR [95% Cl]

PlanesBergqvistDahlManganelliLassenHullComp

Total

3/8521/11711/934/333/113

10/29149/315

10/8843/11623/892/28

9/10211/13369/298

101/1047 167/854

0 28 [0 08 . 1.08)

0 37 [0,20, 0 6810 38 [0 18. 0,85)

179 [0,30, 10,61)0.28 [0,07,0.39 [0.16,0.61 [0.41,

1.07)0.95)0.95)

0.48 [0,36, 0.63)

H0,1 1 10

Favors heparin Favors control

Eigure 4: Risk of asymptomatic venous thromboembolism in a meta-analysis of heparinstudies. (Adapted from Eikeiboom jW, et al.'^ Copyright 2001, with permission from Elsevier

Science.)

heparins or unfractionated heparin ver-

sus placebo or untreated control in

approximately 4000 patients undergo-

ing THR or TKR (Table l).3.4.n,i3-!8

The clinical endpoints were sympto-

matic venous thromboembolism

including deep venous thrombosis and

pulmonary embolism, asymptomatic

deep venous thrombosis by venogra-

phy, major or minor bleeding, or any

cause of mortality.

Table 2 demonstrates the signifi-

cant impact of pharmacologic prophy-

laxis with low-molecular-weight

heparins or unfractionated heparin on

the overall rate of venographically

demonstrated deep venous thrombo-

sis. Prophylaxis decreased the rate of

proximal deep venous thromboses by

two-thirds and the rate of distal deepvenous thrombosis by approximately

reduction favored long-term prophy-

laxis with low-molecular-weight

heparin across each study (Figure

4). ' - The rate of risk reduction was

higher in THR than inT KR .' =

The decrease in asymptomatic

venous thromboembolism correlated

with a reduced number of sympto-

matic events. As shown in Table 3,

extended prophylaxis significantly

decreased symptomatic events occur-

ring postdischarge, with >98% of all

patients in the extended prophylaxis

group free from symptomatic deep

venous thrombosis and pulmonary

embolism.' ' Thus, venographic deep

venous thrombosis is a good surrogate

marker for clinical episodes.

All of these benefits were achieved

with no compromise in safety, as mea-

sured by episodes of major bleeding or



ORTHOPEDICS FEBRUARY 2003 V O L 26 N O 2/ S U P P L

TABLE 3

Incidence of Out-of-Hospital Symptomatic VenousThromboembolism in a Meta-Analysis of Thromboprophylaxis

OutcomeLMWH or

UFHPlacebo or

Untreated Control OR (95% Cl)

No.Neededto Treat

DVT 1.1% (22/1964)P E 0.2% (3/1961)Any VTE 1.3% (25/1 964 )

2.7% (47/1 742)0.6% (11/I 744)3.3% (58/1 744)

0.41 (0.24-0 .68) 620.43 (0.17-1 .06) 2500.38 (0.24-0.61 ) 50

Abbreviations: Cl=confidence inten-at. DVT=deep venous thrombosis, LMWH= low-molecular-weight heparin. OR=odds ratio. PE= pulmonary em bolism. UFH=unfractionated heparin. andVTE=venous thromboembolism.Adapted from Eikelboom JW, et al. '^ Copyright 2001, with permission from Elsevier Science.

following knee or hip arthroplasty sig-

nificantly reduces the number of venousthromboembolic episodes with no

excesses in major bleeding. The data

demonstrate that a decrease in the rate

of asymptomatic venographic deep

venous thrombosis translates into a

decrease in the symptomatic deep

venous thrombosis rate. The reduction

in risk is approximately 20 sympto-

matic events per 1000 treated pa tients.'-

A second meta-analysis of six of

these studies supports these findings

and, therefore, it can be concluded

that extended prophylaxis with low-

molecular-weight heparin results in a

50% odds reduction in the risk of

developing venous thromboembolism

after lower limb arthroplasty.'^ In this

analysis, the overall frequency of

cl inical venous thromboembol ism

was 1.6% after extended prophylaxis

versus 3.3% in patients receiving

placebo. '^ These findings indicate

that >98% of patients receiving long-term prophylaxis with low-molecular-

weight heparin do not experience

clinical symptoms of deep venous

thrombosis and pulmonary embolism.

At this point, extended prophylaxis

appears to be more effective in THR

than in TKR. However, further studies

in knee surgery are required.

COST-EFFICACYThe extent to which low-molecular-

weight beparins such as enoxaparin can

achieve widespread clinical acceptance

or safety. With managed care resting on

a foundation of cost-efficiency, anyagent used for extended thrombopro-

phylaxis must not place significant bur-

dens on the cost of care.

Enoxaparin has been comprehen-

sively studied from a pharmacoeco-

nomic as well as clinical perspective,

and these studies are reviewed in detail

elsewhere.-^" A French decision analysis

model of data from enoxaparin clinical

trials in extended thrombopropbylaxis

has shown that the outpatient adminis-

tration of enoxaparin for 3 weeks to

patients who have had THR is a cost-

effective alternative to perioperative

thromboprophylaxis when weighed

directly against the costs of sympto-

matic thromboembolic events or death

associated with thromboembolic

events.-" A Swedish decision analysis

model found the same results when

enoxaparin was self-administered in the

majority of p atients.'- A decision tree

model that also included lifelong out-comes and indirect costs of care dem on-

strated that 28 days of extended throm-

boprophylaxis with enoxaparin cost

less and increased life expectancy more

than a similar duration of unfractionat-

ed hepadn prophylaxis.^^

Another study was conducted to

compare the cost of extended prophy-

laxis with enoxaparin versus warfarin

in a decision tree analysis of this strat-

egy in patients undergoing THA.^'*Warfarin therapy was classified as min-

imal, moderate, or maximal, depend-

determinations. The cost of prop

is with enoxaparin was then com

with each of these intensities o

farin therapy and found that the

administering enoxaparin ex

that of administering warfarin

approximately 3 weeks. In p

who required maximal monitor

warfarin, enoxaparin could be gi

31 days before its total costs ex

those of warfarin (Table 4)?'* Th

cal factors that enhanced the cost

tiveness of enoxaparin related d

to the expense of monitoring p

receiving w arfarin and the cost o

plications and treatment failu

those patients. Therefore, althouacquisition cost of enoxaparin w

ically higher than that of warfar

total cost associated with admi

tion of the low-molecular-w

heparin remained below that o

farin because of the need for o

monitoring.24

RISK STRATIFICATIOThe primary goal of risk stra

tion is to aid the surgeon in de

which patients require extende

phylaxis after hosp ital dischar

checklist can be used to rate

patient based on points assigne

variety of risk factors that occur

24 hours of surgery.-^ The s

allows the surgeon an opportun

rate the need for extended proph

based on the patient's risk factor

POSTTHROMBOTIC

S Y N D R O M EExtended prophylaxis should

be considered to reduce the r

postthrombotic syndrome, whic

be a long-term complication o

joint arthroplasty.

Many surgeons do not rec

that this is a significant clinica

cern among their patients, po

because long-term (> 10 years) c

foUow-up focuses on evaluation

joint for symptomatic or radiogfailure, rather than a broader a

ment for vascular conditions. P



EXTENDED THROMBOPROPHYLAXIS

However, in clinical studies that

RECOMMENDATIONSGiven current knowledge and sur-

ns' desire to safely m inimize patient

Patients undergoing THR may

In TKR, enoxaparin (30 mg subcu-

patients who have preexisting

TABLE 4

Costs of Total Cl inical Pathway of Extended Thromboprophylaxis:Enoxaparin versus Warfarin

Comparison CrossoverDay* Total Costs^

Enoxaparin versus warfarin (minimum follow-up)Enoxaparin versus warfarin (moderate follow-up)Enoxaparin versus warfarin (maximum follow-up)

19 J711 .36 versus $700.9 521 $801.4 9 versus $797 .9031 $1025.49 versus $1010.50

*The day at which one prophylactic regimen cost cur\-e crossed the comparator and. thus, lostits cost-effectiveness a dvantage.fTotal costs in US dollars at crossover day.Adapted with permission from Friedman RJ, et al.-'' Copyright 2000. Lippincott Williams &Wilkins.

Unless otherwise contraindicated, all

patients undergoing hip or knee arthro-

plasty should be advised to take onebaby aspirin daily for prevention of

stroke, myocardial infarction, and other

arterial complications.

CONCLUSIONLower extremity total joint arthro-

plasty is associated with a high risk of

postoperative venous thromboem-

bolism. Traditionally, antithrombotic

prophylaxis has been administered dur-

ing hospitalization, typically for 5-14days. Currently, patients are spending

less time in the hospital after surgery.

Therefore, they must continue throm-

boprophylaxis after hospital discharge.

Data from clinical studies suggest

that there is a protracted risk of throm-

boembolic disease that extends many

weeks following the procedure.

Extended thromboprophylaxis has

been show n in m ultiple c linical trials to

be a safe and effective strategy for

reducing the risk of venous throm-boembolism after joint replacement. Of

the therapeutic options (eg, low-molec-

ular-weight heparins, unfractionated

heparin, or warfarin), only enoxaparin

is approved for use in extended pro-

phylaxis following THR. Data from

controlled trials provide evidence sup-

porting the notion that prolonging

thromboprophylaxis with enoxaparin

significantly reduces the prevalence of

deep venous thrombosis. This conclu-sion is supported by several pharma-

coeconomic analyses that confirm the

prophylaxis when compared with the

total cost of a thromboembolic event or

compared with extended prophylaxiswith agents that require extensive labo-

ratory monitoring, such as warfarin or

unfractionated heparin.

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