PROPOSAL FOR THE INCLUSION OF LOW MOLECULAR … · PREVENTION OF VENOUS THROMBOEMBOLISM IN...

PROPOSALFORTHEINCLUSIONOFLOWMOLECULARWEIGHTHEPARINSFORTHEPREVENTIONOFVENOUSTHROMBOEMBOLISMINHOSPITALIZEDPATIENTSINTHEWHO

MODELLISTOFESSENTIALMEDICINES

October1st2014

WalterAgenoMarcoDonadini

PantepAngchaisuksiriMarkCrowtherHenryDdunguIsmailElalamy

ZoubidaTaziMezalekPeterVerhammeHenryWatson

ScientificandStandardizationCommitteeonControlofAnticoagulationInternationalSocietyonThrombosisandHaemostasis

DepartmentofClinicalandExperimentalMedicineUniversityofInsubria

Varese,Italywalter.ageno@uninsubria.it

+390332393564

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Medicinesaffectingcoagulationlistedinthe18thEMLApril2013

Heparinsodium Injection:1000IU/mL;5000IU/mL;20000IU/mLin1‐mL

ampoule

Warfarin Tablet:1mg;2mg;5mg(sodiumsalt)

1. Summarystatementoftheproposalforinclusion

Venousthromboembolism(VTE)isoneoftheleadingcausesofmorbidityand

mortalityinhospitalizedpatientsandpulmonaryembolismisresponsiblefor10%of

overalldeaths.Becausesymptomsofdeepveinthrombosisandpulmonaryembolism

arenon‐specific,atimelydiagnosisremainsdifficultandscreeningtestsforVTEare

notcost‐effective.Thus,carefulselectionofpatientsatincreasedriskandapplication

ofadequateprophylacticstrategiesisnecessarytoreducetheburdenofdisease.There

isalargeamountofevidenceshowingtheefficacyofprophylacticstrategiestoprevent

VTEinat‐riskhospitalizedpatients.Pharmacologicprophylaxiswitheitherlow‐dose

unfractionatedheparin(LDUH)orlowmolecularweightheparin(LMWH)hasbeen

showntoreducetheriskofpulmonaryembolismingeneralsurgicalpatientsby75%.

Becauseoftheirgreatereaseofuse(singledailydose)andtheirimprovedsafety

profile(thefrequencyofheparininducedthrombocytopeniaisthree‐foldlowerwith

LMWHthanwithunfractionatedheparin),LMWHhaswidelybecomethemanagement

ofchoiceforprophylaxisofVTEinthissetting.Inpatientsundergoingmajor

orthopedicsurgery,LMWHhasbeenshowntobethemosteffectiveagentbeforethe

arrivalofthedirectoralanticoagulantdrugs(DOACs)byproducinganapproximately

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70%riskreductioninVTEandiscurrentlyrecommendedasthetreatmentofchoicein

thissetting(seebelow).Itwasestimatedthatapproximatelytwooutofthreepatients

undergoingsurgicalproceduresshouldbedeemedeligibletoreceiveantithrombotic

prophylaxis.Unfortunately,theresultsofalargeobservationalstudycarriedoutin

severalcountriesthroughouttheworld(ENDORSE)reportedthatonlyabout60%of

at‐risksurgicalpatientsactuallyreceiveadequateprophylacticstrategies.However,

thisratewidelyvariedamongcountries,beinghighestinwesternEuropeancountries

andlowestinlowandmiddleincomeAsiancountries.IncountrieslikeBangladesh,

India,Pakistan,andThailand,prescriptionratesrangedbetween0.2%and16.3%.

TheserateswerehigherinNorthernAfricancountries(Egypt,Tunisia,Algeria)while

noinformationwasavailableforCentralAfricancountries.Insufficientavailabilityof

drugs,butalsoinsufficientawarenessofpost‐surgicalVTEasamajorclinicalissue

remainthemaindriversforthismajorgapbetweenevidencesandclinicalpractice.For

example,theincidenceofpost‐surgicalvenousthrombosishastraditionallybeen

thoughttobelowinAsianethnicpopulations.However,recentstudieshave

challengedthiscommonviewshowingthatthisincidenceissimilartothatreportedin

Westerncountries.Forthesereasons,webelievethatimprovingaccesstodrugswith

thehighesteffectivenessinthepreventionofVTEinsurgicalpatientshasthepotential

toreducetheburdenofdiseaseandthrombosisrelatedcostsalsoinlowandmiddle

incomecountries.However,thisimprovementcanonlybeachievedinconjunction

withanimprovedawarenessofthislife‐threateningdisease.

2. NameofthefocalpointinWHOsubmittingorsupportingtheapplication

DepartmentofEssentialMedicinesandHealthProducts(EMP/PAU)

3. Nameoftheorganizationconsultedandsupportingtheapplication

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ScientificandStandardizationCommitteeonControlofAnticoagulationofthe

InternationalSocietyonThrombosisandHaemostasis

4. InternationalNonproprietaryName(genericname)ofthemedicine

Lowmolecularweightheparin:enoxaparin,nadroparin,dalteparin,tinzaparin,

reviparin,parnaparin,certoparin,bemiparin

5. Formulationproposedforinclusion

Injectable,subcutaneous.

6. Internationalavailability–sources(manufacturersandtradenames)

Enoxaparin:Clexane/Lovenox(Sanofi‐AventisPharma),Cutenox(GlandChemical),

Dynalix(BioconLimited),Enoxarin(ZuventusHealthCare),Flothin(Ranbaxy

Laboratories),Leeparin(LeeChemBiothecPvt),Lmwx‐PFS(NicholasPiramalIndia),

Lovenox(WatsonPharmaceuticals),enoxaparin(Sandoz),Cardinex(Drug

International),Enoparin(PopularPharmaceuticals),Parinox(InceptaPharma),Novex

(Sothéma),Flumax(Hemolab‐pharma)

Nadroparin:Fraxiparin(Aspen),Seleparina(Italfarmaco),Fraxiparine

(GlaxoSmithKline),Cardioparin(ChandraBhagatPharma),Nadrohep(GlandPharma),

Nadroparin(BharatSerum&Vaccines)

Dalteparin:Fragmin(P.Upjohn),Fragmin(Eisai)

Tinzaparin:Innohep(LeoLaboratories),Innohep(RanbaxyLaboratories)

Reviparin:Clivarin(Abbott),Clivarine(Knoll),Clivarine(Abbott),Clivarina(Abbott),

Lowmorin(BayerYakuhin)

Parnaparin:Fluxum(AlfaWassermann),Fluxum(USV‐Corvette),Lowhepa

(Ajinomoto),Thromboparin(FaranLaboratories)

Certoparin:Sandoparin(Novartis),Sandoparin(Sandoz),Mono‐Embolex(Novartis)

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Bemiparin:Ivor(Rovi),Ivor(Sigma‐Tau),Ivorat(Gineladius),Zibor(Berlin‐Chemie),

Zibor(Menarini),Hibor(Biotoscana),Hibor(DemIlac),Hibor(Valmor),Hepadren

(Rovi),Badyket(Menarini)

7. Whetherlistingisrequestedasanindividualmedicineorasanexampleofa

therapeuticgroup

Weproposelowmolecularweightheparinasapharmacologicalclass.Althoughsome

pharmacokineticandpharmacodynamicdifferencesexistamongdifferentlow

molecularweightheparins,andalthoughenoxaparinhasthebestevidencefor

effectivenessandsafety,alllowmolecularweightheparinsareapprovedforthe

indicationdiscussedinthisproposalandnooneisconsistentlyavailalblewiththe

lowestpriceinallconsideredcountries.

8. Informationsupportingthepublichealthrelevance(epidemiological

informationondiseaseburden,assessmentofcurrentuse,targetpopulation)

VTEisacommondiseaseandamajorhealthproblem.Theannualincidenceratewas

estimatedtobe131.5(95%CI,130.2‐132.9)per100,000personsinarecentstudy

conductedintheUnitedKingdom(1),104(95%CI95‐114)per100,000personsinthe

UnitedStates(2),and57(95%CI47‐67)per100,000personsinAustralia(3).Case

fatalityratesat28daysafterafirstlifetimeVTEhavebeenestimatedtobe5%(95%CI

1‐9%)afteranidiopathicevent,7%(95%CI2‐13%)afteraVTEprovokedbytrauma,

surgeryorimmobilization,and25%(95%CI15‐36%)inpatientswithcancer(4).

Theincidenceoffirst‐timeVTErisesexponentiallywithage,rangingfromaverylow

rate(0.005%/year)amongchildren15yearsofage,toarateof450to600/100,000

peryear(≈0.5%/year)amongindividualsovertheageof80years(5).Ethnicityis

anothermajordeterminantofVTE.StudiescarriedoutintheUnitedStatesreporteda

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significantlyhigherincidenceofdeepveinthrombosisandpulmonaryembolismin

whitepersonsandAfrican‐AmericansthaninAsiansandPacificIslanders(6,7).

MorethanhalfofVTEeventsarerelatedtohospitalizationandare,thus,preventable

(8).Surgicalprocedures,inparticularmajororthopedicsurgeryandcancersurgery

arecommonlycomplicatedbyVTE.Studiesassessingthepresenceofasymptomatic

deepveinthrombosisbasedonobjectivediagnosticscreeningwithvenographyin

patientsnotreceivingprophylaxisreportedincidencesbetween40and60%afterhip

orkneearthroplastyandbetween15and40%aftergeneralsurgery(9).Theestimated

rateofsymptomaticVTEatapproximatelyonemonthaftermajororthopedicsurgery

is4.3%(1.5%pulmonaryembolism)inpatientsnotreceivingprophylaxisand1.8%

(PE1.55%)inpatientsreceivingthromboprophylaxiswithLMWH(10).Inalarge

prospectivestudycarriedoutinpatientsundergoingcancersurgery,thereported

incidenceofsymptomaticVTEwas2.8%afterabdominalsurgery,with87%ofthese

patientsreceivingin‐hospitalprophylaxiswithLMWH(11).Theefficacyandsafetyof

pharmacologicprophylaxisinsurgicalpatientshasbeenconsistentlyshownbythe

resultsofseveralrandomizedcontrolledtrialsandmeta‐analysesandclinical

guidelinesrecommendthatallpatientsundergoinghigh‐riskproceduresshould

receiveappropriatetreatment(10,12).LMWHisconsideredthetreatmentofchoice

forpatientsundergoingmajororthopedicsurgery,beingpreferredoverothereffective

alternativessuchasfondaparinux,LDUH,adjusted‐dosevitaminKantagonists(VKA)

ortheDOACs(10).Thispreferenceisduetothefavourableefficacyandsafetyprofile,

tothefavourablecost‐effectiveness,andtotheverylargeexperiencewiththeuseof

theseagentsworldwide.LMWHisalsorecommendedforhigh‐risksurgicalpatients,

withLDUHorfondaparinuxaspotentialalternatives(12).LMWHisinparticular

proposedforpatientsundergoingabdominalorpelviccancersurgery(12).

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Despiteclear‐cutrecommendations,prescriptionratesofadequate

thromboprophylacticstrategiesremainbelowexpectation.In2008,amultinational,

cross‐sectionalstudy,ENDORSE,reportedtheprevalenceofVTEriskintheacute

hospitalcaresettingandtheratesofat‐riskpatientswhoreceivedeffective

prophylaxisaccordingtorecommendationsfrominternationalguidelines(13).Two‐

thirds(64.4%)ofsurgicalpatientsweredefinedat‐riskforVTE,butonly58.5%of

themreceivedrecommendedVTEprophylaxis.Thestudywascarriedoutinall

continentsandprovidedaninterestingoverviewofdifferencesamongcountries.What

cameoutmoststrikinglyfromthisstudy,albeitnotsurprisingly,wastheverylowrate

ofprescriptionofadequateprophylacticstrategiesdocumentedinsomecountries,

withthelowestratesbeingdocumentedinBangladesh(0.2%),Thailand(0.2%),

Pakistan(10%),India(16%),Venezuela(23%),Russia(26%),SaudiArabia(32%),

Egypt(35%),Turkey(39%),UnitedArabEmirates(43%),Mexico(43%),Colombia

(43%),andBrazil(46%).Reasonsfortheselowprescriptionratesincludelackof

availabilityofrecommendedtherapeuticstrategies,costsofavailabledrugs,concern

aboutbleeding,difficultywithassessingrisklevelofpatients,andlackofawarenessof

VTEasarealprobleminsurgicalpatients.Thislastissuepossiblycontributesto

explainthelowestratesobservedinAsiancountries.Epidemiologicalstudiesfrom

AsiancountriesreportedVTEratesthatarelowerthanthosereportedinWestern

countries(14‐16),althoughayearlyincreasingincidenceandprevalenceofvenous

thrombosiswasconsistentlyshown(14,16),inparticularamonghospitalizedpatients.

Theseincreasingratessuggestedapossibleshiftinperceptionoftheimportanceofthe

disease,ahigherindexofsuspicionandalowerthresholdforperformingdiagnostic

tests(16),buttheuseofthromboprophylaxisremainedextremelylow.Theneedfor

suchashiftisfurthersupportedbyevidencefromprospectiveobservationalstudies

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thatinAsianpatientstheincidenceofsymptomaticVTEafterhighrisksurgeryisnot

negligible(1.5%atonemonth)(17).Forthisreason,inthe“Asia‐PacificThrombosis

AdvisoryBoardconsensuspaperonpreventionofvenousthromboembolismafter

majororthopaedicsurgery”itwasagreedthatVTErepresentsathreatalsotoAsian

patientsandthatcurrentinternationalguidelinerecommendationsfortheroutineuse

ofpostoperativethromboprophylaxisshouldbeimplementedinAsia.Scant

informationisavailablefromotherlowincomecountriesinAfricaorSouthAmerica,

butitishighlylikelythatprescriptionratesinthesecountriesarenobetterthanthose

reportedfromcountriesparticipatingintheENDORSEstudy,thusleavingmillionof

patientsreceivingsurgicalproceduresatincreasedriskofpulmonaryembolismand,

thus,ofVTErelatedmortality.Forexample,across‐sectionalstudycarriedoutin12

hospitalsinSenegalidentified60.3%surgicalpatientsatriskforVTE,ofwhom37.5%

receivedthromboprophylaxis(18).

Forthisreason,thefirsttargetpopulationforthisproposalisrepresentedbyat‐risk

surgicalpatients(usingdefinitionsproposedbyinternationalguidelines)admittedto

hospitalslocatedinlowandmiddleincomecountriesinallcontinents.

9. Treatmentdetails(dosageregimen,duration;referencetoexistingclinical

guidelines;needfortreatmentmonitoringfacilities)

Enoxaparin2000IUqd(moderaterisksurgicalpatients),4000IUqd(highrisk

surgicalpatients,includingmajororthopedicsurgeryinEurope),3000UIbid(major

orthopedicsurgeryintheUS);nadroparin2850IU(generalsurgerypatientsand

majororthopedicsurgerypatients<50kgbodyweight),3800IUqd(majororthopedic

surgerypatients50‐69kgbodyweight),5700IUqd(majororthopedicsurgery>70

kg);dalteparin2500IU(generalsurgery)and5000IUqd(majororthopedicsurgery);

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tinzaparin3.500IUqd(generalsurgerypatients)and50IU/Kgqd(majororthopedic

surgery);reviparin1750IUqd(generalsurgerypatients)and4.200IUqd(major

orthopedicsurgery),parnaparin3.200IUqd(generalsurgerypatients)and4250IUqd

(majororthopedicsurgerypatients);certoparin3000IUqd,bemiparin2500IUqd

(generalsurgerypatients)and3500IUqd(majororthopedicsurgerypatients).

Recommendeddurationofprophylaxisvariesaccordingtosurgicalprocedures.

Extendeddurationpharmacologicprophylaxisisrecommendedforhigh‐riskpatients

undergoingabdominalorpelvicsurgeryforcancer(4weeks)(12)andforpatients

undergoingmajororthopedicsurgery(35days)(10).

Plateletcountmonitoringiscurrentlyrecommendedforpatientsreceivingheparinin

whomcliniciansconsidertheriskofheparininducedthrombocytopeniatobehigher

than1%(19).Forthesepatients,plateletcountmonitoringshouldbeperformedevery

2or3daysfromday4today14,oruntilheparinisstopped(19).Basedonavailable

evidence,theincidenceofheparininducedthrombocytopeniainpostoperative

patientsreceivingLDUHrangesbetween1and5%,inpatientsreceivingLMWH

between0.1and1%(19).

Publichealthneedandevidenceappraisalandsynthesis

10. Summaryofcomparativeeffectiveness(identificationofclinicalevidence,

summaryofavailabledata,summaryofavailableestimatesofcomparative

effectiveness)includingsummaryevidencetableswithGradingof

recommendations

LMWHsweretestedagainstvariouscomparatorsinseveralrandomizedcontrolled

trialsindifferentat‐risksurgicalpopulations.Takingintoaccountthatthereare

severaldifferencesbetweenorthopedicandnon‐orthopedicsurgery,especiallywith

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regardtotheriskofVTE,thesetwogroupsofsurgeriesarepresentedseparately

hereafter.

NonOrthopedicSurgery

‐LMWHversusnoprophylaxis(Table1)

Ameta‐analysisofeighttrialsconductedingeneralandabdominalsurgeryshoweda

reductionoftheriskofsymptomaticVTEofabout70%(riskratio[RR]0.31,95%CI

0.12‐0.81)inpatientswhoreceivedLMWHascomparedtonoprophylaxis(20).

Furthermore,deathfromanycausewaspossiblyreducedbyabout50%(RR0.54,

95%0.27‐1.10)(20).Thesedatahavebeenmorerecentlyconfirmedinameta‐

analysiswhichincludedstudiesofgastrointestinal,gynecologic,urological,and

thoracicsurgery(21).

‐LMWHversusLDUH(Table2)

Resultsfromameta‐analysisof51trialsonmorethan48000generalandabdominal

surgerypatientsshowedthattheriskofsymptomaticVTEwasreducedbyabout30%

(RR0.71,95%0.51‐0.99)inpatientswhoreceivedLMWHascomparedtoLDUH(20).

Thesedatahavebeenconfirmedinamorerecentmeta‐analysisincluding

gastrointestinal,gynecologic,urological,andthoracicpatients(21).

‐LMWHversusfondaparinux

ArandomizedcontrolledtrialwasconductedinpatientsathighriskofVTEwho

underwentabdominalsurgery(22),comparingfondaparinuxtodalteparin.Theresults

showedthatfondaparinuxwasnon‐inferiortodalteparinatreducingthecomposite

outcomeofdeepveinthrombosisdetectedbybilateralvenographyandsymptomatic,

confirmeddeepveinthrombosisorpulmonaryembolism(relativeriskreduction24.6

percent,95%CI‐9.0to47.9).

‐LMWHversusmechanicalprophylaxis

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Dataarelimitedtoonestudyontraumapatients(23)andonestudyongynecologic

oncologypatients(24).Inthefirsttrialtherewasnostatisticallysignificantdifference

intherateofasymptomaticandsymptomaticDVTbetweenpatientswhoreceived

LMWHascomparedtointermittentpneumaticcompression(0.5%versus2.7%,

respectively,p=0.122).Intheothertrial,DVTwasdiagnosedin2outof105patients

receivingLMWHandin1outof106patientsreceivingexternalpneumatic

compression,thusleadingtheauthorstoconcludeforasimilareffectofthetested

interventionsinthepostoperativeprophylaxisofthromboembolism.

Asubgroupanalysisofarecentmeta‐analysis(25),thatincludedalltypeofmechanical

compressions(pneumaticcompression,footcompressionandgraduatedcompression

stockings)ascomparedtoLMWHinseveralgroupsofsurgicalpatients,including

orthopedicones,foundasignificantyhigherriskofDVTamongpatientswhoreceived

mechanicalcompressionascomparedtoLMWH(RR1.80,95%1.16‐2.79).

NotrialsareavailableforcomparisonofLMWHwithaspirin,warfarinorneworal

anticoagulantsinnonorthopedicsurgery.

Basedontheavailableevidence,in2012theAmericanCollegeofChestPhysician

providedanupdatedversionoftheevidence‐basedclinicalpracticeguidelinesforthe

preventionofthrombosisinnonorthopedicsurgicalpatients(12).TheGradingof

RecommendationsAssessment,DevelopmentandEvaluation(GRADE)systemwas

usedtoassesstheevidenceandtoformulaterecommendations(Table3)(26).

Inthecontextofnon‐orthopedicsurgery,therecommendationsontheuseof

thromboprophylaxisarebasedonatrade‐offbetweentheriskofVTEandtheriskof

majorbleedingaftersurgery,thatcanbestratifiedaccordingtoseveralpatient‐and

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surgery‐relatedvariables.TheriskofVTEcanbeconsideredverylow(<0.5%),low

(~1.5%),moderate(~3.0%)andhigh(~6.0%).Ontheotherhand,theriskofmajor

bleedingcanbeconsideredaverage(~1%)orhigh(~2%).Bleedingriskisalso

consideredhighwhenbleedingcomplicationsmayhaveespeciallysevere

consequences(egaftercraniotomy,spinalsurgery,reconstuctiveproceduresinvolving

freeflap).

Recommendationsfortheuseofthromboprophylaxisinnonorthopedicsurgeryare

summarizedinTables4.

OrthopedicSurgery

‐LMWHversusnoprophylaxis(Table5)

Inmajororthopedicsurgery,thatincludestotalhiparthroplasty(THA),totalknee

arthroplasty(TKA)andhipfracturesurgery(HFS),theriskofsymptomaticVTEwas

calculatedfromdataofclinicaltrialsenrollingmorethan16000patients,asfollows:

2.80%(PE1.0%,DVT1.80%)intheinitialpost‐operativeperiod(days0to14)and

1.50%(PE0.50%,DVT1.00%)intheextendedpost‐operativeperiod(days15‐35),for

acumalativepost‐operativeVTEincidenceof4.3%(PE1.50%,DVT1.80%)(10).

Intheinitialpost‐operativeperiod,thebestevidencesuggeststhatLMWHconsistently

reducesDVTbyabout50%afterTHAorTKA(combinedriskratio[RR],0.50,95%CI

0.43‐0.59),withsimilarresultsemergingalsoforHFS.Combiningresultsfromall

relevantstudiesfailedtodemonstrateortoexcludeabeneficialeffectofLMWHonPE

(RR0.58,95%CI0.22‐1.47)(10).

Intheextendedpost‐operativeperiodaftermajororthopedicsurgery,LMWHwas

associatedwithastatisticallysignificantreductionofsymptomaticDVT(RR0.46,95%

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CI0.26‐0.82),whereasabeneficialeffectonPEwasneitherdemonstratednor

excluded(RR0.24,95%0.04‐1.4)(10).

‐LMWHversusLDUH(Table6)

LMWHandLDUHhavebeencomparedintheinitialprophylaxisaftermajor

orthopedicsurgery.Asubgroupanalysisofasystematicreviewoftrialscomparing

LMWHandUFHincluded2800patientswhounderwentarthroplastyorHFS(27).The

resultsshoweda20%relativeriskreductionofprimarilyasymptomaticDVTinfavor

ofLMWH(RR0.80,95%CI0.73‐0.88)whereastheyfailedtodemonstrateorexcludea

beneficialeffectofLMWHonPE(RR0.78,95%CI0.49‐1.24).

‐LMWHversusVitaminKantagonists(VKAs)(Table7‐8)

LMWHhasbeencomparedtoVKAsinmorethan9000patientsinseveraltrialsforthe

initialpost‐operativeperiodafterTHAandTKA.Thecombinedresultsshoweda

significantlyreducedriskofsymptomaticDVTassociatedwithLMWH(RR0.68,95%

CI0.6‐0.78),whereastheyfailedtoestablishorrefuteadifferenceinPE(RR0.68,95%

CI0.22‐2.1)(10).

Withregardtotheextendedprophylaxis,onlyonetrialenrollingmorethan1200

patientscomparedLMWHwithVKA.TherewerenoPEintheLMWHgroupas

comparedto4outof636intheVKAgroup.Nostatisticallysignificantdifferencewas

foundintherateofasymptomaticDVTintheVKAarmascomparedtoLMWHarm(RR,

1.35;95%CI,0.70‐2.6)(28).

‐LMWHversusaspirin(ASA)(Table9)

Evidenceislimitedforthehead‐to‐headcomparisonbetweenLMWHandASA.The

pooledestimatefromtwotrialsinpatientsundergoingTHAorTKAshowedahigher

incidenceofasymptomaticDVTassociatedwithaspirincomparedtoLMWH(RR1.87,

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95%CI1.3‐2.7),whereasPEweretoofewtoprovideanaccurateestimateandno

majorbleedingeventswerereported(10,29,30)

‐LMWHversusfondaparinux(Table10)

SeverallargetrialscomparedfondaparinuxwithLMWHfortheinitialVTEprophylaxis

aftermajororthopedicsurgery.Thepooledresultsfailedtodemonstrateorexcludea

beneficialeffectoffondaparinuxonsymptomaticDVT(RR1.31,0.47‐3.7)andPE(RR

1.32,0.37‐4.74)(10).

‐LMWHversusneworalanticoagulants(Table11)

Severaltrialshavebeenconductedmorerecentlytocompareanewgenerationoforal

anticogulantdrugs(twodirectfactor‐Xainhibitors,rivaroxabanandapixaban,andone

directthrombininhibitor,dabigatran)withLMWHafterTKAorTHA.

Morethan10000patientswereenrolledinrandomizedcontrolledtrials(RCTs)

comparingrivaroxabanwithLMWH.Thepooledresultsshowedastatistically

significantreductioninsymptomaticDVTinrivaroxabanarms(RR0.41,95%CI0.2‐

0.83),whereastheyfailedtotodemonstrateorexcludeabeneficialeffectof

rivaroxabanonPE(RR1.34,95%CI0.39‐4.6)(10).

FourRCTscompareddabigatranwithLMWHinpatientsundergoingTHAorTKA,

enrollingmorethan10000patients.Thepooledestimatesfailedtodemonstrateor

excludeadifferenceinthenumberofsymptomaticVTEsforbothdabigatrandose

regimensof220mg(PE:RR1.22,95%CI,0.52‐2.85;DVT:RR0.7,95%CI0.12‐3.91)

and150mg(PE:RR0.31,95%CI0.04‐2.48;DVT:RR1.52,95%CI0.45‐5.05),as

comparedtoLMWH(10).

Finally,apixabanwascomparedtoLMWHinfourRCTsenrollingmorethan12000

patientsundergoingTHAorTKA.Thepooledanalysisfoundthatapixabansignificantly

reducedsymptomaticDVTby59%(RR0.41,95%CI0.18‐0.95),butfailedto

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demonstrateabeneficialordetrimentaleffectonnonfatalPE(RR1.09,95%CI0.31‐

3.88)(10).

‐LMWHversusmechanicalprophylaxis(Table12)

Pneumaticcompressiondevices(i.e.intermittentpneumaticcompressiondeviceand

venousfootpump)werecomparedwithLMWHinmorethan1000patients

undergoingTHAandTKA.Overall,therewastrendassociatedwithcompression

devicestowardanincreaseinasymptomaticDVT(RR1.38,95%CI0.92‐2.06)andin

nonfatalPE(RR2.92,0.12‐71),evenifnotstatisticallysignificant(10).

Basedontheavailableevidence,in2012theAmericanCollegeofChestPhysician

providedanupdatedversionoftheevidence‐basedclinicalpracticeguidelinesforthe

preventionofthrombosisinorthopedicsurgicalpatients(10).Similarlytothe

methodologyusedfornon‐orthopedicsurgery,theGradingofRecommendations

Assessment,DevelopmentandEvaluation(GRADE)systemwasusedtoassessthe

evidenceandtoformulatetherecommendations(Table3)(26).

Inthecontextoforthopedicsurgery,therecommendationsontheuseof

thromboprophylaxisarebasedonatrade‐offbetweentheriskofVTEandtheriskof

majorbleedingaftersurgery.Formajororthopedicsurgery,differentlyfromnon‐

orthopedicsurgery,thesurgery‐specificriskofVTEfaroutweightsthecontributionof

thepatient‐specificfactors.Indeed,noindividualriskestimationwassufficiently

secureinthisclinicalcontexttomandatedifferentrecommendationsfordifferentrisk

strata.Therefore,recommendationsforthepreventionofVTEinorthopedicsurgery

(summarizedinTable13)arenotbasedonanindividualstratificationoftheriskof

VTEandbleeding.

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11. Summaryofcomparativeevidenceonsafety(descriptionofadverse

effects/reactions;identificationofvariationinsafetyduetohealthsystemsand

patientfactors;summaryofcomparativesafetyagainstcomparators)including

summaryevidencetableswithGradingofrecommendations

TheevaluationofsafetyrelatedtoLMWHincludeshemorrhagicandnonhemorrhagic

complications.

Hemorrhagiccomplications

Withregardtotheriskofbleedingassociatedwiththeuseofthromboprophylaxis

aftersurgicalintervention,adistinctionbetweenorthopedicandnon‐orthopedic

surgeryismadeandthetwogroupsofsurgeryarepresentedseparatelyhereafter.

NonOrthopedicsurgery

‐LMWHversusnoprophylaxis(Table14)

Ameta‐analysisofeighttrialsconductedingeneralandabdominalsurgeryshowedan

approximatedoublingoftheriskofmajorbleeding(RR2.03,95%CI1.37‐3.01)and

woundhematoma(RR1.88,95%CI1.54‐2.28)associatedwithLMWH,ascomparedto

noprohylaxis(20).Thesedatahavebeenmorerecentlyconfirmedinameta‐analysis

whichincludedstudiesofgastrointestinal,gynecologic,urological,andthoracic

surgery(21).

‐LMWHversusLDUH(Table14)

Resultsfromameta‐analysisof51trialsonmorethan48000generalandabdominal

surgerypatientsfailedtodemonstrateortoexcludeabeneficialeffectofLMWHas

comparedtoLDUHonmajorbleedingandwoundhematoma(RR0.89,95%CI0.75‐

1.05)(20).Thesedatahavebeenconfirmedinamorerecentmeta‐analysisincluding

gastrointestinal,gynecologic,urological,andthoracicpatients(21).

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‐LMWHversusfondaparinux

Arandomizedcontrolledtrialcomparedfondaparinuxtodalteparininpatientsathigh

riskofVTEwhounderwentabdominalsurgery(22).Theresultsshowedapossible

increaseintheriskofnonfatalmajorbleedingwithfondaparinux(RR1.43,95%CI

0.93‐2.21),butdifferencesintherisksoffatalbleedingandbleedingrequiring

reoperationwereneitherconfirmednorexcluded.

‐LMWHversusmechanicalprophylaxis

Specificdataforthiscomparisonarelimitedtoonestudyontraumapatients(23)and

onestudyongynecologiconcologypatients(24).Inthefirsttrialtherewasno

statisticallysignificantdifferenceintherateofmajorbleedingbetweenpatientswho

receivedLMWHascomparedtointermittentpneumaticcompression(4ineach

group).Intheothertrial,thefrequencyofbleedingcomplications,measuredbythe

numberofrequiredperioperativetransfusions,andestimatedintraoperativeblood

losswassimilarbetweenthetwogroups.

Asubgroupanalysisofarecentmeta‐analysis(25,28),thatcomparedalltypesof

mechanicalcompression(pneumaticcompression,footcompressionandgraduated

compressionstockings)toLMWHinseveralgroupsofsurgicalpatients,including

orthopedicones,foundastatisticallysignificantreductionintheriskofmajorbleeding

withcompressiondevicesascomparedtoLMWH(RR0.51,95%CI0.40,0.64)

‐NotrialsareavailableforcomparisonofLMWHwithaspirin,warfarinorneworal

anticoagulants.

Orthopedicsurgery(Table15)

‐LMWHversusnoprophylaxis

18

Inmajororthopedicsurgery,thebaselineriskofmajorbleedingwasestimatedforthe

initialpost‐operativeperiod(days0to14)fromtheplaceboarmofLMWHtrials,

resultinginamedianrateof1.5%(10).Thisestimateisconsistentwiththatfoundina

systematicreview,rangingfrom1%to2%(27).Theexpectedriskofmajorbleeding

withLMWHhasbeenshowntobeveryclosetothatofplacebo,withalargeCI(RR

0.81,95%CI0.38‐1.72)(10,31).

Similarly,intheextendedpost‐operativeperiod(days15to35),resultsfromameta‐

analysisfailedtodemonstrateorexcludeaneffectofLMWHonmajorbleeding(RR

0.43,95%CI0.11‐1.65)(10).

‐LMWHversusLDUH

LMWHandLDUHhavebeencomparedintheinitialprophylaxisaftermajor

orthopedicsurgery.Asubgroupanalysisofasystematicreviewoftrialscomparing

LMWHandUFHincluded2800patientswhounderwentarthroplastyorHFS(27).The

pooledanalysisfailedtodemonstrateorexcludeabeneficialeffectofLMWHas

comparedtoUFH(RR0.91,95%CI0.75‐1.09).

‐LMWHversusVKAs

LMWHhasbeencomparedtoVKAsinmorethan9000patientsinseveraltrialsforthe

initialpost‐operativeperiodafterTHAandTKA.Thecombinedresultsshowedno

significantdifferenceinmajorbleedingevents(RR1.36,95%CI0.95‐1.96).

Withregardtotheextendedprophylaxis,onlyonetrialenrollingmorethan1200

patientscomparedLMWHwithVKA.Asubstantialincreaseinmajorbleedingwas

foundwithVKAs(RR3.9,95%CI1.9‐8.1)(10).

‐LMWHversusaspirin(ASA)

19

Evidenceislimitedforthehead‐to‐headcomparisonbetweenLMWHandASA.Inthe

twotrialsinpatientsundergoingTHAorTKAnomajorbleedingeventswerereported

inbotharms(29,30).

‐LMWHversusfondaparinux

SeverallargetrialscomparedfondaparinuxwithLMWHfortheinitialVTEprophylaxis

aftermajororthopedicsurgery.Thepooledresultsshowasignificantincreasein

bleedingrequiringre‐operationassociatedwithfondaparinux(RR1.85,95%CI1.1‐

3.11),eveniftherewasnotastatisticallysignificantdifferenceintherateofmajor

bleeding(RR1.35,95%CI0.89‐2.05)(10).

‐LMWHversusneworalanticoagulants

Severaltrialshavebeenrecentlyconductedtocompareanewgenerationoforal

anticogulantdrugs(twodirectfactor‐Xainhibitors,rivaroxabanandapixaban,andone

directthrombininhibitor,dabigatran)withLMWHafterTKAorTHA.

Withregardtorivaroxaban,inapooledanalysisofseventrialsenrollingmorethan

10000patients,therewasatrendtowardincreasedmajorbleedingandbleeding

requiringreoperation,althoughnotstatisticallysignificant(majorbleeding:RR1.58

95%CI,0.84‐2.97;bleedingrequiringreoperation:RR2.095%CI0.86‐4.83;

combined:RR1.73,95%CI,0.94‐3.17)(10).

FourRCTscompareddabigatranwithLMWHinpatientsundergoingTHAorTKA,

enrollingmorethan10000patients.Thepooledestimatesfailedtodemonstrateor

excludeadifferenceinthenumberofmajorbleedingeventsforbothdabigatran

dosageregimensof220mg(RR1.06,95%CI,0.66‐1.72)and150mg(RR0.71,95%CI

0.42‐1.19)(10).

20

Finally,apixabanwascomparedtoLMWHinfourRCTsenrollingmorethan12000

patientsundergoingTHAorTKA.Thepooledanalysisfailedtodemonstrateorexclude

adifferenceinthenumberofmajorbleeding(RR0.76,95%CI0.44‐1.32)(10).

‐LMWHversusmechanicalprophylaxis

Pneumaticcompressiondevices(i.e.intermittentpneumaticcompressiondeviceand

venousfootpump)werecomparedwithLMWHinmorethan1000patients

undergoingTHAandTKA.Thepooledanalysisshowedastatisticallysignificant

reductionoftheriskofmajorbleedingassociatedwithcompressiondevices(RR,0.32,

95%CI0.12‐0.89)(10).

Non‐hemorrhagiccomplications

Heparininducedthrombocytopenia(HIT).Thispotentiallyseverecomplicationis

representedbyafallinplateletcountafterexposuretoheparinandanassociatedpro‐

thromboticsyndrome.Indeed,heparin‐dependentIgGantibodiesbindto

multimolecularcomplexesconsistingofplateletfactor4boundtoheparin,thus

causingplateletsactivation(withreleaseofhighlyprothromboticmicroparticles)and

theirremovalfromthecirculation(withconsequentthrombocytopenia).

SeveralfactorsinfluencetheincidenceofHIT,includingthetypeandpreparationof

heparin(UFHorLMWH)andtheheparin‐exposedpatientpopulation,withthe

postoperativepatientspresentingahigherrisk.

ArecentCochranesystematicreviewandmeta‐analysisspecificallycomparedthe

incidenceofHITafterexposuretoUFHorLMWHafteranysurgicalintervention.The

resultsshowastatisticallysignificantreductionintheriskofHITwithLMWHas

comparedtoUFH(riskratio0.24,95%CI0.07‐0.82)(32).

21

Osteoporosis.Inadditiontoitsanticoagulanteffects,heparinbindstoanumber

ofproteinsandcells,includingosteoblasts,whichthenreleasefactorsthatactivate

osteoclastsandpromoteboneloss.ComparedtoUFH,LWMHhasloweraffinityfor

proteinsandcells,resultingalsoinadecreasedbindingtoosteoblasts.

Long‐termuseofUFHhasbeenassociatedwitha2.2–5%incidenceofheparin‐induced

osteoporoticfracture,butaccuratedataforLMWHdataarescarce.Indeed,arecent

systematicreviewidentifiedonly9casesofLMWH‐inducedosteoporosisfrom13

articles(33).Withregardtothecomparisonoftheriskofosteoporosisbetween

heparins,onlytwosmalltrialshavebeenconducted,bothinpregnantwomenwho

havebeenassignedtoreceiveprophylacticdosesofUFHorLMWHduringpregnancy.

Inthefirsttrial,meanbonedensityofthelumbarspinewassignificantlylowerinthe

UFHgroupthanintheLWMHgroup.Moreover,bonedensitymeasurementsdidnot

differbetweentheLMWHgroupandacontrolgroupofhealthyuntreatedwomen(34).

Inthesecondtrial,oneoutof49women(2.3%)intheLMWHgrouphadsignificant

bonelossatthetotalproximalfemur(definedasadecreaseof>10%),comparedwith

noneofthe40patientsintheUFHgroup(35).Theauthorsoftheabovementioned

systematicreviewconcludethat,untillargeclinicaltrialsaredesignedtoinvestigate

pre‐andpost‐treatmentbonedensityandtocomparedifferentdosagesofLMWH

effectonthebonedensityindifferentpatientgroups,noaccurateconclusionscanbe

madeontheriskofosteoporosisrelatedtoLMWH.

12. Summaryofavailabledataoncomparativecostsandcost‐effectivenesswithin

thepharmacologicalclassortherapeuticgroup(rangeofcostsoftheproposed

medicine;comparativecost‐effectivenesspresentedasrangeofcostperroutine

outcome)

22

CollectingdatafromdifferentcountiesincludingAlgeria,Argentina,Brazil,India,Morocco,

Thailand,Tunisia,andUganda,thecostsofprophylacticdosesofLMWHrangedfrom2.25

to9.5USDperdoseforthe20mgprophylacticdoseofenoxaparin(20mg)to4.75to18.5

USDperdoseforthe40mgprophylacticdoseofenoxaparin,thatisthemostwidelyused

LMWHacrosscountries.BiosimilarLMWHcanbefoundatlowercosts,whereavailable.

Studiesassessingthecost‐effectivenessofVTEprophylaxisinhospitalizedpatientshave

beencarriedoutinWesterncountries.Theuseofpharmacologicprophylaxiswasrecently

confirmedtobeassociatedwithsubstantialcostsavingsinstudiesfromAustralia,Europe

andNorthAmerica(36‐38).ThetotalcostofprophylaxiswithLMWHwaslowerthanthe

costwithUFHinapopulationofhighriskmedicalpatients(39).Nocost‐effectiveness

studiesofVTEprophylaxisareavailablefromdevelopingcountries.However,cost‐

effectivenessstudiescomparingLMWHandUFHforthetreatmentofacuteVTEfrom

ChinaandBrazilfoundlowercostswiththeformerthanwiththelatter(40,41).

Regulatoryinformation

13. Summaryofregulatorystatusofthemedicine(differentcountries)

Inallcountries,LMWHisapprovedforthepreventionofVTEinsurgicalpatientswith

moderateorhighriskforVTE;forthepreventionofVTEinmedicalpatientswith

congestiveheartfailure(NYHAclassIIIorIV),respiratoryfailure,acuteinfectionoracute

rheumatologicdiseasewithatleastoneriskfactorforVTE;forthepreventionofblood

clotintheextra‐corporealcirculationduringhemodialysis;fortreatmentofDVTwithor

withoutPE;forthetreatmentofunstableanginaandnon‐Q‐waveAMI(inconjunction

withaspirin);forthetreatmentofAMIwithST‐segmentelevation.Indicationsmayvary

acrossLMWHs

23

14. Availabilityofpharmacopoeialstandards

BritishPharmacopoeia:Yes

InternationalPharmacopoeia:Yes

UnitedStatesPharmacopoeia:Yes

EuropeanPharmacopoeia:Yes

15. ProposedtextfortheWHOModelFormulary

Basedoncurrentevidence,medicinesinthefollowingtwoclassesofparenteral

anticoagulants(UFHandLWMH)areincludedasessentialmedicinesforthe

preventionofvenousthromboembolisminhospitalizedpatientsundergoinghighrisk

surgicalprocedures(e.g.cancersurgeryandmajororthopedicsurgery).WHO

recommendsandendorsesthelocalimplementationofprotocolsforVTEprevention

andemphasizestheimportanceofusingtheseproductsinaccordancewith

internationalandnationalguidelines.LMWHhaveadvantagesoverUFHandshouldbe

preferredwhereavailable.

24

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31

Table1.RiskofVTEinnonorthopedicsurgery:LMWHversusnoprophylaxisOutcomes Baselinerisk RiskLMWH

(95%CI)Relativeeffect(95%CI)

FatalPE Lowrisk RR0.54(0.27‐1.1)3per1000 2per1000(1‐3)

Intermediaterisk6per1000 3per1000 (2‐7)

Highrisk12per1000 6per1000(3‐13)

SymptomaticVTE Lowrisk RR0.31(0.12‐0.81)15per1000 5per1000(2‐12)

Intermediaterisk30per1000 9per1000(4‐24)

Highrisk60per1000 19per1000(7‐49)

Table2.RiskofVTEinnonorthopedicsurgery:LMWHversusLDUHOutcomes RiskLDUH RiskLMWH(95%

CI)Relativeeffect(95%CI)

FatalPE Lowrisk RR1.04(0.89‐1.2)3per1000 3 per1000(1‐3)

Intermediaterisk6per1000 6 per1000(2‐7)

Highrisk12per1000 12 per1000(3‐13)

SymptomaticVTE Lowrisk RR0.71(0.51‐0.99)7per1000 5per1000(4‐7)

Intermediaterisk13per1000 9per1000(7‐13)

Highrisk26per1000 18 per1000(13‐26)

32

Table3.Strenghtofrecommendationsgradingsystem

GradeofRecommendation BenefitvsRiskandBurdens

MethodologicStrengthofSupportingEvidence

Strongrecommendation,high‐qualityevidence(1A)

Benefitsclearlyoutweighriskandburdensorviceversa

Consistentevidence fromrandomizedcontrolledtrialswithoutimportantlimitationsorexceptionallystrongevidencefromobservationalstudies

Strongrecommendation,moderate‐qualityevidence(1B)

Benefitsclearlyoutweighriskandburdensorviceversa

Evidencefromrandomizedcontrolledtrialswithimportantlimitations(inconsistentresults,methodologicflaws,indirectorimprecise)orverystrong

evidencefromobservationalstudies

Strongrecommendation,low‐orvery‐low‐qualityevidence(1C)

Benefitsclearlyoutweighriskandburdensorviceversa

Evidenceforatleastonecriticaloutcomefromobservational

studies,caseseries,orrandomizedcontrolledtrials,withseriousflawsorindirect

evidenceWeakrecommendation,high‐qualityevidence(2A)

Benefitscloselybalancedwithrisksandburden

Consistentevidencefromrandomizedcontrolledtrialswithoutimportantlimitationsorexceptionallystrongevidencefromobservationalstudies

Weakrecommendation,moderate‐qualityevidence(2B)

Benefitscloselybalanced withrisksandburden

Evidencefromrandomizedcontrolledtrialswithimportantlimitations(inconsistentresults,methodologicflaws,indirectorimprecise)orverystrong

evidencefromobservationalstudies

Weakrecommendation,low‐orvery‐low‐qualityevidence(2C)

Uncertaintyintheestimatesofbenefits,risks,andburden;

benefits,risk,andburdenmaybecloselybalanced

Evidenceforatleastonecriticaloutcomefromobservational

studies,caseseries,orrandomizedcontrolledtrials,withseriousflawsorindirect

evidence

33

Table4.Recommendationsforthromboprophylaxisinvariousriskgroupsinnonorthopedicsurgery RiskofmajorbleedingRiskofsymptomaticVTE

Averagerisk(~1%) Highrisk(~2%)orseverecomplications

Verylow(<0.5%) NospecificprophylaxisLow(~1.5%) MechanicalprophylaxisModerate(~3%) LMWH(Grade2B)or

LDUH(Grade2B)orMechanicalprophylaxis(Grade2C)

Mechanicalprophylaxis(Grade2C)

High(~6%) LMWH(Grade1B)or LDUH(Grade1B)plus

Mechanicalpropylaxis(Grade2C)

Mechanicalprophylaxisuntilriskofbleedingdiminishesand

pharmacologicprophylaxiscanbeadded(Grade2C)

Table5.RiskofVTEinmajororthopedicsurgery:LMWHversusnoprophylaxisOutcomes Baselinerisk Riskdifferencewith

LMWH(95%CI)Relativeeffect(95%CI)

NonfatalPE Initialprophylaxis 0.58(0.22‐1.47)10per1000 4fewerper1000

(from8fewerto5more)Extendedprophylaxis 0.24(0.04‐1.4)

5per1000 4fewerper1000(from5fewerto2more)

SymptomaticDVT Initialprophylaxis 0.5(0.43‐0.59)18per1000 9fewer per1000

(from7fewerto10fewer)Extendedprophylaxis 0.46(0.26‐0.82)

10per1000 5fewerper1000(from2fewerto7fewer)

Table6.RiskofVTEinmajororthopedicsurgery:LMWHversusLDUHOutcomes RiskLDUH Riskdifferencewith

LMWH(95%CI)Relativeeffect(95%CI)

PE Initialprophylaxis 0.78(0.49‐1.24)4per1000 1 fewerper1000

(from2fewerto1more)SymptomaticDVT Initialprophylaxis 0.80(0.73‐0.88)

12per1000 2fewer per1000(from2fewerto3fewer)

34

Table7.RiskofVTEinmajororthopedicsurgery:LMWHversusVKAs‐initialprophylaxisOutcomes RiskVKAs Riskdifferencewith

LMWH(95%CI)Relativeeffect(95%CI)

NonfatalPE Initialprophylaxis 0.68(0.22‐2.1)2per1000 1 fewerper1000

(from2fewerto3more)SymptomaticDVT Initialprophylaxis 0.68(0.6‐0.78)

5per1000 2fewer per1000(from1fewerto2fewer)

Table8.RiskofVTEinmajororthopedicsurgery:VKAsversusLMWH‐extendedprophylaxisOutcomes RiskLMWH RiskdifferencewithVKAs

(95%CI)Relativeeffect(95%CI)

NonfatalPE Extended prophylaxis 9.1(0.49‐169)6per1000 45 more per1000

(from5fewerto96more)SymptomaticDVT Extended prophylaxis 1.35(0.7‐2.6)

12per1000 4fewer per1000(from4fewerto20more)

Table9.RiskofVTEinmajororthopedicsurgery:ASAversusLMWHOutcomes RiskLMWH RiskdifferencewithASA

(95%CI)Relativeeffect(95%CI)

SymptomaticDVT Full35‐day prophylaxis 1.87(1.3‐2.7)12per1000 11more per1000

(from4moreto21more)Table10.RiskofVTEinmajororthopedicsurgery:fondaparinuxversusLMWHOutcomes RiskLMWH Riskdifferencewith

fondaparinux(95%CI)Relativeeffect(95%CI)

NonfatalPE Initialprophylaxis 1.32(0.37‐4.74)4per1000 1 more per1000

(from2fewerto13more)SymptomaticDVT Initialprophylaxis 1.31(0.47‐3.7)

8per1000 2more per1000(from4fewerto22more)

35

Table11.RiskofVTEinmajororthopedicsurgery:neworalanticoagulantsversusLMWHOutcomes Relativeeffect

(95%CI)NonfatalPE RiskLMWH Riskdifferencewith

rivaroxaban(95%CI)Full35‐d prophylaxis 1.34(0.39‐4.6)

6per1000 2 more per1000(from3fewerto20more)

RiskLMWH Riskdifferencewithdabigatran220mg(95%CI)

Full35‐d prophylaxis 1.22(0.52‐2.85)6per1000 1moreper1000

(from3fewerto10more)RiskLMWH Riskdifferencewith

dabigatran150mg(95%CI)Full35‐d prophylaxis 0.31(0.04‐2.48)

6per1000 4fewerper1000(from5fewerto8more)

RiskLMWH Riskdifferencewithapixaban(95%CI)

Full35‐d prophylaxis 1.09(0.31‐3.88)6per1000 0 moreper1000

(from4fewerto16more)SymptomaticDVT

RiskLMWH Riskdifferencewithrivaroxaban(95%CI)

Full35‐d prophylaxis 0.41(0.2‐0.83)12per1000 7fewerper1000

(from2fewerto10fewer)RiskLMWH Riskdifferencewith

dabigatran220mg(95%CI)Full35‐d prophylaxis 0.70(0.12‐3.91)

12per1000 4fewerper1000(from11fewerto36more)

RiskLMWH Riskdifferencewithdabigatran150mg(95%CI)

Full35‐d prophylaxis 1.52(0.45‐5.05)12per1000 6moreper1000

(from7fewerto51more)RiskLMWH Riskdifferencewith

apixaban(95%CI)Full35‐d prophylaxis 0.41(0.18‐0.95)

12per1000 7fewerper1000(from1fewerto10fewer)

36

Table12.RiskofVTEinmajororthopedicsurgery:mechanichalcompressionversusLMWHOutcomes RiskLMWH Riskdifferencewith

compressiondevices(95%CI)

Relativeeffect(95%CI)

NonfatalPE Initialprophylaxis 2.92(0.12‐71)4per1000 7moreper1000

(from3fewerto80more)SymptomaticDVT Initialprophylaxis 1.38(0.92‐2.06)

8per1000 3moreper1000(from1fewerto8more)

Table13.Recommendationsforthromboprophylaxisinorthopedicsurgery

THA TKA HFSInitialprophylaxis(minumumof10to14days)

LMWH,fondaparinux,apixaban,dabigatran,rivaroxaban,LDUH,VKA,aspirin(allGrade1B)

orICPD(Grade1C)

LMWH,fondaparinux,LDUH,VKA,aspirin(allGrade2B)

orIPCD(Grade1C)

Extendedprophylaxis(upto35days)Suggestiontoextendthromboprophylaxisupto35days(Grade2B)

IrrespectiveoflenghtoftreatmentorconcomitantIPCDLMWHinpreferencetofondaparinux,apixaban,dabigatran,rivaroxaban,LDUH(allGrade2B),VKA,aspirin(allgrade2C)

LMWHinpreferencetofondaparinux,LDUH

(allGrade2B),VKA,aspirin(allgrade2C)

Table14.Riskofmajorbleedinginnonorthopedicsurgery

Riskofmajorbleeding(95%CI) Relativeeffect(95%CI)Noprophylaxis LMWH RR2.03(1.37‐3.01)

Lowriskpopulation12per1000 24 per1000(16‐36)

Mediumriskpopulation22per1000 45 per1000(30‐66)

LDUH LMWH RR0.89(0.75‐1.05)Lowriskpopulation

19per1000 17 per1000(14‐20)Intermediaterisk

35per1000 31 per1000(26‐37)

37

Table15.RiskofmajorbleedinginmajororthopedicsurgeryRiskofmajorbleeding(95%CI) Relativeeffect

(95%CI)Noprophylaxis RiskdifferencewithLMWH(95%CI)

Initialprophylaxis 0.81(0.38‐1.72)15per1000 3fewerper1000

(from9fewerto11more)Extendedprophylaxis 0.43(0.11‐1.65)

5per1000 3fewer per1000(from4fewerto3more)

RiskLDUH RiskdifferencewithLMWH(95%CI)Initialprophylaxis 0.91(0.75‐1.09)

16per1000 1fewerper1000(from4fewerto1more)

RiskVKAs RiskdifferencewithLMWH(95%CI)Initialprophylaxis 1.36(0.95‐1.96)

11per1000 4moreper1000(from1fewerto11more)

RiskLMWH RiskdifferencewithVKAs (95%CI)Extendedprophylaxis 3.93(1.91‐8.11)

14per1000 41moreper1000(from13moreto100more)

RiskLMWH Riskdifferencewithfondaparinux(95%CI)

Initialprophylaxis 1.35(0.89‐2.05)15per1000 5more per1000

(from2fewerto16more)RiskLMWH Riskdifferencewithrivaroxaban

(95%CI)Full35‐dayprophylaxis 1.58(0.84‐2.97)

15per1000 9more per1000(from2fewerto30more)

RiskLMWH Riskdifferencewithdabigatran220mg(95%CI)

Full35‐dayprophylaxis 1.06(0.66‐1.72)15per1000 1moreper1000

(from5fewerto11more)RiskLMWH Riskdifferencewithdabigatran

150mg(95%CI)Full35‐dayprophylaxis 0.71(0.42‐1.19)

15per1000 4fewerper1000(from9fewerto3more)

RiskLMWH Riskdifferencewithapixaban(95%CI)

Full35‐dayprophylaxis 0.76(0.44‐1.32)15per1000 4fewerper1000

(from8fewerto5more)RiskLMWH Riskdifferencewith

compressiondevices(95%CI)Initialprophylaxis

15per1000 10fewerper1000(from2fewerto13fewer)

0.32(0.12‐0.89)