VTEprophylaxisandproceduralanticoagulation:FocusonOrthopedicsurgeries

SaraMahmoud,BPharm,PharmDcand,BCCCS,RPh

ClinicalPharmacist,AlWakra Hospital

CPDofficecoordinator,HamadMedicalCorporation

LearningObjectives:

• ListtheavailableanticoagulantsinHMCformulary

• ComparedifferentpharmacologicalagentsusedforVTEprophylaxisandtherapy

• ReviewCHESTandAAOSguidelinesinpreventingVTEinorthopedicsurgery

• Outlinetheguidelinesforinterruptinganticoagulationandbridgingtherapyinsurgicalpatients

PharmacologicalagentsusedforVTEprophylaxisandtherapy

Shortacting Maintenance therapyagents (long)

Onsetofaction Rapid Variable(warfarin: 5-7days)

Duration(Halflife) Short Long

Examples LMWH,UFH Warfarin,NOAC/DOAC

Coagulationcascade

LMWH

UFH

ShortactingEnoxaparin Dalteparin Unfractionated

Heparin(UFH)Mechanismof

actionInhibitfactorXa Inhibitantithrombin

III+factorXa

DosingProphylacticTherapeutic

40unitsOD SC1mg/kgBIDSC1.5mg/kgODSC

5000unitsOD SC120u/kgBIDSC200u/kgODSC

5000uBIDorTID80u/kgbolus

followed by18u/kgMonitoring Anti-factorXa aPTT q6hours

Pharmacokinetics Renalimpairment:reducedoseby50%

Lessaccumilated inrenalimpairment

Safeinrenalimpairment&

dialysis

MaintenancetherapyWarfarin Dabigatran Rivaroxaban

Mechanismofaction

Competes withVitaminKreceptorsonthelivertoformclottingfactors

Directthrombininhibitor

Direct FactorXainhibitor

Dosing ⋍ 5mg 150mgBID 15mgBID 21daysThen,20mgOD

Monitoring INR NA NATimetopeak 5-7days 1hr,(delayedbyfood

2hrs)2-4hrs

Halflifeelimination

20-60hours 12-17Hrs(elderly:14-17hrs)

5-9Hrs(Elderly:11-13hrs)

Prolongedbyrenalimpairment

Q:FACTORMYTH?

• ApatientistobestartedononeoftheNovelAnticoagulants(NOAC)today.ThepatientneedshortactingLMWHorbridgingtherapysuchasinwarfarin

cases?FACT/MYTH

MYTH!

Novelanticoagulantsexerttheireffectimmediatelywithoutrequirementofbridgingtherapy

VTEProphylaxis

VTEinsurgery

• VenousThrombo-embolism(VTE)isacommoncomplicationofsurgery

• PEisthemostcommoncauseofpreventabledeathinhospitalizedpatientsinsurgery

• PostoperativeDVTisoftenasymptomatic

• ItissuggestedthatroutinescreeningforDVThaslowsensitivity

• VTEoccursinabout3%ofpatientsundergoingorthopedicsurgerydespiteprophylaxis (highestintotalkneeandhipsurgeries)

• IncidenceofclinicallyevidentDVTis2-5%

VTEprevalenceaftermajororthopedicsurgeryinabsenceofprophylaxis

Procedure DVTTotal PE(Fatal)

Hiparthroplasty 42-57% 0.9-28%(0.1-2%)

Kneearthroplasty 31-85% 1.5-10% (0.1-1.7%)

Hipfracturesurgery 46-60% 3-11%(2.5-7.5%)

Answer:Pleasenotethatthesenumbersarebeforetheneweraofearlyambulationofsurgicalpatients

RiskfactorclassificationforVTEformationRisklevel CalfDVT Proximal

DVTClinical PE FatalPE

LowriskMinorSurgeryinpt <40yrs noriskfactors

2% 0.4% 0.2% <0.01%

ModerateriskMinorsurgeryinpatient +additionalriskfactors40-60yr oldpatient+NOriskfactors

1—20% 2-4% 1-2% 0.1-0.4%

HighriskSurgeryin>60yr old+additionalriskfactor

20-40% 4-8% 2-4% 0.4-1%

HighestriskSurgeryinpt >40yrsmultipleriskfactorsHip/Kneearthroplasty,hipfracturesurgery

40-80% 10-20% 4-10% 0.2-5%

RiskfactorsforVTEActivecancerPreviousVTE(except superficialveinthrombosis)Reducedmobility(3foldincrease)Elderly (>70yrs)Heart FailureoranyformofrespiratoryfailureAcutemyocardialinfarctionorischemicstrokeAcute infectionorrheumatological disorderObesity(BMI>30)

Ongoinghormonal therapy(oralcontraceptive)*

Criticalillness

Othersuggestedriskfactors- SIGNNHS

FamilyHistoryofVTEVaricoseveins

Raolixifene orTamoxifene (breastcancer)

Pregnancy(10foldincrease),Puerperium(post-partum:25foldincrease)

CentralVenousCatheter(11.5foldincrease)

ProphylaxisKeypoints

• Totalhip/kneereplacementsurgeryshouldbeplacedonDVTprophylaxis• Considerextendedprophylaxisinmajorsurgeries• Allothersurgeries:basedonclinicalappraisalofthepatient’sindividualriskfactors• AspirinisnotrecommendedforDVTprophylaxis• Inpatientswithincreasedriskofbleeding:usemechanicalprophylaxis• Somearticlesrecommendedacombinationofmechanicalandpharmacological

prophylaxis• TheAustralian&NewZealandworkingpartyonthemanagementofVTErecommend

toprescribeVTEprophylaxisexceptiftherearecontraindications(thrombocytopenia,elevatedINR,hepaticdisease,activebleeding,highriskofbleeding)

AgentsusedforVTEprophylaxisEnoxaparin Dalteparin Unfractionated

Heparin(UFH)Mechanismof

actionInhibitfactorXa Inhibitantithrombin

III+factorXa

Dosing 40unitsOD SC(obese)

5000unitsOD SC 5000uBIDorTID

Monitoring Nomonitoringrequired

Pharmacokinetics Renalimpairment:30mgdailySC

Lessaccumulatedinrenalimpairment

Safeinrenalimpairment&

dialysis

MechanicalVTEprophylaxis

Q:FACTORMYTH?

• ElasticstockingisequivalenttomechanicalcompressionsinDVTprophylaxis

MYTH!

ElasticstockingsshouldNOT beusedtopreventVTE,theyareinferiortomechanicalcompressions

GUIDELINESACCP,AAOS

CHESTguidelinesrecommendationsIndication Totalhip/kneearthroplasty orHipfracturesurgery

Recommendation

VTEprophylaxisforminimum10-14days

Agents Preferredagent:LMWH, UFHLessfavored:Fondaparinux,Dabigatran,Apixaban,Warfarin(INR2.5)- increasedriskofbleedingNostrongevidence:Aspirin,Pneumaticcompression

Pneumaticcompressions

Highriskofbleeding(previousmajor bleeding,renalfailure,antiplateletagent,surgicalbleedingrisk)Compliance shouldbefor18hrsperday

Timing ForLMWH,initiate12hoursbeforesurgeryResume12-24hourspostsurgery(lessriskofbleeding)

CHESTguidelinesrecommendations

Indication Majororthopedicsurgery

Recommendation VTEprophylaxisfor35daysvs10-14days

Agents Preferredagent:LMWH, UFHLessfavored:Fondaparinux,Dabigatran,Apixaban,Warfarin(INR2.5)- increasedriskofbleedingNostrongevidence:Aspirin,Pneumaticcompression

Recommendation CombinationofpharmacologicalandmechanicalprophylaxisBasedoncochrane meta-analysis

NoncompliancetoIPCD

Dabigatran/Apixaban

Recommendation DopplerUltrasoundscreeningforpatientspostmajororthopedicsurgery

QUESTION:WHATISTHEPREFERREDVTEPROPHYLAXISAGENTBASEDONTHEGUIDELINES?

• LowMolecularWeight(Enoxaparin/Dalteparin)

• UnfractionatedHeparin

• Apixaban

• Dabigatran

• Aspirin

• Warfarin

• Fondaparinux

• Rivaroxaban

• Pneumaticcompression

Answer:LowMolecularWeightHeparin

20%reductioninDVTin favorofLMWH

Equivalent,notenoughdataaboutbleeding

Equivalent,butusedhigherdoseDab.

Comparedveryhighdose,moreDVT

LessasymptomaticDVTwithLMWH

IncreasedbleedingeFond.

Inc.riskofmajorbleeding

LessbleedingwithIPCD,non-inferior

DOSINGOFNOAC INORTHOPEDICSURGERY

Kneereplacement Hipreplacement

Dabigatran 110mggiven1-4hoursaftersurgery

110mggiven1-4hrsaftercompleting

surgeryRivaroxaban 10mgdaily

10-14 daysUpto35days

10mgdaily10-14days

upto35days

NoProphylaxis

Indication Isolatedlower leginjurythatrequiresimmobilization

Indication KneearthroscopywithnohistoryofpriorDVT

Therapeuticanticoagulationandproceduralguidelines

ANTICOAGULATION

• Anticoagulationistheprocessofbloodthinning.Thisisusedtopreventclotformationincertaindiseasessuchasatrialfibrillation,valvereplacement,thrombosis.Itisalsousedtotreatcertainconditionssuchasacutedeepvein

thrombosis,pulmonaryembolismoranyformofthrombosis.

INDICATIONSFORANTICOAGULATION

• Non-Valvular Atrialfibrillation*

• Valvular heartdiseaseandprostheticheartvalves

• Mechanicalvalvevstissuevalve

• Venousthromboembolism(DVT,PE,Otherthrombosis…)

• Inheriteddisease(proteinC,Sdeficiency)

• Autoimmunediseasesrelatedtoincreasedthromboticrisk(antiphospholipidsyndrome)

DOALLPATIENTSWITHAFREQUIREANTICOGAULATION?

• No

DECISIONTOANTICOAGULATION

RiskofthrombosisCHAD-VAS2score

RiskofbleedingHASBLEDscore

CHA2DS2-VASCSCORE

C Congestive heartfailureH Hypertension(>140/90orontherapy)A2 Age>75yearsD DiabetesS2 Priorstroke orTIAV Vasculardisease(PAD,MI,…)A Age65-75Sc Gender (Sexcategory):Female

RISKOFTHROMBOSISBASEDONCHAD2VASC2

0 01 1.3%2 2.2%3 4%5 6.7%6 9.8%7 9.6%8 12.5%9 15.2%

HAS-BLEDSCORE

H Hypertension (SBP>160) 1

A Abnormal renalfunctionAbnormalhepaticfunction

11

S Stroke: priorhistoryofstroke 1

B Bleeding:priorhistoryofmajor bleeding 1

L LabileINR(unstable)

E Elderly>65 1

D Prioralcohol,medsthancanpredisposebleeding(NSAIDs,antiplatelets)

11

INTERRUPTIONOFANTICOAGULATIONANDBRIDGINGINSURGERY

Riskofbleedinginthesurgicalprocedure Riskofthrombosis

High(especiallymechanicalvalve)*

LowHighLow

Donotinterruptanticoagulation

Interruptanticoagulation Bridging Nobridging

WARNING!

• Epiduralanaesthesia:DoNOTuseanyoftheNOACbecauseoftheincreasedriskofspinalorepiduralhematoma• Resume24hoursafterremovalofepiduralcatheter

INTERRUPTION- WARFARIN

Agent INR>3(abovetarget)*

INR2-3(therapeutic)

INR<2(sub-

therapeutic)Warfarin Discontinue>5

daysbeforesurgery

Discontinue5daysbeforesurgery

Discontinue 3-4daysbefore

surgery

CheckINR24hoursbeforesurgery

INTERRUPTION- DOAC

Agent Lowbleedingrisk(surgery) Intermediate orhighbleedingrisk(surgery)

Dabigatran Cl >80:>24hrsCl50-79:>36hrsCl30-49:>48hrsCl:15-29:>72hrs

Cl<15:Nodata>96hrs*

Cl>80:>48hrsCl50-79: >72hrsCl:30-49:>96hrsCl:15-29:>120Cl<15:Nodata

Rivaroxaban Cl>30: >24hrsCl15-29:>36hrsCl<15:Nodata,

Consideranti-Xa level

Cl>30:>48hrsCl<30:Nodata

Surgerybleedingrisk

Renalfunction

EMERGENCYSITUATION

BRIDGING

AGENTSUSEDINBRIDGING

Lowmolecularweightheparin Unfractionatedheparin

MoreconvenientMaynotrequiremonitoring Safestoptioninrenalimpairment

Monitoring:aPTT q6hrs thenq12whendoseisdetermined

RenalImpairment+Obese:MonitorantiFactorXa levels

DOSING

Enoxaparin Dalteparin UFH

Dose 1mg/kg BIDOR1.5mg/kgdaily

120u/kg BIDOR200u/kgdaily

80u/kg bolusfollowedby18u/kgadjustedbasedonapTT

RenalImpairment Reducedose50%Cl<30:MonitorDialysis: Notapproved

Lessaccumilated SAFE!

Monitoring AntifactorXa aPTT q6hrs

KEYPOINTSINBRIDGING

• WhenINR<2,initiatebridgingtherapy

• NextscheduleddoseNOAC

• HoldUFH4hoursbefore

• HoldLMWH12hrs before

• HeparinInducedthrombocytopenia:Lepirudin

• Neverinitiatewarfarininpaient withHITaslongasPLT<50

RESUMING- POSTSURGERY

• Basedonpostproceduralbleedingrisk:

• Warfarin24-48hours

• Warfarin:Bridgeifrequired(basedonCHADVASandHASBLED)

• UntilINRistherapeutic>2formorethan24hoursorafter5dayswhicheveriscloser

• NOAC:Donotbridge

• ResumeNOAC:24hrs (lowpostproceduralbleedingrisk)

• ResumeNOAC:48-72hours(Highpostproceduralbleedingrisk)

REFERENCES

• G.Agnelli,PreventionofVenousThromboembolisminSurgicalPatients.Circulation.2004;110[supplIV]:IV-4–IV-12

• CHESTguidelinesVTEprophylaxisinorthopedicsurgery2012

• AAOSguidelinesVTEprophylaxis

• ACCguidelinesforbridgingtherapyinnon-valvular AFpatients2017

• CHESTguidelinesforpreandpostproceduralanticoagulation