8
Adv anced S tudies in Medicine  4 4 5 ABSTRACT  T h ere ar e more t h an 170 000 h os p it al ad m is - sions each year for deep vein thrombosis (DVT) in the United States. Moreover, there are approxi- mately 90 000 readmissions for recurrent venous thromboembolic events, with an average length of hospital stay between 5 days and 7 days. This article reviews the clinical evidence related to inpatient and outpatient treatment options and their efficacies in achieving therapeutic goals for the clinical management of DVT. It also reports the medical evidence relating to eligibility criteria and dosing, as well as the American College of  Chest Physicians recommendations regarding duration of therapy. (  Ad van c e d S tu d ie s in Me d ic in e . 2002;2(12):445-451) D eep vein thrombosis (DVT) is a perva- sive health problem, affecting 2 million people in the United States annually. 1 As many as 60 000 de aths are ca use d by pulmonary embolism (PE) every year. As many as 600 000 pulmonary emboli will occur with approximately 60 000 deaths from these throm- botic events. Secondary complications such as post- phlebitic syndrome and pulmonary hypertension con- tribute significantly to long-term morbidity and mortality in this patient population. While the death toll is tragic, the financial burden is significant; the cost of care for patients with DVT is an estimated $1.5 bil li on a nnua ll y . 2 Clinical evidence documents the prevalence of unde- tected PE in patients with acute DVT. In a study of 622 patients with acute DVT but without PE, Meignan et al 3 reported that radionuclide lung scanning revealed abnor- malities in 82% of the patients; PE was thought to be present in 40% to 50% of the patients. These findings have strong implications for the clinical management of  DVT, with the goals of preventing thrombus extension, thrombus embolization, early and late thrombus recur- rence, and possibly postthrombotic syndrome (although clinical evidence in this last area is inconclusive). Prompt administration of anticoagulant therapy is essential to preventing clot propogation and pul- monary emboli. Clinical evidence suggests that if  patients achieve a therapeutic activated partial thromboplastin time quickly with heparin, the less recurrent disease occurs subsequently. 4 An examina- tion of the current armamentarium for treating DVT may offer insights as to which treatment modalities are most efficacious. Figure 1 illustrates the efficacy of various approach- es to DVT clinical management in accomplishing treatment goals, according to the current medical lit- erature. In the United States, many physicians are placing inferior vena cava filters in patients who have extensive thrombosis in the deep femoral system up to the iliacs, in addition to administering anticoagulation therapies. However, using inferior vena cava filters in such circumstances in advance has not been supported REVIEW ARTICLE LO W -M O LEC U LA R- W EIGHT HEPA RI N IN THE TREA TMENT OF ACU TE D EEP VEI N THRO M BO SIS A N D PU LM O NA RY EM BO LISM * G eno J .M erl i,M D  * B as ed on a pr esent at ion g iven by D r M erli at t he A m erican C ol l eg e of Physi ci ans A nnua l Sess ion.  The L ud w i g A. K ind Pr ofessor of M ed i ci ne, D irector of t he D ivisio n o f I nt er na l M ed i ci ne , Tho m a s J ef f erson U ni ver si t y, Phi l adel phi a, Pennsyl va ni a. A d dr ess co rr espo nd ence to: G eno J . M erl i , M D , D i r ect or , D ivision o f I nt er na l M edi ci ne , J ef f er son M edica l C ol lege, Tho m a s Jef f erson U ni ver si ty,W al nut T ow ers,1 0 2 5 W alnut St , 8 t h Fl oor , Room 8 2 2 , Phil a del phi a , PA 1 9 1 0 7 .

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Advanced S tudies in  Medicine   445

ABSTRACT

 There are more than 170 000 hospital admis-sions each year for deep vein thrombosis (DVT) in

the United States. Moreover, there are approxi-mately 90 000 readmissions for recurrent venousthromboembolic events, with an average lengthof hospital stay between 5 days and 7 days. Thisarticle reviews the clinical evidence related toinpatient and outpatient treatment options andtheir efficacies in achieving therapeutic goals forthe clinical management of DVT. It also reportsthe medical evidence relating to eligibility criteriaand dosing, as well as the American College of Chest Physicians recommendations regardingduration of therapy.( Advanced Studies in Medicine. 2002;2(12):445-451)

Deep vein thrombosis (DVT) is a perva-sive health problem, affecting 2 millionpeople in the United States annually.1

As many as 60 000 deaths are caused bypulmonary embolism (PE) every year.

As many as 600 000 pulmonary emboli will occurwith approximately 60 000 deaths from these throm-

botic events. Secondary complications such as post-phlebitic syndrome and pulmonary hypertension con-tribute significantly to long-term morbidity andmortality in this patient population. While the death

toll is tragic, the financial burden is significant; thecost of care for patients with DVT is an estimated $1.5billion annually.2

Clinical evidence documents the prevalence of unde-tected PE in patients with acute DVT. In a study of 622patients with acute DVT but without PE, Meignan et al3

reported that radionuclide lung scanning revealed abnor-malities in 82% of the patients; PE was thought to bepresent in 40% to 50% of the patients. These findingshave strong implications for the clinical management of DVT, with the goals of preventing thrombus extension,thrombus embolization, early and late thrombus recur-

rence, and possibly postthrombotic syndrome (althoughclinical evidence in this last area is inconclusive).

Prompt administration of anticoagulant therapyis essential to preventing clot propogation and pul-monary emboli. Clinical evidence suggests that if patients achieve a therapeutic activated partialthromboplastin time quickly with heparin, the lessrecurrent disease occurs subsequently.4 An examina-tion of the current armamentarium for treating DVTmay offer insights as to which treatment modalitiesare most efficacious.

Figure 1 illustrates the efficacy of various approach-es to DVT clinical management in accomplishingtreatment goals, according to the current medical lit-erature. In the United States, many physicians areplacing inferior vena cava filters in patients who haveextensive thrombosis in the deep femoral system up tothe iliacs, in addition to administering anticoagulationtherapies. However, using inferior vena cava filters insuch circumstances in advance has not been supported

REVIEW ARTICLE

LO W -M O LEC U LA R-W EIG H T H EPA RIN IN TH E TREA TM EN T O F A C U TE

D EEP VEIN TH RO M BO SIS A N D PU LM O N A RY EM BO LISM*

G eno J. M erli, M D 

*Based on a presentation given by D r M erli at theAm erican C ollege of Physicians A nnual Session.

  The Ludw ig A. Kind Professor of M edicine, D irector ofthe D ivision of Interna l M edicine, Thom as JeffersonU niversity, Philadelphia, Pennsylvania.

Address correspondence to: G eno J. M erli, M D ,Director, D ivision of Internal M edicine, Jefferson M edicalC ollege, Thom as Jefferson U niversity, W alnut Tow ers, 1025W alnut St, 8th Floor, Room 822, Philadelphia, PA 19107.

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446 Vol. 2, No. 12   August 2002

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by the medical literature. In terms of anticoagulationtherapies, both heparin and low-molecular-weightheparin (LMWH) have proven effective in prevent-ing embolization and extension as well as reducingrecurrence. Hypothetically, LMWH and heparin

may also prevent postthrombotic syndrome.LMWH may restore patency, but at this time insuf-ficient clinical evidence exists to confirm these sup-positions. Thrombolysis has proven effective inachieving 4 of the 5 treatment goals, but the extentto which it prevents embolization is questionable atthis point. Following is a review of the clinical evi-dence related to the treatment options and their effi-cacies in achieving therapeutic goals for the clinicalmanagement of DVT. Excluded from the followingtrials were patients with hereditary or acquired coag-ulation disorders, creatinine clearance less than 30

cc/min, pregnancy, or cancer and unspecified con-comitant chemotherapy.

ENOXAPARIN VERSUS UNFRACTIONATED HEPARIN

A report by Simonneau5 et al shows that throm-boembolic disease recurred in 1.5% (N=67) of patients in an enoxaparin treatment arm, as com-pared to 10.4% (N=67) of subjects in the heparingroup. In a study, de Valk et al6 compared the effica-cy and safety of 2 subcutaneous doses of dana-paroid, a long-acting agent, with that of continuous intravenous administration of unfractionated heparin (UFH) in the treatmentof 209 patients believed to have venous throm-boembolism (VTE). Patients were randomlyassigned to either low-dose danaparoid (intra-venous loading dose of 1250 U followed by1250 U administered subcutaneously twicedaily [N=65]); high-dose danaparoid (intra-venous loading dose of 2000 U followed by2000 U administered subcutaneously twicedaily [N= 63]); or UFH (intravenous loading

dose of 2500 U followed by dose-adjusted con-tinuous infusion [N=60]). Treatment lasted atleast 5 days. A significant reduction in recur-rence or extension of VTE was seen in patientsreceiving high-dose danaparoid (8 of 63[13%]), as compared with patients receivingintravenous UFH (17 of 60 [28%]; relative riskwas 0.45 [0.21 to 0.96 (95% confidence inter-val [CI]). Occurrence of major and minor bleed-

ing was similar in the 3 groups. A report fromLindmarker7 showed dalteparin sodium administeredat 200 units/kg once per day to a maximum of 18 000units resulted in fewer instances of recurrent throm-boembolic disease (12%), as compared to heparin

(17%). All 3 investigators report no differencesbetween LMWH and heparin in major bleedingepisodes.

Additional evidence suggesting that LMWHtherapy results in fewer recurrences of DVT and PEhas been reported by Hull in the New England 

Journal of Medicine .8 This double-blind clinical trialcompared fixed-dose subcutaneous LMWH (t inza-parin), once daily with adjusted-dose intravenousheparin, given by continuous infusion for the initialtreatment of patients with proximal-vein thrombo-sis. Six of 213 patients who received tinzaparin 175

units/kg (2.8%) and 15 of 219 patients who receivedintravenous heparin (6.9%) experienced newepisodes of VTE (P = .07). Major bleeding associat-ed with initial therapy occurred in 1 patient receiv-ing tinzaparin (0.5%) and in 11 patients receivingintravenous heparin (5.0%), showing a reduction inrisk of 91% (P = .006). However, this apparent pro-tection against major bleeding was lost during long-term therapy. Another clinical trial comparingreviparin with UFH 9 showed no statistically signifi-

G oals of Supportive IVC

therapy care filter H eparin LM W H Throm bolysis

Prevent     ?em bolization

Prevent extension   Reduce   recurrence

Restore patency   ?  

Prevent

postthrom botic   ? ?   syndrom e

Figure 1.Therapeutic Goals and Treatment Options for DVT

D VT = deep vein throm bosis; IVC = inferior vena cava; LM W H = low -m olecular-

w eight heparin.

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Advanced S tudies in  Medicine   447

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cant difference between the 2 drugs in the measureof return episodes of VTE. (Table 1)

A landmark study by Levine et al in 1996 evaluat-ed the safety and efficacy of enoxaparin administeredto outpatients.10 Patients with acute proximal DVT

were randomly assigned to receive either intravenousstandard heparin in the hospital (253 patients) orLMWH (247 patients received 1 mg of enoxaparinper kilogram of body weight subcutaneously twicedaily) administered primarily at home. The studydesign allowed outpatients taking LMWH to gohome immediately and hospitalized patients takingLMWH to be discharged early. All the patientsreceived warfarin starting on the second day. Of the247 patients receiving LMWH, 13 (5.3%) hadrecurrent thromboembolism, as compared with 17(6.7%, 95% CI) of the 253 patients receiving stan-

dard heparin. Five patients (2%) receiving LMWHhad major bleeding, as compared with 3 patients(1.2%) receiving standard heparin. In a separatestudy reported simultaneously, Koopman et al11

also demonstrated the safety and efficacy of outpa-tient administration of LMWH . Patients were ran-domly assigned to 1 of 2 study arms: adjusted-doseintravenous standard heparin administered in thehospital (198 patients), or fixed-dose subcutaneousLMWH administered at home (202 patients).Seventeen (8.6%) of the 198 patients who receivedstandard heparin and 14 (6.9%) of the 202patients who received LMWH experienced recur-rent thromboembolism (95% CI). Major bleedingoccurred in 4 patients (2.0%) assigned to standardheparin and in 1 patient (0.5%, 95% CI) assignedto low-molecular-weight heparin, as shown inTable 2. However, despite such convincing clinicalevidence, many physicians in the United States arenot using LMWH to treat patients with throm-boembolic disease.

Table 3 shows findings from 3 separate meta-analyses of safety and efficacy of LMWH, as com-

pared with UFH.

12-14

Outcomes for recurrent VTE,major bleeds, and mortality were consistently betterfor LMWH, as compared to UFH. Once-a-dayadministration was compared to twice-a-day dosingof LMWH and UFH in a randomized controlledtrial of patients with proximal and distal clots.15

Investigators found that once-a-day dosing withenoxaparin 1.5 mg/kg was equally as safe and effica-cious as 1 mg/kg q 12h and constant infusion IV of 

heparin; in both regimens, safety and efficacy werecomparable to that of standard heparin therapy.

While most of the medical evidence regardingthe safety and efficacy of LMWH focuses on thetreatment of DVT, only limited data are available on

the use of LMWH to treat acute symptomatic PE.

Study G roup RTE D VT PE M aj Bld

H ull8 Tinzaparin 6 (3% ) 3 (1% ) 3 (1% ) 1 (0.5% )

(213)

U FH 15 (7% ) 6 (3% ) 9 (4% ) 11 (5% )

(219)

C olum bus21 Reviparin 27 (5% ) 17 (3% ) 10 (2% ) 16 (3% )

(510)

U FH 25 (5% ) 13 (3% ) 12 (2% ) 12 (2% )

(511)

 Table 1.Clinical Outcomes Trials:LMWH Treatmentof DVT/PE

LM W H = low -m olecular-w eight heparin; D VT = deep vein throm bosis; PE = pul-m onary em bolism ; RTE = recurrent throm boem bolism ; M aj Bld = m ajor bleed-

ing; U FH = unfractionated heparin.

Levine et al10 Koopm an et al11

Enoxaparin U FH N adroparin U FH

(n = 247) (n = 253) (n = 202) (n = 198)

RTE 5.3 6.7 6.9 8.6

M ajor bleeding 2.0 1.2 0.5 2.0

D eath 4.4 6.7 6.9 8.1

H ospital (days) 1.1* 6.5 2.7 8.1

 Table 2.Efficacy:Suitable Proximal DVT10

*120 (48% ) were exclusively treated in the outpatient setting.D VT = deep vein throm bosis; U FH = unfractionated heparin; RTE = recurrent

throm boem bolism .Table adapted w ith perm ission from reference 10.

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This subgroup of patients was selected foranalysis in a random controlled trial of 612patients with symptomatic PE who did notrequire thrombolytic therapy or embolecto-my.9 Patients were randomly assigned to

either SC LM WH (tinzaparin) once daily, orIV UFH. In the fi rst 8 days of treatment,2.9% of 308 patients assigned to receiveUFH reached at least 1 of the endpoints, ascompared with 3.0% of 304 patientsassigned to LMWH (95% CI). By day 90 of the study, 7.1% of patients assigned to UFHand 5.9% of patients assigned to LMWHhad reached at least 1 of the following end-points: death, recurrent thromboembolism,or major bleed (P = .54). However, the riskof major bleeding was similar in the 2 treat-

ment groups throughout the study. Thesefindings suggest that initial treatment of PEwith LMWH is at least as safe and effectiveas is treatment with UFH.

Looking at randomized trials of dal-teparin, another formulation of LMWHcurrently in use, studies by Lindmarker etal,7 Fiessinger et al,16 and Luomanmaki et al17

found no significant differences betweendalteparin and UFH for the variables of morbidity, PE/DVT, major bleeding, orthrombocytopenia.

In conclusion, a composite of all relevantstudy findings suggests that LMWH out-comes for recurrent thromboembolic diseaseand major bleeding are superior to those forUFH (Figure 2). Yet within the United Stateshealthcare system, UFH is used more widelythan is LMWH, largely due to lack of proto-col development for outpatient care withLMWH.

CRITERIA FOR   SELECTING   PATIENTS FOR

OUTPATIENT ANTICOAGULATION THERAPY 

Figure 3 offers a graphic illustration of combined clinical evidence regarding theincidence of major bleeding and recurrentthromboembolism in patients who are givenUFH and in patients who receive LMWH .Based upon these study findings and theirexclusion criteria, the following should be

448 Vol. 2, No. 12   August 2002

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Figure 2.Clinical Efficacy:LMWH vs UFH Venous Thromboembolism22

LM W H = low -m olecular-w eight heparin; U FH = unfractionated heparin.Reprinted w ith perm ission from reference 22.

Leizorovicz et al12 Lensing et al13 Siragusa et al14

10 d–23 m o follow -up 3–6 m o follow -up 90 d follow -up

VTE n = 2045 n = 1086 n = 1228

recurrence 2.82% vs 4.63% 3.1% vs 6.6% 2.5% vs 4.5%

RR 0.66 (0.41–1.07) RR 0.47 (0.27–0.82) RR 0.5 (0.3–0.9)

P = .09 P < .01 P < .02

M ajor n = 2045 n = 1512 n = 1694

bleed 2.43% vs 4.04% 0.8% vs 2.8% 2.2% vs 4.7%

RR 0.65 (0.36–1.16) RR 0.32 (0.15–0.69) RR 0.44 (0.20–0.70)

P = .15 P < .005 P = .04

M ortality n = 2045 n = 1086 n = 1733

3.30% vs 4.83% 3.9% vs 7.1% 3.3% vs 5.9%

RR 0.72 (0.46–1.40) RR 0.53 (0.31–0.90) RR 0.51 (0.2–0.9)

P = .16 P < .04 P = .01

 Table 3.Meta Analyses of LMWH vs IV UFH DVT Treatment

LM W H = low -m olecular-w eight heparin; U FH = unfractionated heparin; D VT = deepvein throm bosis; VTE = venous throm boem bolism ; RR = relative risk.

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Advanced S tudies in  Medicine   449

considered as absolute contraindications foroutpatient treatment with LMWH:

• Active bleeding• Cardiopulmonary instabili ty

• Hereditary bleeding disorders• History of heparin induced

thrombocytopenia• Allergy to heparin.

Social and medical relative contraindica-tions for outpatient treatment with LMWHinclude the following:

• Geographic inaccessibility• Potential for medication noncompliance• Inability to support cost of drug

• Pregnancy• Hereditary or acquired thrombotic disorders• Peptic ulcer disease, gastrointestinal, or gen-

itourinary bleeding within 6 weeks• Uncompensated comorbidities• Concomitant medical problems (eg, CrCl < 30

cc/min)• Pulmonary embolism (hemodynamically stable).

This was placed under the relative risk categorybecause many US physicians are not clinicallycomfortable with treating patients with uncom-plicated PE on an outpatient basis.

Koopman et al11 reported that 69% of the patientswere eligible for outpatient treatment of DVT; Levine etal10 and Yusen et al18 respectively reported that only 33%and 18% of the subjects met the criteria to be treated athome. Within our facility at Thomas Jefferson University,we find that approximately 45% of patients meet eligibil-ity criteria for outpatient anticoagulation therapy.

DOSING REGIMENS

Whether to administer once- or twice-a-day dosingof therapy remains controversial. Table 4 summarizesthe incidence of major bleeding and recurrent DVTunder various dosing regimens, but it is important tostress that these studies did not exclude patients on thebasis of weight. However, in studies where dosing wasfixed and not adjusted on actual body weight, out-comes for primary endpoints were less favorable (Table5). In our study of once- versus twice-daily dosing

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Figure 3.LMWHvs IVUFH

M ajor

A uthor W T Bleed RVTE

Sim onneau5 N o lim it 0 1/67

(enoxaparin) (1% ) q12h

H ull8 N o lim it 0.5% 6/213

(tinzaparin) (3% ) qd

Levine10 N o lim it 2% 13/247

(enoxaparin) (5.3% ) q12h

 Table 4.Once- vs Twice-Daily Dosing

RVTE = recurrent venous throm boem bolism .

LM W H = low -m olecular-w eight heparin; U FH = unfractionated heparin.

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with enoxaparin15 in which no weight limits wereplaced upon subjects, we found no significant differ-ence in the outcomes of recurrent VTED or majorbleeding within the qd and q12h study arms.However, in a subgroup analysis there was a higher

incidence of recurrent VTED in obese patients and inpatients with cancer who received qd dosing than forthose patients who received q12h dosing, but the vari-ance was not statistically significant. Nonetheless, it

does raise some questions surrounding dosing, whichagain surface in reports from Partsch et al.19 This studyof the safety and efficacy of dalteparin showed 5.3%(N=67) of subjects within the qd (200 units/kg) studyarm experienced major bleeds and 5.3% experienced

recurrent PE. In the 12 h D (100 units/kg) study arm,1.5% (N=64) experienced major bleeds and 1.6%experienced recurrent PE.

Protocol for outpatient anticoagulation therapy atThomas Jefferson University is based on recommenda-tions from the American College of Chest Physicians(ACCP) consensus conference.20 The ACCP recom-mendations, as detailed in Table 6, call for administra-tion of warfarin initiated on day 1 or day 2 withcontinuation of LMWH for at least 5 days, until aninternational normalized ratio (INR) value of 2 to 3 isachieved for 2 consecutive days.

In summary, UFH has long been the mainstay of therapy for DVT and PE. However, over the last 10years, LMWHs have been replacing this therapy fortreating thrombotic events. LMWH s are betterabsorbed, have a longer half-life, and do not requiremonitoring.19 A number of studies have demonstratedthe safety and efficacy of LMWHs in treating patientswith thromboembolic events. LMWHs have changedthe paradigm of care for thromboembolic disease: out-patient treatment or shorter hospital stay for inpatients.

REFERENCES

1. H irsh J, H oak J. M anagem ent of deep vein throm bosis and

pulm onary em bolism : a statem ent for healthcare profession-

als from the council on throm bosis (in constitution w ith the

council on cardiovascular radiology), Am erican H eart

Association. C irculation 19 96 ;93 :22 12 -22 45 .

2. G oldhaber SZ, Visani L, De Rosa M . Acute pulm onary

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3. M eignan M , Rosso J, G authier H , et al. System atic lung

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in patients w ith proxim al deep venous throm bosis.Arch

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4. H ull RD , Raskob G E, Brant R, et al. Relation betw een the

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heparin treatm ent for deep vein throm bosis.Arch Intern

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450 Vol. 2, No. 12   August 2002

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M ajor

A uthor W T Bleed RVTE

Koopm an11 Fixed dose 0.5% 14/202

(nadroparin) (6.9% ) q12h

Lindm arker7 Fixed dose 0% 11/91

(dalteparin) (12% ) qd

de Valk6 Fixed dose 1% 8/63

(danaparoid) (13% ) q12h

C olum bus21 Fixed dose 1.9% 27/510

(reviparin) (5.3% ) q12h

 Table 5.Once- vs Twice-Daily Dosing

3 to 6 months

– First event with reversible or tim e-lim ited risk factor

> 6 months– Idiopathic V TE, first event

12 months to lifetime

– First event w ith

– C ancer until resolved

– Anticardiolipin antibody

– Antithrom bin deficiency

– Recurrent event, idiopathic or w ith throm bophilia

 Table 6.ACCPDuration of Therapy26

D ata adapted w ith perm ission from reference 26.

RVTE = recurrent venous throm boem bolism .

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Advanced S tudies in  Medicine   451

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