PRACTICE GUIDELINES FOR ANTICOAGULATION MANAGEMENT 3RD EDITION

From the Division of Hematology and Pharmacy with contributions from the Division of Cardiology, the Thrombosis Research Group, Department of Dentistry and Department of Neurology

These guidelines are based on the 2012 ACCP guidelines for antithrombotic therapy and incorporate the usual practice at the Jewish General Hospital.

Authors: Mark Blostein, MD Ryan Kerzner, M.Sc. June 2012

A French version is available upon request. Une version française est disponible sur demande.

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From the Division of Hematology with

contributions from the Division of Cardiology,

the Thrombosis Research Group, Department

of Dentistry and Department of Neurology

These guidelines are based on the 2008 ACCP guidelines for antithrombotic therapy and incorporate the usual practice of the anticoagulation clinic at the SMBD-Jewish General Hospital.

Chapters

1. OverviewofAnticoagulantMedications ....................... 3

2. ReversalAgents ............................................................. 9

3. ConversionfromOneAnticoagulanttoAnother ........ 12

4. AtrialFibrillation ......................................................... 13

5. Venous Thrombosis (DVT/PE) ..................................... 18

6. Heart Valves ................................................................ 25

7. BridgingTherapy ......................................................... 26

8. UseofCombinedTherapy........................................... 30

9. Coronary Artery Disease/ Heart Failure ...................... 31

10. Cerebrovascular (CVA) Disease ................................... 32

11. Heparin-InducedThrombocytopenia(HIT) ................. 33

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IntroductionTheseguidelinesweredevelopedtoserveasatoolforphysiciansandotherhealthcareprofessionalstohelpwiththemanagementof anticoagulation. They should in no way be used to replace clinical judgment. We are not responsible for any adversemedical outcomes as such responsibility lies with the treating physician.TheHematologyorThrombosisconsultservicescanal-waysbeconsultedforspecificpatientswithmorecomplexneeds. Pharmacy can be consulted as well for help with dosing and monitoringofanticoagulantmedications.

Abreviations

ACS AcuteCoronarySyndromeAF AtrialFibrillationaPTT activatedPartialThromboplastinTimeCHF CongestiveHeartFailureCrCl CreatinineClearanceDVT DeepVeinThrombosisFFP Fresh Frozen PlasmaHIT Heparin-InducedThrombocytopeniaINR InternationalNormalizedRatioLMWH LowMolecularWeightHeparinMI MyocardialInfarctionPE Pulmonary EmbolismpRBC packedredbloodcellsTIA TransientIschemicAttackUFH UnfractionatedHeparin

VTE Venous Thromboembolism

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.Overview of Anticoagulant Medications

A. Unfractionated heparin

. Inhibitsthrombinbyacceleratingtheactivityof antithrombin.

.Doseofheparin. Treatment:80units/kgIVbolus(ifdesired)then

18units/kg/hrIVinfusion.CheckaPTT6hoursafterbolusandadjustinfusiontomaintainaPTTwithinthe therapeuticrangeestablishedbythelocallaboratory.— Itisrecommendedtouseanalgorithm-based

dosingprotocol— ConsultThrombosisifweight>120kg

.Prophylaxis:5000unitsscq12hr(orq8hrifobesei.e.weight>120kg).

.Therearenodoseadjustmentsrequiredforrenalfailure

B. Low Molecular Weight HeparinEnoxaparin (Lovenox®)Dalteparin (Fragmin®) Tinzaparin (Innohep®)

. DirectlyinhibitsfactorXaactivity

. Doseofenoxaparin. Treatment:1.5mg/kgscqdayor1mg/kgscBID(the

latterregimenispreferredinACSandobesity)— Renalfailure(CrCl15-30mL/min):1mg/kgscqday

. Prophylaxis:40mgscqday(exceptpost-ophip/kneesurgeries:30mgscBID)— Renalfailure(CrCl15-30mL/min):30mgscqday

1.

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. Doseofdalteparin. Treatment:200units/kgscqday

— Renalfailure(CrCl15-30mL/min): ConsiderAnti-Xalevelsfordoseadjustments

. Prophylaxis:5000unitsscqday. Doseoftinzaparin

. Treatment:175units/kgscqday

. Prophylaxis:3500units/kgscqday. ConsultThrombosisifweight>120kgforallforms ofLMWH

.Monitoring. RoutinemonitoringisnotrequiredforLMWHs. AntiXalevels,whichmustbeapprovedbyThrombosis

orHematology,maybeusefulinthefollowing situations:— Renal failure— Extremeweights— Pregnancy— Recurrentthrombosesontherapeuticdoses

C. Warfarin (Coumadin®)

. InhibitsthepropersynthesisofthevitaminK-dependent clottingfactors.

. Initiatewarfarinat5-10mgpoqday.Considerlowerdosesintheelderly,patientswithimpairednutrition,liverfailure,congestiveheartfailure,orwithahighriskofbleeding.

. Nodoseadjustmentisrequiredinrenalfailure.

. AninitialINRshouldbedoneonDay3.In the absence of any bleeding,thewarfarindoseshouldbeadjustedbasedonthetablebelow.AnINRshouldthenbedoneevery 3-4days,untiltheINRistherapeuticandstable.

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. TheINRshouldbecheckedwithin1-2weeksofanychangeindose.

. AnyINRthatfallsbelowthetherapeuticrangeshouldbecheckedwithin1-2weekswhetherornotthedoseisadjusted.

. INRsshouldbecheckedevery8weeks(6weeksfor mechanicalvalves)andonlyifINRvaluesarestable.

. For verystablepatientsi.e.withinthetherapeuticrange fortheprevious6months,INRsmaybecheckedevery 12weeks(doesnotapplytopatientswithmechanicalvalves)

INR Dose Adjustment

<2.0 Increaseweeklydoseby10-20%,considerbridging

2.0-3.0 None

3.1-4.0 Decreasedoseby10-20%

4.1-6.0 Omitonedosethenrestartwithalowerdose(10-20%)

6.1-10.0 OmittwodosesandremeasureINRin48hours

>10.0 HoldWarfarinandAdminister2.5mgVitaminK, RemeasureINRin48hours

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D. Rivaroxaban (Xarelto®)

. InhibitsFactorXa

. IndicatedforthepreventionofVTEinpatientswhohaveundergoneelectivetotalhipreplacementortotalkneereplacementsurgery,forthepreventionofstrokeandsystemicembolisminpatientswithatrialfibrillation, andforthetreatmentofDVTwithoutsymptomatic pulmonaryembolism.

. Dose: . Fororthopaedicprophylaxis:10mgpoqday(14days

forkneereplacement/35daysforhipreplacement). ForAtrialFibrillation:20mgpoqdayor15mgpoqday

ifCrCl30-49mL/min. FortreatmentofDVT:15mgpoBIDfor3weeks,

followedby20mgpoqdayorfollowedby 15mgpoqdayifCrCl30-49mL/min

. Contraindicatedinsevererenalfailure(CrCl<30mL/min)

. Noanticoagulationmonitoringrequired

E. Dabigatran (Pradax®)

. Direct thrombin inhibitor

. Indicatedforthepreventionofstrokeandsystemic embolisminpatientswithatrialfibrillationandforthepreventionofVTEinpatientswhohaveundergone electivetotalhipreplacementortotalkneereplacementsurgery.

. Doseinatrialfibrillation:. 150mgpoBIDor. 110mgpoBIDifage>75orinpatientswithincreased

riskofbleeding

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. Doseinhip/kneereplacementsurgery. 220mgpoqdayor. 150mgpoqdayifage>75

. Contraindicatedinsevererenalfailure(CrCl<30mL/min),cautionforpatientswithmoderaterenalimpairment (CrCl30-50mL/min)

.Monitoring . Normally,noanticoagulationmonitoringrequired . PTT:INSENSITIVE:Ifabnormalthenthereis

significantdrugpresent.However,anormalPTT doesnotnecessarilymeanthereisnoeffectof dabigran.

. Thrombin Time(TT):TOOSENSITIVEbuta normalTTassuresthatthereisnoremaining anticoagulanteffectofdabigatran.Anabnormal thrombintimefromdabigatrandoesnotimply thathemostasisisimpaired.

F. Fondaparinux (Arixtra®)

. InhibitsFactorXa

. DoseforVTEprophylaxis. 2.5mgscqday

. DoseforVTEtreatmentandforsuspectedHIT. 5mgscqdayifweight<50kg. 7.5mgscqdayifweight50-100kg. 10mgscqdayifweight>100kg

. DoseforUnstableAngina/NSTEMI. 2.5mgscqday

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. DoseforSTEMI(inpatientswhoaremanagedwith thrombolyticsorwhoinitiallyaretoreceivenoform ofreperfusiontherapy). 2.5mgIVx1,then2.5mgscqday

. Notrecommendedinsevererenalfailure (CrCl<30mL/min)

. Nomonitoringrequired

G. Argatroban

. Direct thrombin inhibitor

. Indicatedinpatientswithheparin-induced thrombocytopeniawhorequireanticoagulation.

. Doseandmonitoring. Initial:2mcg/kg/mincontinuousIVinfusion

(0.5mcg/kg/minifmoderatehepaticimpairment).. SendaPTT2hoursafterinitiationoftherapy. AdjustdosetoreachtargetaPTTof1.5to3Xbaseline. Infusionrateshouldnotexceed10mcg/kg/min. ArgatrobanprolongstheINR,thuscomplicatingthe

monitoringofwarfarin.. Nodoseadjustmentsrequiredinrenalfailure

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.Reversal Agents

A. Protamine

. Doseforheparinreversal(max. dose 50 mg):. Unfractionatedheparin:

— 1mgIVper100units(ifadministeredwithin previous30minutes)

— 0.5mgIVper100units(if30-60minuteshaveelapsedsinceheparinadministration)

— 0.25mgIVper100units(ifmorethan2hours haveelapsedsinceheparinadministration)

. Enoxaparin:1mgIVper1mg(only50%effective)

. Dalteparin:1mgIVper100units(only75%effective)

. Tinzaparin:1mgIVper100units(only80%effective). Protamineshouldbeadministeredoveratleast 10minutestoavoidseverehypotensionandpatientsmustbemonitoredforanaphylactoidreactions.

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B. Vitamin K/Octaplex/Fresh Frozen Plasma

. ThefollowingtablesummarizesthemanagementofanticoagulatedpatientsonwarfarinwitheitherelevatedINRs,bleeding,orinneedforurgentreversalforsurgical/medicalprocedures:

* Octaplexcandidate:patientonwarfarinorvitaminKdeficientrequiringurgent normalizationoftheirINRforactivebleedingorurgentsurgery(<6hours)

** Contraindication toOctaplex:historyofHIT,allergy toproduct,high riskofthrombosis(recentMI,PE,DVT,CVA)

Bleeding INR Action

No <4.5 mDecreasewarfarindoseby10-20%

No 4.5-10 mHoldwarfarinuntilINRtherapeuticmRestartatlowerdose

No >10 mHoldwarfarinuntilINRtherapeuticmVitaminK2.5mgPOx1mRestartatlowerdose

No >2andurgentprocedureneeded

mHoldWarfarinmOctaplexcandidate*: —VitaminK10mgIVover30min —OctaplexasperBloodBank protocol —INRcorrectswithin1hourmNotOctaplexcandidate**: —VitaminK5-10mgIVover30min —FFP15mL/kg —INRcorrectswithin8hours

Yes >2

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Dosing of Octaplex:. 1000UifINR<3.0. 2000UifINR3.0-5.0. 3000UifINR>5.0

Vitamin K particularities:. HighdosesofvitaminKmaylowerINRmorethanis necessaryandmayleadtowarfarinresistanceforup to one week.

. OralvitaminKisthetreatmentofchoiceduetoits predictableefficacyandtoitssafetyandconvenience

. IVvitaminKmaybeassociatedwithanaphylaxis.It shouldbereservedformoreurgentsituationsto reverseanticoagulation.

. ResponsetoSCvitaminKmaybeunpredictableandsometimesdelayed

Dabigatran/Rivaroxaban. Noavailablereversingagent. SupportivecarewithpRBCsandFFPwhiledrugwears off(dependingonhalflifeandcreatinineclearance)

. Dialysissuggestedfordabigatranbutefficacyunproven

. HEMATOLOGYORTHROMBOSISCONSULTSUGGESTED

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CrClFROM

Dabigatran/ Rivaroxaban

TO Dabigatran/ Rivaroxaban

Unfrac-tionatedheparin

30-50 mL/min

24hoursafterlastdose

startimmediatelyafterdiscontinuingIVheparin

>50 mL/min

12 hours afterlastdose

startimmediatelyafterdiscontinuingIVheparin

Low Molecular WeightHeparin

30-50 mL/min

12-24hours afterlastdose

start6hours afterlastdose

>50 mL/min

6-12hours afterlastdose

start6hours afterlastdose

Warfarin

30-50 mL/min

4daysbeforediscontinu-ing.CheckINR4daysafterwarfarininitiation

Start4daysafter discontinuingwarfarin orwhenINR<2.0

>50 mL/min

2daysbeforediscontinu-ing.CheckINR4daysafterwarfarininitiation

Start4daysafter discontinuingwarfarin orwhenINR<2.0.

.A. Unfractionated Heparin to Low Molecular Weight Heparin

. InitiateLMWH1-2hoursafterthediscontinuation ofintravenousunfractionatedheparin

. VTEprophylaxismaybeinitiated2hoursafter discontinuationofIVheparin

B. Low Molecular Weight Heparin to Unfractionated Heparin

. Initiateunfractionatedheparinwithoutbolus6-12hours afterthelastdoseofLMWH

C. Dabigatran

3.Conversion from One Anticoagulant to Another

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.Atrial Fibrillation

A. Indications for indefinite anticoagulation therapy

. Paroxysmal,persistent,orpermanentatrialfibrillation oratrialflutter

. Patientsshouldinitiallybestratifiedforstrokeriskandbleedingrisktodetermineappropriatetherapyand management.

B. Stratification of patients

. StrokeriskusingtheCHADS2 score:

C= CongestiveHeartFailure–1pointH= Hypertension–1pointA= Age>75years–1pointD= Diabetesmellitus–1pointS= PriorstrokeorTIA–2points

4.

CHADS2 Score Adjusted stroke rate without anticoagulation, %/yr (95% CI)

0 1.9(1.2–3.0)

1 2.8(2.0–3.8)

2 4.0(3.1–5.1)

3 5.9(4.6–7.3)

4 8.5(6.3–11.1)

5 12.5(8.2–17.5)

6 18.2(10.5–27.4)

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. StrokeriskusingtheCHA2DS2-VAScscore:

C= CHForLVEF≤40%–1pointH= Hypertension–1pointA= Age≥75years–2pointsD= Diabetesmellitus–1pointS= PriorstrokeorTIAorthromboembolism–2pointsV= Vasculardisease(priorMI,peripheralarterydisease,or aorticplaque)–1pointA= Age65-74years–1pointSc= Sexcategory(female)–1point

CHA2DS2- VASc Score

Adjusted stroke rate, %/yr

0 0%

1 1.3%

2 2.2%

3 3.2%

4 4.0%

5 6.7%

6 9.8%

7 9.6%

8 6.7%

9 15.2%

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.MajorbleedingriskusingtheHAS-BLEDscore:

H= Hypertension–1pointA= Abnormalrenalorhepaticfunction–1pointeachS= Stroke–1pointB= Bleeding–1pointL= LabileINRs–1pointE= Elderly(Age>65years)–1pointD= Drugoralcohol–1pointeach

. Calculate CHADS2 score . CHADS2≥2→Oralanticoagulant . CHADS2=0or1→calculateCHA2DS2-VASc. CHA2DS2-VAScisrecommendedifCHADS2≤1 . CHA2DS2-VASc=0→noantithrombotictherapy . CHA2DS2-VASc=1→OralanticoagulantorASA,

oralanticoagulantpreferred . CHA2DS2-VASc≥2→Oralanticoagulant.. Vigilanceisrequiredinpatientswithhighriskofmajor

bleeds(HAS-BLED≥3).Closermonitoringandfollow-upiswarrantedinthispopulation.

. Aspirin(≥80mg)iseffectivebutnotaseffective as warfarin.

CHA2DS2- VASc Score

Adjusted stroke rate, %/yr

0 0%

1 1.3%

2 2.2%

3 3.2%

4 4.0%

5 6.7%

6 9.8%

7 9.6%

8 6.7%

9 15.2%

HAS-BLED score Major Bleeds (%/yr)

0 1.13

1 1.02

2 1.88

3 3.74

4 8.70

5 12.50

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C. Choice of oral anticoagulant

. Currently,theoralvitaminKantagonist,warfarin (Coumadin®),isthemostwidelyused.Fordosing informationonwarfarin,seepage5.

. AnalternativevitaminKantagonistisnicoumalone (Sintrom®),forpatientsallergictowarfarin.

. Needtomaintain an INR of 2.0-3.0 with vitamin K antagoniststopreventembolicstroke.

. Patientswithchronicatrialfibrillationofunknown duration,intheabsenceofanacuteembolicevent,donotrequireheparintherapyduringtheinitiationof warfarintherapy.

. Dabigatran(Pradax®),anoraldirectthrombininhibitor,andrivaroxaban(Xarelto®),anoralfactorXainhibitor, arenewalternativestovitaminKantagonists.

. Bothdabigatranandrivaroxabanareasefficaciousas warfarininpreventingstroke,withlowerriskofintracra-nialbleeding.However,theyareexcretedprimarilybythekidney,lackanantidote,andarenotreadilymonitoredwithstandardlaboratorytests.

. ItisthepracticeoftheJGHAnticoagulationClinicthatpatientsoverof75yearsoldwithcreatinineclearances lessthat50mL/minnotusedabigatran.Forthose patientsovertheageof75whoseCrCl>50,dabigatran, ifprescribed,shouldbeusedatadoseof110mgpoBID.

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D. Atrial Fibrillation following open heart surgery

.Warfarinisrecommendedfor3monthsfollowingopenheartsurgery,providedthepatientrevertstonormalsinus rhythm.

E. Cardioversion of Atrial Fibrillation

. ForAF<48hours,anticoagulationisnotrequiredprior tocardioversion

. ForAF>48hours(orofunknownduration),warfarinisrecommendedfor3weeksbeforeandatleast4weeksaftersuccessfulcardioversion.Thedurationofwarfarintherapy,regardlessofcardioversionoutcome,willbedecidedbythetreatingcardiologist.

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.Venous Thrombosis (DVT/PE)

A. Standard Treatment

. Intheabsenceofanycontraindications,warfarinisthetreatmentofchoiceforDVT/PE.ThetargetINRis2.0–3.0.

. Therapeuticheparintherapy(eitherUFHorLMWH)shouldbeinitiatedconcomitantlywithwarfarin.Amini-mumof5daysofheparintherapyisrequiredanditcanbediscontinuedoncetheINR>2.0fortwoconsecutivedays.

. For a 1stunprovoked(without an obvious risk factor) DVT/PE-warfarinshouldbecontinuedforat least 3 months maintainingtheINRbetween2.0-3.0,andpossiblycontin-uedindefinitelydependingontheriskofthrombosisvs.bleedingandpatientpreference.

. For a 2ndunprovokedDVT/PE-warfarinshouldbecon-tinued,possiblyindefinitely.ContinueduseofwarfarinshouldbeevaluatedinThrombosisClinicannually,takingintoaccountanynewpatient-relatedfactorsthatcouldaltertherisk-benefitbalanceoflongtermuseofwarfarin.

. Foraprovoked(secondary)DVT/PEi.e.aDVT/PEduetoatemporaryriskfactor(e.g.surgery,pregnancy,plastercast,etc)-warfarinshouldbecontinuedfor3 months (INRmaintainedbetween2.0and3.0)followingthe withdrawalofthetemporaryriskfactor.

. ShouldtheINRfallbelow2.0duringthefirstthreemonthsoftherapyafteraDVT,therapeuticLMWH shouldbeinstitutedandwarfarinadjusteduntilthe INRis>2.0fortwoconsecutivedays.

. Analternativetreatmenttowarfarin,forDVTswithout symptomaticPEandapprovedbyHealthCanada,isrivaroxa-banalone,withoutheparin,atadoseof15mgpoBIDfor 3weeksfollowedby20mgpoqday.Totaltreatmenttimeisusuallyfor3monthsbutcanbeextendedforuptooneyear.Itisnotrecommendedtobeusedforgreaterthanoneyear.

5.

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B. Duration and type of heparin

. Aminimumoffivedaysofheparintherapyisrequired for the treatment of a DVT/PE to allow for warfarin to beginitsanticoagulanteffect.

. LMWHispreferabletointravenousUFHduetoits favourablepharmacokineticprofile.

. IVheparinshouldbeusedonlyinsituationswhere bleedingisaconcernandaquickreversalofheparinis desiredorinthepresenceofsevererenalfailure (i.e.CrCl<15mL/min).

C. Inferior Vena Cava (IVC) Filters

. IVCfiltersshouldbeplacedinonlytwosituations. Whenanticoagulationisabsolutelycontraindicated. WhenaPEislikelytoresultinafatalitydueto

compromisedrespiratoryfunction. AThrombosis/Hematology/Pulmonaryconsultshouldbe obtainedpriortotheplacementofanIVCfilter.

. AnticoagulationshouldberesumedassoonasmedicallyfeasibleinallpatientswithacuteVTEandIVCfilters.

D. Thrombophilia Testing

. Thereisnoindicationtoperformthrombophiliascreeningtestingduringtheacutethromboticevent.

. Itisrecommendedthatthrombophiliatestingbe performedonlybytheThrombosisClinic.

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. Thrombophiliatestingisusuallydoneinallpatientswithunprovokedandpregnancy-associatedDVTsforthe followingreasons:

1. Secondaryprophylaxisdecisionsinhighrisksituations2. Primaryprophylaxisin1stdegreerelatives3. Thepresenceofathrombophiliawill,onoccasion

althoughnotusually,affectthedurationoftherapywith warfarin

. Inpatients<55yearsofage,thefollowingthrombophiliasshouldbetestedfor:. Antithrombin,ProteinCandProteinSdeficiency. FactorVLeidenandProthrombinG20210A. LupusAnticoagulantandAnticardiolipinantibodies. HomocysteineandFactorVIIIlevels

. Inpatients>55yearsofage,thefollowingthrombophiliasshouldbetestedfor:. FactorVLeidenandProthrombinG20210A. LupusAnticoagulantandAnticardiolipinantibodies. HomocysteineandFactorVIIIlevels

E. Treatment of VTE in Pregnancy

. PregnantwomendiagnosedwithaVTEshouldbetreatedwithfulldoseLMWH(e.g.dalteparin200units/kg/qdayorenoxaparin1.5mg/kg/qday)fortheremainderoftheirpregnancy.Patientsshouldcompleteatleast6months ofanticoagulationincludingtreatmentthroughout pregnancyand6weekspost-partum.

.Warfariniscontraindicatedduringthefirsttrimesterofpregnancybecauseoftheriskofteratogenicity.

. Primaryprophylaxis(withprophylaxisdosesofLowMolecularWeightHeparin)isreservedforthrombophilicwomenduringthesixweekspost-partum.

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. Secondaryprophylaxis(withprophylaxisdosesofLowMolecularWeightHeparin)duringpregnancyisindicatedinwomenwhohaveaprevioushistoryofanunprovokedVTE,aVTEassociatedwithestrogenuse,pregnancy,and/orobesityoraVTEassociatedwithathrombophilia.AnticoagulationpostpartumcanbeeitherwarfarinorLMWH,asneitherareexcretedinbreastmilkandbotharesafeforthenewborn.

F. Cancer associated VTE

. ItisrecommendedthatanticoagulationforthefirstsixmonthsafteraVTEbedalteparin(200units/kg/qdayforthefirstmonththen150units/kg/qdayforthefollowing 5months)orenoxaparin(1.5mg/kg/qdayforthefirstmonththen1.125mg/kg/qdayforthefollowing 5months).Thereafter,anticoagulationcaneitherbeLMWHorwarfarindependingonpatientpreferenceandco-morbidconditions(e.g.ongoingchemotherapy.)

. Anticoagulationtreatmentshouldbecontinuedindefinitelyaslongasthemalignancyisactiveorchemotherapyisongoing.

G. Thrombosis in the setting of a lupus anticoagulant

. Allvenousandarterialthromboticeventsinthesettingofalupusanticoagulantorananticardiolipinantibodyshouldbetreatedwithlifelongwarfarintherapy,main-taininganINRof2.0-3.0.

H. Recurrent fetal loss

.Womenwithrecurrentfetalloss,definedasatleastthree 1st trimester losses, two 2nd trimester losses or one3rd tri-mesterlossinthesettingofapositivelupusanticoagulantoranticardiolipinantibodyshouldbetreatedthroughoutthepregnancywithprophylacticLMWHdose(eitherdalte-parin5000unitsscqdayorenoxaparin40mgscqday)andASA80mgpoqdayforallsubsequentpregnancies.

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. Theroleofanticoagulanttherapyinwomenwithrecurrentfetallossandotherthrombophiliasiscontroversialandsuchwomenshouldbeenrolledincurrentlyavailableclinical trials.

I. VTE prophylaxis

. AllpatientsadmittedtohospitalforasurgicalinterventionorforacutemedicalillnessshouldreceiveVTEprophylaxisunlesstheyaredeemedtobelowriskorifanticoagula-tioniscontraindicated.

. RefertotheJGHVTEprophylaxisprotocolforthe completeprophylaxisguidelines.

. RiskassessmentscoresforVTEincludethePaduascore(formedicalpatients)ortheCapriniscore(forsurgicalpatients).

Padua risk assessment score for medical patients (score of < 4 is considered low risk)

Risk Factor Points

Activecancer 3

PreviousVTE(withtheexclusionofsuperficialveinthrombosis) 3

Reducedmobility 3

Alreadyknownthrombophiliccondition 3

Recent(>1mo)traumaand/orsurgery 2

Elderlyage(>70y) 1

Heartand/orrespiratoryfailure 1

Acutemyocardialinfarctionorischemicstroke 1

Acuteinfectionand/orrheumatologicdisorder 1

Obesity(BMI>30) 1

Ongoinghormonaltreatment 1

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Caprini risk assessment score for surgical patients (score of < 3 is considered low risk)

1 Point 2 Points 3 Points 5 Points Age41-60y Age61-74y Age>75y Stroke (<1 mo)

Minorsurgery Arthroscopicsurgery History of VTE Elective arthroplasty

BMI>25kg/m2 Majoropen surgery(>45min)

Family history of VTE

Hip,pelvis,or legfracture

Swollenlegs Laparoscopic surgery(>45min)

FactorVLeiden Acutespinalcordinjury (< 1mo)

Varicose veins Malignancy Prothrombin 20210A

Pregnancyor postpartum

Confinedtobed (>72h)

Lupus anticoagulant

Historyofunex-plainedorrecurrentspontaneousabortion

Immobilizing plastercast

Anticardiolipinantibodies

Oralcontraceptives or hormone replacement

Central venous access

Elevatedserumhomocysteine

Sepsis(<1mo) Heparin-inducedthrombocytopenia

Seriouslungdisease,includingpneumonia(<1 mo)

Othercongenitaloracquiredthrom-bophilia

Abnormalpulmonaryfunction

Congestiveheart failure (< 1 mo)

History of inflammatoryboweldisease

Medicalpatient atbedrest

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. Inmostpatients,therecommendedagentisenoxaparin40mgscqday.Inthecaseofsevererenalfailure (CrCl15-30mL/min),enoxaparin30mgscqdaymaybeused.ForCrCl<15mL/min,heparin5000unitsscBIDmaybeused.

. Somepatientpopulationsusedifferentformsof anticoagulationasVTEprophylaxis:

. Hipfracturepre-op:heparin3500unitsscq8h

. Hipfracturepost-op:enoxaparin30mgscBIDx35days

. Totalhiporkneearthroplasty:rivaroxaban10mgpoqdayorenoxaparin30mgscBIDx35days(hip) orx 14days(knee)

. AlthoughLMWHshavenotbeenshowntobesuperiortoUFHtherapyforVTEprophylaxis(exceptinorthopaedicpatients),theyarepreferableforthefollowingreasons:

i) Easierimplementationwillleadtomoreuniversaluse

ii) MuchlowerriskofHIT

iii) LessneedforCBCmonitoring

iv)OncedailyinjectioninlieuofBIDorTIDinjections

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.Heart Valves

A. Bioprosthetic Heart Valves:

. Patientswhoundergovalvereplacementwithbiopros-thetic valves in the mitral positionandwithoutatrialfibrillationoraleftatrialthrombusrequireanticoagula-tionwithwarfarin(tokeepanINRbetween2and3)forthreemonthsfollowedbyASA(80mg)indefinitely

. Patientswhoundergovalvereplacementwithbiopros-thetic valves in the aortic positionrequireanticoagulationwithASA80mg/qdayforthreemonths

B. Mechanical Heart Valves

. Allpatientswithmechanicalheartvalvesrequirelifelongwarfarintherapy.ThetargetINRisdefinedasfollows:. Low risk valves:St.Jude’s,CarboMedics,andMedtronic

valvesintheaorticpositionrequireanINRof2.0-3.0.. High risk valves:Allothervalvesintheaorticposition

andallvalvesinthemitralposition,requireanINRof2.5-3.5.Otherhighriskfeaturesincludethefollowing:

1)Patientswhosuffersystemicembolismdespiteadequateanticoagulationwithwarfarin,

2)Patientswithleftventriculardysfunction,3)Patientswithatrialfibrillation,4)Patientswithleftatrialenlargement,5)Patientswithcagedballorcageddiskvalves.

. Heparinshouldbeaddedtopatientswhoaresubthera-peuticonwarfarininthefollowingsituations:

a) HighriskmechanicalvalvepatientswithanINR<2.0b) LowriskmechanicalvalvepatientswithanINR<1.5

6.

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Risk AF VTE Mechanical heart valve

High m CHADS2 = 5or6

mCVAorTIAwithinthepast 3months

mRheumaticvalvular heart disease

m VTE within the past3months

m Severe thrombo-philia(ex:deficiencyinproteinsC, Sorantithrombin,antiphospholipidantibodies)

m Mitral valve prosthesis

mOlderaorticvalveprosthesis

mCVAorTIAwithin thepast6months

Mod-erate

m CHADS2 =

3or4m VTE within the past3to 12 months

m Recurrent VTEmActivecancer(treatedwithin 6monthsor palliative)

mBileafletaorticvalveprosthesis andoneofthefol-lowingriskfactors:-AF-PriorCVAorTIA-Hypertension-Diabetes -CHF -Age>75years

Low m CHADS2 =

0 to 2, with no priorCVAorTIA

mVTE>12monthsago,single episode,no other risk factors

mBileafletaorticvalveprosthesiswith none of the above risk factors

.Bridging Therapy

A. Peri-operative Management of Anticoagulation

. Indicationsforbridgingtherapy:

Patientsonwarfarin therapy foratrialfibrillation,venousthromboembolism (VTE) or mechanical heart valves who are at high or moderate riskofdevelopingthromboembolism.

7.

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Day -5

Day -4

Day -3

Day -2

Day -1

Day 0 Surgery

Day +1

Day +2

Day +3

D/C warfarin

dalteparin200units/kgscqdayorenoxaparin1.5mg/kg/qday

dalteparin100units/kgscqdayorenoxaparin0.75mg/kg/qday

warfarinatregulardoseNodalteparin

.Continuewarfarinatregulardose

. High Risk* Operative Procedure: dalteparin 5000unitsscqday orenoxaparin 40mgqday(prophy-lacticorlowdose)

. Low Risk Operative Procedure: dalteparin 200units/kgscqdayorenoxaparin 1.5mg/kg/qday (fulldose)

Risk AF VTE Mechanical heart valve

High m CHADS2 = 5or6

mCVAorTIAwithinthepast 3months

mRheumaticvalvular heart disease

m VTE within the past3months

m Severe thrombo-philia(ex:deficiencyinproteinsC, Sorantithrombin,antiphospholipidantibodies)

m Mitral valve prosthesis

mOlderaorticvalveprosthesis

mCVAorTIAwithin thepast6months

Mod-erate

m CHADS2 =

3or4m VTE within the past3to 12 months

m Recurrent VTEmActivecancer(treatedwithin 6monthsor palliative)

mBileafletaorticvalveprosthesis andoneofthefol-lowingriskfactors:-AF-PriorCVAorTIA-Hypertension-Diabetes -CHF -Age>75years

Low m CHADS2 =

0 to 2, with no priorCVAorTIA

mVTE>12monthsago,single episode,no other risk factors

mBileafletaorticvalveprosthesiswith none of the above risk factors

. Recommendedbridgingtherapy(notneededinlowriskpatients):

* high bleeding risk operative procedures e.g. Major Orthopedic surgery, Genitourinary surgery, Neurosurgery, Vascular Surgery, Endoscopy with possibilityofbiopsy,AbdominalHysterectomy

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. LMWH is NOT to be given within 24 hours of a surgical procedure.

. For high risk surgeries (e.g. neurosurgery) or surgeries associated with a high incidence of bleeding (e.g. urologic procedures), it is suggested that the pre-surgical dalteparin dose on Day -1 and/or the post-operative doses of dalteparin be omitted.

. The pre-operative LMWH dose on Day-1 should not be given prior to neuraxial anaesthesia.

B. Surgical procedures in patients with renal impairment

. Patientswithmoderaterenalimpairment (CrCl15-30mL/min)shouldreceiveonlyprophylacticdosesofLMWHforbridging.

. Patientswithsevererenalimpairment(CrCl<15mL/min)shouldreceiveintravenousunfractionatedheparin,asdescribedonpage3,forbridging.

Note

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C. Surgical procedures in patients on dabigatran

D. Surgical procedures that do not necessarily require interruption of warfarin therapy

1)Dentalprocedures DentalprocedurescanbeperformedaslongastheINR<3.0,especiallyforproceduresperformedintheDepartmentofDentistryattheJewishGeneralHospital.Verycomplexproceduresmayrequiretheperioperativebridgingprotocol.

2)Endoscopieswithoutpolypectomyorbiopsy3)Cystoscopieswithoutbiopsies

4)Cataractsurgery

(CLCr, mL/min)

Half-life (hours)

Timing of procedure after last dose of dabigatran

Timing of resump-tion of dabigatran after surgery (depends on procedure)

>80 13 2days Theeveningonthedayafter surgery

<50-80 15 2days As above

>30to≤50 18 4days As above

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.Use of Combined Therapy

Theuseofcombinedtherapyofwarfarinandantiplateletagents(includinglowdoseaspirin)isdiscouragedduetothehigherriskofbleedinginpatientsoncombinedtherapy.

Exceptions include the following:

1)Forsecondaryprophylaxisofischemicheartdiseaseinpatientswithcoronaryarterydiseasewhoareundertheageof75.

2)Antiplateletagentsincludingaspirinorclopidogrelorboththatareusedpostpercutaneouscoronaryarteryintervention(PCI).

3)Patientswithmechanical valveswhoaredeemed high riskforcerebrovasculareventsasdefinedbyoneofthefollowingfactors: a)Systemicembolismdespiteadequateanticoagulation

with warfarin,

b)Leftventriculardysfunction,

c)Concomitantatrialfibrillation,

d)Leftatrialenlargement,

e)Cagedballorcageddiskvalves.

8.

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.Coronary Artery Disease/ Heart Failure

. ThemainindicationfortheuseofwarfarinincoronaryarterydiseaseisinpatientswithacuteMIandwithanyoneofthefollowingriskfactors:. Largeanteriormyocardialinfarction. Significantheartfailure. IntracardiacthrombusonEchocardiography. History of a thromboembolic event.

Inthesecases,combinedtherapyofwarfarin(INR2.0-3.0)andlowdoseaspirin(80mg/qday)isrecommended.ThedurationofwarfarintherapyisthreemonthswhereasASAiscontinuedindefinitely.

. Othercardiacindicationsforchronicanticoagulationtherapy:. Rheumaticmitralvalvedisease. Patientswithmitralvalveprolapsethatexperience

systemicembolismdespiteASAtherapy. It is not recommended that patients with low ejection

fractions from chronic heart failure be anticoagulated with warfarin unless they have one or more of the following factors:

1. Atrial fibrillation

2. Documented left ventricular thrombus on echocar-diography

3. Previous systemic arterial event

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.Cerebrovascular (CVA) Disease

.Warfarintherapyisindicatedinpatientswhosufferacerebrovasculareventfromacardioembolicsourceasevidencedbyoneofthefollowingriskfactors:

1.Presenceofatrialfibrillation

2.Presenceofalowejectionfraction(<30%)

3.Presenceofcardiacthrombusonechocardiogram

4.ACVAimmediatelypostMI

. Otheruncommonindicationsfortheuseofwarfarininthesettingofcerebrovasculardiseaseneedtobeclearlystatedbythereferringneurologistandcanincludethefollowing:. Patent foramen ovale. Carotiddissection. Cerebral venous thrombosis. Pedunculatedormobileatheromataateitheraortic

archorcarotidbifurcation. Symptomaticandveryhighgradecarotidstenosis

inpatientsawaitingendarterectomy. RecurrentTIA/strokedespitetrialofallofthe

antiplateletagents. Stroke/TIAinthesettingofalupusanticoagulantor

anticardiolipinantibody(itisnotclearthatwarfarin issuperiortoantiplateletagents)

. Centralretinalveinocclusioninthesettingofalupusanticoagulantoranticardiolipinantibody

10.

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.Heparin-Induced Thrombocytopenia (HIT)

A. Definition/recognition (The 4Ts):

a) THROMBOCYTOPENIA:Theplateletcountfallsby 50%ormorefrombaseline.

b) TIMING:Occursbetweendays4-14ofheparintherapyc) THROMBOSIS:Thepresenceofavenousorarterial

thromboticeventd) ALTERNATIVE DIAGNOSIS:Analternativeexplanation

forthethrombocytopeniaislesslikely

B. Procedure to Follow In Suspected HIT:

a) Reviewthedefinition/recognitionsectionb) Stopallheparinsources(iv,sc,catheterflushes,dialysis)c) Consult Thrombosisd) DrawbloodforaHITantibodyassay(1yellow&

1 blue tube)e) Orderbilateralultrasoundsofthelowerextremitiesf) Starttherapywithfondaparinux.Argatrobanisasecond-

lineagent,reservedforpatientswithsevererenalfailure(CrCl<30mL/min)orforpatientswhomayrequireacutereversalofanticoagulation.

g) Donotgiveplatelettransfusionsunlesspatientis bleedingsignificantly

h) Whenwarfarintherapyisindicated,donotinitiateuntilplateletsrecoverto>150x109/L or back to baseline.

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Madepossiblebyunrestrictededucationalgrantsfrom PfizerCanadaandSanofi.