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Extended Venous Thromboembolism ProphylaxisAfter Total Hip Replacement

A Comparison of Low-Molecular-Weight Heparin With Oral Anticoagulant

Charles Marc Samama, MD, PhD; Muriel Vray, PhD; Jeanne Barre, MD; Jean-Noel Fiessinger, MD;Nadia Rosencher, MD; Thomas Lecompte, MD; Gerard Potron, MD; Joseph Basile, MD;Russell Hull, MBBS, MSc; Denise Desmichels, PhD; for the SACRE Study Investigators

Background: Oral anticoagulants and low-molecular-weight heparin are both recommended for venous throm-boembolism prophylaxis after total hip replacement. Todate, these regimens have not been compared by means ofclinical end points in the extended prophylaxis setting.

Methods: We randomly assigned 1279 patients 3 daysafter total hip replacement surgery to fixed-dose subcu-taneous low-molecular-weight heparin (reviparin so-dium, 4200 anti-Xa IU) or adjusted-dose oral anticoagu-lant (international normalized ratio, 2-3; acenocoumarol)for a 6-week period. The primary end point was the fail-ure rate, defined as the combined clinical events of a con-firmed symptomaticthromboembolic event, a major hem-orrhage, or death.Allpatientswere followed up throughoutthe study interval. The primary objective was to comparethe observedcumulative failure rate in the low-molecular-weight heparin vs oral anticoagulant group.

Results: In the intent-to-treat population, objectively

documented symptomatic thromboembolic events oc-

curred in 15 (2.3%) of 643 patients vs 21 (3.3%) of 636patients receiving low-molecular-weight heparin or oralanticoagulants, respectively (P =.30; 95% confidence in-terval for the difference, 0.8% to 2.8%). Major bleed-ing occurred in 9 (1.4%) of 643 patients vs 35 (5.5%) of636 patients receiving low-molecular-weight heparin ororalanticoagulants,respectively (P=.001). Thefailureratewas 24 (3.7%) of 643 patients compared with 53 (8.3%)of 636 patients who received low-molecular-weight hep-arin or oral anticoagulants (P =.001).

Conclusions:A significantly higher benefit-risk ratiowasobserved for patients undergoing elective hip replace-ment who received extended out-of-hospital prophy-laxis with low-molecular-weight heparin vs acenocou-marol. Low-molecular-weight heparin prophylaxis wasat least as effective as oral anticoagulants, but with amarked improvement in safety.

Arch Intern Med. 2002;162:2191-2196

POSTOPERATIVE DEEP veinthrombosis and pulmonaryembolism are feared compli-cations after orthopedic sur-gery. Patients who undergo

total hip replacement are at high risk forcomplicating venous thromboembolic dis-ease.1,2 Low-molecular-weight heparin regi-mens have simplified pharmacologic pro-phylaxis because of the use of a fixed-doseonce-daily subcutaneousinjectionthatdoes

not require anticoagulantmonitoring. Low-molecular-weight prophylaxis is effective,safe, and cost-effective in patients under-going elective hip surgery.3-8 Clinical is-sues that are currently debated include theuncertainty as to the relative effectivenessand safety of extended low-molecular-weightheparinprophylaxisvs extendedoralanticoagulantregimens after electivehipsur-gery. Multiple studies have compared ex-tended out-of-hospital low-molecular-

weight heparin prophylaxis against placeboin patients undergoing elective hip sur-gery with the use of a venographic endpoint.8-12 A significantand clinically impor-tant difference was consistently notedamong thestudiesin favor oflow-molecular-weight heparin prophylaxis. Extended low-molecular-weight heparin prophylaxis waseffective and safe.

Adjusted-doseoral anticoagulant pro-phylaxishasbeenastandardofcareinmany

countries for in-hospital thromboprophy-laxisinpatientsundergoingelectivehipsur-gery. Clinical customhas extended theuseoforalanticoagulantout-of-hospitalprophy-laxis for many weeks after elective hipsur-gery. Oral anticoagulation avoids the needforasubcutaneousinjectionandisrelativelyinexpensive.Nevertheless,theuseoforalan-ticoagulant regimens mandates frequentmonitoringof international normalizedra-tio(INR)tomaintainatherapeuticINRand

ORIGINAL INVESTIGATION

Author affiliations are listedat the end of the article. A listof the principal investigatorswho recruited patientsfor the SACRE Study(Study Comparing OralAnticoagulants With Reviparin)appears on page 2196.

(REPRINTED) ARCH INTERN MED/VOL 162, OCT 28, 2002 WWW.ARCHINTERNMED.COM2191

2002 American Medical Association. All rights reserved.on May 29, 2011www.archinternmed.comDownloaded from
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to minimize theriskof bleeding complications.Inthepost-operativesetting,therehasbeenconsiderableconcernaboutan increasedriskof major bleedingcomplicationswith theuseoforalanticoagulantregimens. Thisis a moreproblem-aticissueoncethepatientleavesthehospitalbecauseoflessfrequentINRmonitoring andsubsequent doseadjustmentof the oralanticoagulant.To date,the relativeeffectivenessand, in particular, safety of extended out-of-hospital low-molecular-weight heparin prophylaxis vs oral anticoagu-lantshas not been compared in a large randomized trial inpatients undergoing elective hip surgery.

Symptomatic deep vein thrombosis and pulmo-nary embolism occur infrequently in patients undergo-ing elective hipsurgery and receiving pharmacologic pro-phylaxis.8-12 Accordingly, in designing and implementinga randomized trial of extended prophylaxis comparingactive prophylactic regimens in patients undergoing elec-tive hipsurgery, it is relevant to reportthe individual find-ingsfor efficacyandsafety andthe cumulativefailurerates.

Wethereforeperformed a large randomizedtrial evalu-ating theeffectiveness andsafetyin real-world practice con-ditions of a fixed-doseonce-dailylow-molecular-weighthep-arin regimen (reviparin sodium) compared withadjusted-dose oral anticoagulant therapy (acenocoumarol) for theprevention of objectively confirmed symptomatic venousthromboembolic disease during the 6-week postoperativeperiod in patients undergoing elective hip surgery.

METHODS

STUDY DESIGN

The SACRE study (Study Comparing Oral Anticoagulants WithReviparin) wasa multicenter, randomized trial comparing aceno-coumarol (Sintrom;NovartisPharma, Rueil-Malmaison, France)in an adjusted dose with low-molecular-weight heparin (Cliva-rin; Knoll-France,Levallois-Perret, France) administeredoncedailyfor the 6-week intervalafter total hip replacement surgery. Sixty-

five centers in France participated in the trial. The protocol wasapproved by the institutional review board at each center.

PATIENTS

Consecutive eligible patients 18 years or older scheduled to un-dergo elective unilateral primary total hip replacement sur-gery who gave an informed consent were enrolled in the studythe day before surgery. Patients were eligible if they had noneof the following: femoral neck fracture, current active bleed-ing or disorders contraindicating anticoagulant therapy, a his-tory of deep vein thrombosis or pulmonary embolism, heparin-induced thrombocytopenia, peptic ulcer, allergy to radiopaquecontrast medium, use of aspirin or ticlopidine hydrochloride,renal insufficiency, liver failure,acute endocarditis, recent stroke

(6 months), uncontrolled hypertension, pregnancy, alcohol-ism, or inability to follow instructions.A randomized computer-derived treatment schedule was

used to assign the patients to receive low-molecular-weight hep-arin subcutaneously or acenocoumarol orally. Central random-ization was stratified for each center. Within each stratum therandomization schedule was balanced in blocks of 4.

TREATMENT REGIMENS

The patients received reviparin sodium (4200 anti-Xa IU, 1 sub-cutaneous injection) as an initial dose 12 hours preoperatively,

except in patients undergoing regional anesthesia. After surgerywas completed, patients received a once-a-day subcutaneous in-

jection of reviparin sodium (4200 anti-Xa IU) for 3 1 days. Thefirst postoperative injection was performed in the evening,ie, be-tween 6 and 10 hours after surgery. If no clinical symptoms orsigns of deep vein thrombosis, pulmonary embolism, or majorbleeding were reported, patients were randomized to either con-tinue receiving reviparin at the same dosage or crossed over toacenocoumarol for a 6-week interval after surgery. In the pa-tients crossed over to acenocoumarol, the dose of acenocouma-rolwas adjusted to achieve an INRbetween2.0 and3.0 for2 con-secutivedays, andthenreviparin treatment wasdiscontinuedwhenthese 2 consecutive INRs were obtained.

SURVEILLANCE AND FOLLOW-UP

All patients were examined daily during the in-hospital period.Each patient wasfollowed up duringhospitalization andafter dis-charge. At discharge, patients received a log book in which treat-ment and surveillance were recorded (ie, platelet count twiceweekly during the first 3 weeks of reviparin treatment and onceweekly thereafter, or weekly INR in the acenocoumarol group).To respect pragmatic conditions, no dosing algorithm was pro-vided by the study committee for the acenocoumarol group. Pa-tients were asked to report any bleeding or thromboembolicepi-sode to their physician. In addition,anybleedingepisode required

a recordof thecomplete bloodcell count (and anINRin theaceno-coumarol group). Four clinical visits were planned during thestudy: at preinclusion, at randomization, at discharge, andat theend of the treatment period (between 6 and 9 weeks). Completeblood cell counts andINR estimateswere obtained after surgery,at discharge, and if a bleeding episode occurred.

Patientswith overt signs or symptomsof deepvein throm-bosis or pulmonary embolismunderwent objective testing. Pa-tientswithsuspecteddeepveinthrombosisbasedonclinicalfind-ings underwent venography or duplex scanning. Patients withsuspected pulmonaryembolismbasedon clinical signsor symp-tomsunderwentventilation-perfusion scanningor angiography.

Bleeding was defined as major if it wasclinically overtandmet any of the following criteria: (1) it was associated with adecrease in the hemoglobin level of more than 20 g/L com-

pared with the prerandomization level (day 3); (2) it requiredthe transfusion of 2 U or more of packed red blood cells afterrandomization; (3) it was digestive, intracranial, retroperito-neal, or intraocular; (4) it was located at the surgical site andrequired a reoperation; or (5) according to the investigator sopinion, it led to discontinuation of the study treatment. Clini-cally serious bleeding was also recorded and defined as (1) lead-ingto reoperation, (2) leading to thetransfusion of 3 U or moreof packed red blood cells, or (3) responsible for delayed heal-ing, prolonged hospitalization, rehospitalization, or sepsis.Bleeding was defined as minor if it was clinically overt with-out meeting any of the major bleeding criteria.

Dataon the outcomemeasures of effectiveness (symptom-atic venousthromboembolism),safety (bleedingcomplications),and death that provided the primary cumulative end point for

the study wereinterpreted by a centraladjudicating committee.The radiologic images were reviewed. Adjudication was madeby 3 committeemembers not involvedin the patientscare.Theresultsof objectivetestswereinterpretedindependentlyandwith-out the interpreters knowledge of theotherresults, thepatientsclinical findings, or the patients treatment group.

STATISTICAL ANALYSIS

The primary end point was the cumulative rate of failure, whichwas defined as a combined outcome of a confirmed symptom-atic thromboembolic event, major bleeding, or death. The study




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planned to include 1400 patients (700 in both arms) under theassumption of a failure rate of 4% with acenocoumarol and 1%with reviparin. From these assumptions, a study of 1280 pa-tients would provide a 95%probability(power)of rejecting, witha 2-sided test at significance level of .05, the hypothesis that therate of failure would be greater than 3% in one group comparedwiththe other.With an expected percentage of patients notreach-ing the eligibility criteria of 10%, it was decided to include 1400patients.

The primary analysis was performed on an intent-to-treatanalysis including all patients randomized andtreated by at least1 dose of drug and who did not develop any event on the day ofrandomization. Comparisons of the primary clinical end pointsinvolvedtime-to-eventanalysisby use of Kaplan-Meier plots andlog-rank methods. In cases where a patient had multiple events,the time to event wasdeterminedby thetime to thepatients firstevent. The failure rate was compared between the 2 groups bymeans of a 2 test. A 95% confidence interval for the differencebetween the 2 groups in the incidence of events was calculatedwith the normal approximation of the binomial distribution.

A per-protocol analysis was performed on patients withno protocol violations. Protocol violations were defined by thefollowing: (1) patient wrongly randomized, (2) patient treatedby unauthorized treatment, (3) duration of treatment less than5 weeks or more than 7 weeks (except in the case of an event)or unknown duration of treatment, (4) follow-up assessmentless than 6 weeks, and (5) systematic use (screening) with ve-nous duplex ultrasonography in asymptomatic patients.

For the intent-to-treat analysis, only confirmed events oc-curring during the 9 weeks of follow-up were considered fail-ures independent of the duration of treatment.

All bleeding events defined as minor, major, clinically sig-nificant, or not clinically significant are described separately.

Data were analyzed with SAS software (version 6.12, SASInstitute Inc, Cary, NC).

RESULTS

STUDY PATIENTS

The recruitment of patients began September 1, 1997, andended October 31, 1999. Thefollow-upof thepatientswas

completed in January 2000. A total of 1337 patients wereincluded in the study. Of these patients, 1322 underwenttotal hipreplacement surgery and1289 were randomly as-signed to receive either reviparin or acenocoumarol.

Thirty-threeeligiblepatientsundergoingtotal hipre-placementwere notrandomized because of thefollowing:death (n=1), thromboembolic accident before random-ization (n= 7), age younger than 18 years (n = 1), bleed-ing episode before randomization (n= 4), adverse effects(n= 6), declined participation (n= 3), physician decision(n= 2), use of other anticoagulant (n =2), iodine allergy(n= 1),prothrombin time less than 70% (n= 1),forgotten

randomization (n=1), and local organization problems(n=4).Table 1 summarizes the patient populations in-

cluded for both intent-to-treat and per-protocol analy-ses and the reasons for excluding patients from the effi-cacy analysis. The baseline characteristics of the patientswere similar in the 2 treatment groups (Table 2).

INTENT-TO-TREAT POPULATION

Among the 643 patientstreated with reviparin, 15 (2.3%)developed at least 1 thromboembolic event, as com-pared with 21 (3.3%) of the 636 patients assigned to re-ceive acenocoumarol, an absolute difference of 1.0%(95%

confidence interval for the difference, 0.8% to 2.8%; 2

P =.30) (Table 3).During the study at least 1 major bleeding event oc-

curred in 9 patients (1.4%) treated with reviparin com-pared with 35 patients (5.5%) treated with acenocouma-rol, an absolute difference of 4.1% (2 P=.001) (Table 3).Five patientsreceiving reviparin hadclinicallyseriousbleed-ing, compared with 20 patients receiving acenocoumarol(including 1 fatal bleeding episode). In patients with ma-jor bleeding in the acenocoumarol group, the median(range) INR at discharge was 2.6 (1.0-15.2). The median

Table 1. Intent-to-Treat and Per-Protocol Populationsand Reasons for Exclusion

ReviparinSodium

(n = 644)Acenocoumarol

(n = 645)

Intent-to-treatReasons for exclusion

No treatment 1 6

Event at randomization 0 3

Total population, No. (%) 643 (99.8) 636 (98.6)Per-protocol

Reasons for exclusion

Patient wrongly included 9 21

Use of unauthorized treatment 4 4

Premature discontinuation oftreatment (or unknown duration)

52 80

Too-long duration of treatment 31 61

Too-short follow-up duration 52 48

Systematic echo Doppler 16 23

No. (%) of patients with1 protocol violation

143 (22.2) 197 (30.5)

Total population, No. (%) 501 (77.8) 448 (69.5)

Table 2. Baseline Characteristics of the Study Patients

ReviparinSodium

(n = 644)Acenocoumarol

(n = 645)

Sex, % F 51 50

Age, mean SD, y 66 11 65 12

Weight, mean SD, kg 74 11 74 14

Body mass index, mean SD, kg/m2 27 4 27 4

Blood pressure, mean SD, mm Hg

Systolic 140 15 140 16

Diastolic 79 10 79 10

Heart rate, mean SD, beats/min 75 10 74 10

Predisposing factors, No. of patients

History of varicose veins 142 140

History of malignancy 3 1

History of congestive heart failure 5 2

Hi story of chronic respi rator y failure 6 10

Obesity 94 95

Osteoarthritis 2 0

Myeloproliferative syndrome 1 1

Preoperative infection 3 0

Type of anesthesia, No. of patients

General 403 393

Regional 241 252




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INR the day before or concomitant with the bleeding epi-sode was3.4 (1.4-6.4); however, this measurementwasper-formed in only 19 patients despite the study protocol rec-ommendations, andit wasinthetherapeuticrange (between2 and 3) in 8 patients among the 19. In the acenocouma-

rol group, major bleeding occurred between the 1st andthe 27th treatment days (median, day 9). Thirteen pa-tients (2.0%) receiving reviparin developed at least 1 mi-nor bleeding episode, as compared with 17 patients(2.7%)treated by acenocoumarol (95% confidenceintervalfor thedifference, 1% to 2.3%; 2 P=.44). The site of clinical se-rious bleeding was the operative site in 19 patients (3 inthe reviparin group vs 16 in the acenocoumarol group);11 required a repeatoperation (2 in the reviparin group vs9 in theacenocoumarol group), whichoccurred mostly af-ter discharge.

During the study (intent-to-treat population), 60 pa-tients (9.3%) required at least 1 blood transfusion in thereviparin group as compared with 65 (10.2%) in theaceno-coumarol group (P=.59). The median number of units ofpackedred blood cells transfused was2 (range, 1-3) in thereviparin group and 2 (range, 1-6) in the acenocoumarolgroup. In patients with at least 1 bleeding event (major orminor), the median number of units of packed red blood

cells transfused was 2 (range, 2-3) in the reviparin groupand 2 (range, 1-6) in the acenocoumarol group (Table 3).Two patients in the acenocoumarol group died:

on the 4th postoperative day and 18th postoperativeday of myocardial infarction and gastrointestinal tractbleeding, respectively.

The failure rate was 24 (3.7%) of 643 patients com-pared with 53 (8.3%) of 636 patients who received low-molecular-weight heparin or oral anticoagulants, respec-tively, an absolute difference of 4.6% and relative riskreduction of 55% (2 P = .001) (Table 3). Analysis by thelog-rank test, which takes into account the duration un-til the first clinical event, showed a clinically and statis-tically significant difference between the groups (P.001)

in the frequency of the combined cumulative end point(Figure) in favor of low-molecular-weight heparin.In 2 patients receiving low-molecular-weight hep-

arin, a low platelet count was observed at day 31 (110103/L) and day 36 (2103/L), respectively, leadingto discontinuation of the treatment. However, accord-ing to the adjudication committee, the reviparin treat-ment was not thought to be involved in the occurrenceof these events.

PER-PROTOCOL POPULATION

The per-protocol analysis showed similar findings(Table 4). The failure rate in the reviparin group (4.2%)

was significantly lower than the failure rate in the aceno-coumarol group (10.3%). The absolute difference was6.1% (95% confidence intervals of the difference, 2.8%-9.4%), with a 2 P =.001.

DURATION OF TREATMENTAND DURATION OF FOLLOW-UP

The duration of the study treatment was similar in the 2groups (mean SD, 40.5 8.8 days in the reviparin groupand 39.512.9 days in the acenocoumarol group).

100

95

90

85

800 10 20 30 40

643Reviparin

No. at Risk

625 623 622 620

636Acenocoumarol 597 587 583 583

5 15 25 35 45

No. of Days of Follow-up

%E

ventFree

Reviparin Sodium

Acenocoumarol Log-rank P


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The follow-up duration was similar between the 2groups(meanSD, 53.9 16.5 days in the reviparin groupand 52.719.2 days in the acenocoumarol group).

COMMENT

The findings of this multicenter clinical trial demonstratethat extended out-of-hospital prophylaxis with low-molecular-weight heparin is at least as effective as oralanticoagulant treatment (Table 3). The regimen of low-molecular-weight heparin in this trial resulted in signifi-cantly fewer major bleeding complications (P=.001). Theincidence of clinically serious bleeding wasalso much lessfrequent in patients receiving low-molecular-weight hep-arin (P=.001) (Table 3). Thefailure rate was clinically andstatistically significantly higher in patients receiving oralanticoagulants (P=.001) (Table 3, Figure).

Acenocoumarol is a relatively short-acting oral an-ticoagulant. Its elimination half-life is close to 9 hours,and the effect duration reaches 48 to 72 hours. When theSACRE study wasdesigned,oral anticoagulant agents werealready no longer the standard anticoagulant agents inFrench orthopedic units; however, among vitamin K an-

tagonists, acenocoumarol was well known and was themost prescribed agent.To date, the debate as to whether extended out-of-

hospital oral anticoagulant prophylaxis or low-molecular-weight heparin is preferred remains unresolved. To ourknowledge, our randomized trial is the first to comparelow-molecular-weight heparin vs oral anticoagulants forextended out-of-hospital prophylaxis in patients under-going elective hip surgery. The superior benefit-risk ra-tio of the regimen of low-molecular-weight heparin usedin this trial compared with acenocoumarol suggests thatin this context low-molecular-weight heparin prophy-laxis is preferred.

Our findings are based on objectively documented

symptomatic events. Our findings cannot be attributedto bias; therandomizationwassuccessfulbecause thebase-linecharacteristicsof the patientswerecomparablein eachgroup, and the study was conducted rigorously to en-sure that the participating clinicians adhered to the pro-tocol. No systematic visit was scheduled between dis-charge and the end of the treatment period so as not tomodify the usual patient care, and only the occurrenceof a bleeding or thrombotic event could have led the pa-tient to contact his or her physician. The symptomaticend points were adjudicated by a central committee with-out knowledge of the treatment groups, thus avoiding adiagnostic bias. The symptomatic end points were dis-persed across centers rather than being confined to a few

centers. For these reasons it is likely that our results aregeneralizable to the population at large.Oral anticoagulant prophylaxis requires frequent

monitoring of the INR and adjustment of the anticoagu-lant dose, aiming for a treatment range with the INR of2.0 to 3.0 for optimal effectiveness and safety. However,prophylactic doses have to be adjusted to the same INRrange (2-3) as therapeutic doses, and, accordingly, vita-min K antagonisttreated patients are exposed to a higherdegree of anticoagulation. In contrast, low-molecular-weight heparinprophylaxis is administered in a fixed dose,

using a high-risk rather than a treatment dose, and an-ticoagulant monitoring is not required. The increased fre-quency of major andserious bleeding associated with oralanticoagulant use in this trial likely reflects the inherentdifficulties associated with the postoperative use of vi-tamin K antagonists in this clinical setting.

Our study provides clinically relevant informationthat is of practicalvaluefor physicians andsurgeons. Mul-tiple studies8-12 comparing low-molecular-weight hepa-rin against placebo in the hospital and for an extendedperiod out of the hospital demonstrate the need for ex-tended prophylaxis. A recent trial13 comparing in-hos-pital prophylaxis with low-molecular-weight heparin inproximity to surgery (6 hours postoperatively)againstoralanticoagulants showed superiority for low-molecular-weight heparin. Our trial extends this knowledge froman in-hospital setting to 6 weeks postoperatively and alsofavors low-molecular-weight heparin.

A potential limitation of low-molecular-weight hep-arin prophylaxis in the out-of-hospital setting is the needfor subcutaneous administration of this regimen. This ismore of a perceived than actual limitation; a recent ran-domized trial14 documented that self-administration by

the patient or a family member is as efficacious as ad-ministration by a home care nurse. Low-molecular-weight heparin offers the simplicity of a once-daily injection without the need for anticoagulant monitoringand the close dependence on the primary care physicianthat monitoring requires. Oral anticoagulant prophy-laxis is inexpensive, but the cost of its administration isincreased by the need for monitoring of the INR.

A large epidemiologic study15 using a linked hospitaldischarge database provided by the State of California un-derpins the need for extended out-of-hospital prophy-laxis in patients undergoing elective hipsurgery. This epi-demiologic study reportedthe outcomes in 19586 patientsafter total hip replacement, 95% of whom received in-

hospital prophylaxis. Of the patients with symptomatic ve-nousthromboembolism, 76%experienced these events af-ter discharge from thehospital (mediantime, 17 days aftersurgery). The overall frequency of documented venousthromboembolism within 3 months of surgery was 2.8%.This symptomatic rate is lowerthan incidencerates in stud-ies using screening venography,8-13 reflecting that in mostcases the venous thrombi do not cause symptoms that thepatients or the physicians perceive as significant. How-ever, these thrombi and, in particular, proximal thrombiare the source for fatal pulmonary embolism, which is of-ten unrecognized clinically.12-13

Because our SACRE study assessed the frequency ofsymptomatic objectively documented venous thrombo-

embolic events rather than venous thrombotic events de-tected by screening venography, the observed overall rateswere low. This was expected in planning theSACRE study,and for this reason the cumulative event rates were se-lected as the primary endpoint. Similarly,using symptom-atic end points, a recent trial16 of in-hospital prophylaxisshowed superiority of low-molecular-weight heparinvs oralanticoagulants in patients undergoing elective hip sur-gery. In the SACRE study, all patients received low-molecular-weight heparin prophylaxis for at least 31 daysafter surgery and were then randomized to continue low-




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molecular-weight heparin prophylaxis or to receive oralan-ticoagulant prophylaxis. For thisreason, the SACRE studyaddresses the commonly asked question as to the effec-

tiveness and safety of oral anticoagulant prophylaxis afterinitial low-molecular-weight heparin prophylaxis.

In summary, our study shows that the extended useof low-molecular-weight heparin given in a single sub-cutaneous injection per day is superior to acenocouma-rol prophylaxis in patients undergoing elective hip sur-gery and that it avoids the need to monitor the level ofanticoagulation. These data, together with the cited lit-erature, provide the clinician using evidence-based medi-cine with the opportunity to optimize the use and choiceof extended out-of-hospital prophylaxis in patients un-dergoing elective hip surgery.

Accepted for publication April 3, 2002.

From the Departement dAnesthesie-Reanimation, Cen-tre Hospitalier Universitaire Avicenne, Assistance Publique-Hopitaux de Paris, UniversiteParis 13, Bobigny, France (DrSamama); InstitutNational de laSanteetdelaRechercheMedi-cale SC4, Service des Maladies Infectieuses, Hopital PaulBrousse,Villejuif,France(DrVray);Departement dAnesthesie-Reanimation, Centre Hospitalier Universitaire Robert De-bre, Reims, France (Dr Barre); Service de Medecine Vascu-laire, Hopital Europeen Georges Pompidou, Paris, France (DrFiessinger); Departement dAnesthesie-Reanimation, Centre

HospitalierUniversitaire Cochin, Paris(Dr Rosencher); Labo-ratoire dHematologie, Centre Hospitalier Universitaire Re-gional de Nancy, Nancy, France (Dr Lecompte); LaboratoiredHematologie, Centre Hospitalier Universitaire Robert De-bre, Reims (Dr Potron); Polyclinique Chirurgicale, SaintGeorges de Didonne, France (Dr Basile); Thrombosis Re-search Unit, University of Calgary, Alberta (Dr Hull); andKnoll-France, Levallois-Perret, France (Dr Desmichels).

This study was supported by Knoll-France, Levallois-Perret, France. The local investigators received US $400 perpatient included in the study, and the institution of the in-vestigator-in-chief (Dr Samama) received a final grant ofUS $4000.

Corresponding author and reprints: Charles Marc Sa-mama, MD, PhD, Departement dAnesthesie-Reanimation,Hopital Avicenne-125, route de Stalingrad, 93009 BobignyCEDEX, France (e-mail: [email protected]).

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Principal Investigators of the SACRE Study

Albi: C. Duges.Alencon: P. Dequire, L. Zarhloule.Amiens:A. Grohens. Angers: D. Marlat, M. Arnou, J. N. Prime, P.Le Coz, T. Godin,G. Senly.Argenteuil: A. Landais, F. Tan-donnet.Auch: M. Leger. Bar Le Duc:J. Preaut. Beauvais: B.Al Nasser, J. L. Palacios, L. Lapasset. Bordeaux: M. Estebe.Brest:J.L. Arzur, L. Gerard, J. M. De Sarrazin, B. Combot,H. Coat, O. Santybout, H. Cougard, J. Keromnes.Clermont-Ferrand:J. P. Levai,V. Fenies. Clichy: T. Chevalier, J. Marty.Colmar:R. Roedel,D. Jochim.Corbeil-Essonnes:P. Feuillade.Creteil: A. Gilton. Dax: B. Labes, J. C. Gardes. Gassin: M.Poupeney, H. Farines. Illkirch: F. Bertrand. La Roche-sur-Yon: D. Tissier. Lavelanet: Y. Der Sarkissian. Le KremlinBicetre:J. Y. Nordin, F. Michaut Paterno. Le Mans: M. Ger-mond, P. Veyrac, C. Rebillard, A. Khoury, G. Bazin. Lille:M. Delecroix. Lourdes:J. Basile. Lyon: N. Clermont. Marcqen Baroeul: J. Y. Poithier. Marseille: M. Dupont, Y. He-mon. Meulan: P. Haffner,F. Prigent. Montauban: P. Devallet,P. Giraud. Montpellier:J. N. Chrisment, Y. Allieu, M. Kas-sim, J. F. Lubrano, J. Deschodt. Moulins: M. Laine. Nancy:D. Mole, D. Roche, J. L. Bauer, H. Coudane, C. Nicout.Nantes: M. Babin, R. B. Busch. Narbonne: B. Segondy, J. P.Klein. Nimes: P. Cuvillon, V. LeClerc, J. F. Pibre, O. Lar-cena, P. Rignault, T. Julien, J. Laval. Orthez: C. Segrestain,

X. Desrez. Paris:J. P. Moulinie, N. Rosencher, T. Judet, A.Babinet, P. Coriat, D. Heitz, O. Langeron, J. M. Debue, J.M. Richard, L. Jeanne. Pau: P. Gardes, A. LeGrand.Perpignan: P. Atthar, S. Tournoud, J. P. Mau, J. P. Giardi,G. Bonada. Provins: J. C. Gallier, R. Charon. Rennes: J. P.Estebe, S. Kieffer, J. M. Roy. SaintDoulchard:P. Viale.Saint-Mande:J. M. Saissy, J. P. Ducoureau. Selestat:J. North, D.Borcos. Suresnes: A. Kouadri. Tarbes: C. Robert. Toulon:D. Fyon. Tours: C. Pere.



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