DurationofAnticoagulationforVTE

DavidKaplan,MDAssistantProfessor,UniversityofUtah;SaltLakeCity,Utah

Objectives:• Restateindicationsfortime-limitedanticoagulationtherapy

followingvenousthromboembolism.• Restatetheindicationsforindefiniteanticoagulationfollowing

venousthromboembolism.• Discussandoutlineaprocessbywhichshareddecision-makingcan

takeplacewithpatientswhenselectingadurationofanticoagulationfollowingvenousthromboembolism.

ThrombosisGuidelines2016– UpdatesthatChangePractice

DurationofAnticoagulationforVTEDavidA.Kaplan,M.D.April22nd,2016

Learningobjectives• Indicationsfortime-limitedanticoagulationforVTE

• IndicationsforindefiniteanticoagulationfollowingVTE

• Reviewaprocessofshareddecisionmakingwithpatientstohelpdeterminethelengthofanticoagulation

Definitions

Definitions• Otherterms:• Indefinite• Chronic• Time-limited

• DOACs

• Inmostcases3monthsvs.indefinite

Dx

(0-10days) 3months >3months

OptimaldurationofanticoagulationVTERecurrence:consequences BleedingfromextendedACPost-thromboticsyndrome(↑6x) Majorbleeding(↑2.6x@1year)CTEPH (~3%) IntracranialbleedingFatalpulmonaryembolism(3.6%)Fatalbleeding

JThromb Haemost 2013;11:795–805JVasc Surg.2009;49(3):704NEngl JMed.2004;350(22):2257

PatientpreferencesFearofVTEvs.fearofbleeding

SenseofwellbeingMonitoring

Cost

Optimaldurationofanticoagulation

• Aslongasanticoagulationisnotcontraindicated…• Virtuallyalwaysbeneficialfor3months• Benefitafter3monthsdependsonrecurrencerisk,bleedingrisk

• 0-3months:benefit>risk• Forevery1000VTEpatientstreatedforlessthan3-6months:

• 53moreVTErecurrences• 5fewermajorbleeds (CI:0.22-1.32)• 2fewerdeaths(CI:0.68-1.38)

• >3months:twopossiblescenarios• VTEriskreduction>riskofbleeding• Riskofbleeding>VTEriskreduction

Why3monthsoftherapy(minimum)?

• SymptomaticdistalDVT– warfarinvs.notreatment• Symptomaticextension• 0%vs.29%at3months

• ProximalDVT– warfarinvs.lowdoseUFH• RecurrentVTE• 0%vs.47%at3months

• VTE– warfarinfor4weeksvs.3months• RecurrentVTE• 2-10xrateofrecurrencewithshorterduration

Lancet1985;2:515NEJM1979;301:855Lancet1992;10;340Thromb Haemost.995;74(2)

Whynot6months(or9or12or…)?• Pooledanalysisfrom7randomizedtrials• n=2925VTEpatients

• “…threemonthsofanticoagulanttreatmentresultedinasimilarriskofrecurrenceaftertreatmentwasstoppedtoalongerdurationoftreatment…”

06121824Timesincestoppingtreatment(months)

BMJ2011;342:d3036

Whynot6months(or9or12or…)?

• PADIS-PERCT• 2015:n=371

JAMA.2015;314(1):31-40

Whyindefinitetherapy?• UnprovokedVTE– recurrence• 10%at1year• 30%at5years

• RecurrentunprovokedVTE– recurrence

Haematologica 2015;100(2)

Whyindefinitetherapy?• RecurrentVTEreduction• WarfarinINR2-3:~90%• WarfarinINR1.5-2:~60%(withnoreductioninbleedingrisk)• Aspirin:~30%

• DOACs• Dabigatranvs.warfarin• Dabigatranvs.placebo• Rivaroxabanvs.placebo• Apixabanvs.placebo• >80%recurrentVTEreduction

VTEriskrecurrence• Lowrisk• Surgery• 1%at1year• 5%at5years

• Intermediaterisk• Non-surgicaltransientriskfactor• 5%at1year• 15%at5years

• Highrisk• Unprovoked,cancer• 10%at1year• 30%at5years• Perhapsmuchhigherifrecurrent,cancer-associated

Duration:3monthsORindefinite

• LowandintermediateVTErecurrencerisk:3months• TreatmentofVTE• ↓Shorttermrecurrencerisk• ProvokedVTE• FirstunprovokeddistalDVT• Patientswithahighbleedingrisk

• HighVTErecurrencerisk:Indefinite• ↓Longtermrecurrencerisk• UnprovokedVTE• Cancer-associatedVTE

VTEriskfactor:surgery

• Surgery:RR9.6-70duringthefirst6postoperativeweeks• Riskpersistsformonths• Variableriskaccordingtotypeofsurgeryandotherriskfactors• Age• HistoryofVTE• Malignancy• Medicalcomorbidities• Thrombophilia• Timeinsurgery• Timeunderanesthesia• Durationofimmobilization

BMJ2009;339:b4583

VTEriskfactor:surgery• 91dayincidenceofVTEamongpatientswithoutcancer

• Neurosurgery:0.5-2.3%• Headandneck:0.1-0.2%• Cardiothoracic:0.4-1.4%• Vascular:0.2-2.8%• Gastrointestinal:0.2-1.6%• Urologic:0.3-1%• Gynecologic:0.3%• Orthopedic:0.2-2.4%• Other(wounddebridement):0.9%

• Higheramongcancerpatients

• 56%VTEoccurredafterhospitaldischarge

Thromb Haemost 2003;90:446

VTEriskfactors:non-surgicaltransient

• Majortrauma• Plastercast• Minorinjury(3-5x↑)• IVdruguse(femoralvein)• Pregnancy,postpartum(>4x↑)• Estrogen– OCPs,HRT(2-4x↑)• Immobilization-- ≥3days• Extendedtravel– eg,flight≥8hours(2-4x↑)• Medicalillness• Obesity• OtherRx:testosterone,tamoxifen,glucocorticoids,bevacizumab

ArchInternMed.2008;168(1):21BrJHaematol.2001;112(3):641BMJ.2009;339:b2921AnnInternMed.2005;143(10):697JAMA.2004;292(13):1573ArchInternMed. 2010;170(19):1710-1716

VTEriskfactor:cancer

• Highriskofrecurrence:~15%peryear• Active:treatedinthepast6months,persistent,progressive• Otherfactors

• Chemotherapy• Metastases• CVC• Higher riskcancers

• HightotalmortalityandVTEmortality

• Highbleedingriskindependentofanticoagulation

NEngl JMed.2003;349(2):146- 153Blood.2002;100(10):3484

Predictingbleedingrisk• Severalmodelsdeveloped

• Novalidatedbleedingpredictiontool

• Riskfactors:• Age>65• Age>75• Previous bleeding• Cancer• Metastaticcancer• Renalfailure• Thrombocytopenia• Previous stroke• Diabetes• Anemia• Antiplatelettherapy• Pooranticoagulantcontrol• Comorbidity andreducedfunctional capacity• Recentsurgery• Frequentfalls• Alcohol abuse

PredictingbleedingriskLowrisk(0RFs) Moderaterisk(1RF) Highrisk(≥2RFs)

Anticoagulationafterfirst3months

Baselinerisk(%/y) 0.3 0.6 ≥2.5

Increasedrisk(%/y) 0.5 1.0 ≥4

Totalrisk(%/y) 0.8 1.6 ≥6.5

·Estimatesonly·Precisionlimitedbyvariableseverityoffactors·Temporalrelationships·Variabledefinitions

PredictingVTErecurrencerisk• Severalmodelsdeveloped• Novalidatedrecurrencepredictiontool

Lowrisk High risk

Surgicallyprovoked

Recurrentunprovoked

Unprovoked

Non-surgicallyprovoked

Cancer

Canwefurther riskstratifypatientshere?

5%/y 15%/y1%/y

VTEriskfactors:persistent• Malesex,RR~1.6• aPL,RR~2• Hereditarythrombophilia, RR~1.5• “highrisk”thrombophilia• proteinS,proteinC,antithrombin IIIdeficiency,homozygous factorVLeidenandhomozygous prothrombin genemutations

• Asianethnicity,RR~0.8• Residualthrombus inproximalveins,RR~1.5• Post-thrombotic syndrome, RR~2.6

“Prothrombotic abnormalitiesdonotappeartoplayanimportantroleintheriskofarecurrentthromboticevent.Testingforprothrombotic defectshaslittleconsequencewithrespecttoprophylacticstrategies.Clinicalfactorsareprobablymoreimportantthanlaboratoryabnormalitiesindeterminingthedurationofanticoagulationtherapy.”

AnnInternMed.2001;135(5):367JAMA. 1998;279(21):1679-1681

PredictingVTErecurrence:D-dimer• Predictivevalue• Patient-levelmeta-analysis,7studies,n=1818• D-dimermeasurementafterstoppinganticoagulation• D-dimer+:HR2.59(3.7vs.8.8per100patient-years)

AnnInternMed. 2010;153(8):523-531

PredictingVTErecurrence:D-dimer• TwomajorstudiessinceAT9• DULCIS• SerialD-dimer• NoM:Fdifference• Negative:3%/year

• KearonC,SpencerFA,O'KeeffeDetal• AnnualizedVTErecurrence

AnnInternMed.2015;162(1):27-34Blood.2014;124(2):196-203

D-dimer(-) D-dimer (+)Men 8% 16%

Women 5% 10%

*Norecurrencesamongwomenwhowereonestrogen

PredictingVTErecurrence:D-dimer

• Recurrenceriskstratification:possiblyhelpfulinselectpatients

• Dataconflicting

• Possiblynotusefulinmen,womenwithestrogenprovocation

• ACCP,ISTH:5%annualizedriskthreshold:• WouldresultofD-dimerinfluencepatientdecision?• ConsidertestinginwomenwithunprovokedVTEwhowerenottakingestrogentofurtherriskstratify?• D-dimernegative->reclassifiedasintermediaterisk->stopanticoagulation?• D-dimerpositive->remainsinhighriskgroup->resumeanticoagulation?

Thromb Haemost 2010;8:2313–5

VTErecurrencevs.bleeding• After3monthsofanticoagulation• IfACstopped:VTErecurrence->FatalPE,CTEPH,PTS• IfACcontinued:bleeding->majorbleeding,fatalbleeding

• Casefatalityrate• VTE

• During first6monthsofAC:11.3%• Afterdiscontinuation ofAC:3.6%

• Bleeding• During first6monthsofAC:11.3%• Beyond6months:???

AnnInternMed.2010;152(9):578-589

Bleedingcasefatalityrate• 11.3%usedasestimateinguidelines• Possiblylower?• RE-COVER

• dabigatran:5%• VKA:4.2%

• EINSTEIN-PE• rivaroxaban:7.7%• VKA:5.8%

• AMPLIFY• apixaban:6.7%• VKA:4.1%

• Hokusai-VTE• edoxaban:3.6%• VKA:15% NEngl JMed2009;361:2342-52

NEngl JMed2012;366:1287-97NEngl JMed2013;369:799-808NEngl JMed2013;369:1406-15NEngl JMed2013;368:699-708

Indicationsfor3monthsAC• VTEprovokedbysurgery• Bleedingrisknotconsidered• Lowrecurrencerisk• IndefiniteAC->increaseinmajorbleedingwithoutbenefit• StrongrecommendationagainstindefiniteAC

• VTEprovokedbynon-surgicalfactor/unprovokeddistalDVT• Higherrecurrencerisk• IndefiniteAC->increaseinmajorbleedingwithoutbenefit• StrengthofrecommendationagainstindefiniteACweakerforpatientswithlowormoderatebleedingrisk

• StrongrecommendationagainstindefiniteACforhighrisk

IndicationsforindefiniteAC• FirstunprovokedproximalDVTorPE• Highrecurrencerisk,reducedbyindefiniteAC• Lowormoderatebleedingrisk:weakrecommendationinfavorofindefiniteAC

• Highbleedingrisk:strongrecommendationagainstindefiniteAC

• SecondunprovokedVTE• Veryhighrecurrencerisk,largereductioninriskbyindefiniteAC• Lowbleedingrisk:strongrecommendationinfavorofindefinite• Moderatebleedingrisk:weakrecommendationinfavorofindefinite

• Highbleedingrisk:weakrecommendationagainstindefiniteAC

IndicationsforindefiniteAC• VTEandactivecancer• Veryhighrecurrencerisk,reducedbyindefiniteAC• Lowormoderatebleedingrisk:strongrecommendationforindefinite• Highbleedingrisk:weakrecommendationforindefinite

ProvokedVTE Unprovoked VTE Cancer-associatedVTE

Stopafter3months FirstVTE

RecurrentVTEDistalDVT ProximalDVTand/orPE

Lowormoderatebleedingrisk

Highbleedingrisk

Stopafter3months IndefinitetherapyStopafter3months

Indefiniteoruntilcancer“notactive”

Highbleedingrisk

Stopafter3months

Shareddecisionmaking• Considerstrengthofevidence• Surgicallyprovoked:3months• Cancer:indefinite• FirstunprovokedVTEwithhighbleedingrisk:3months• SecondunprovokedVTEwithlowbleedingrisk:indefinite• Allothersituations:grayareasremain,personalizetreatment

• DVTvs.PE• Recurrentprovoked• Persistentriskfactors• Fears• Hobbies• Burdensoftherapy• VKAvs.DOAC

NEngl JMed.1997;336(6):393

CTEPH• ChronicThromboembolicPulmonaryHypertension• NoRCTs• Highqualityindirectevidence

• Recurrenceriskhigh

• Severeconsequencesofrecurrence

• Recommendation:indefiniteanticoagulation(1B)

Superficialveinthrombosis• RiskfactorssimilartoDVT,PE• Smallstudies:NSAIDs,UFH,LMWH,VKA• CALISTO• n=3000• placebovs.fondaparinux2.5mg/dfor45days• LowerextremitySVT≥5cm• 85%RRRincompositeoutcome• Onepatientwithmajorbleedingineachgroup

• Recommendation:prophylacticdoseofLMWHorfondaparinux for45days(2B)

NEngl JMed .2010;363(13):1222- 1232

UpperextremityDVT• NoRCTs• Observationalstudies• RecurrentVTEandPTS:lowerextremity>upperextremity

• RiskfactorsgenerallysimilartoLEDVT• CVC• Cancer

UpperextremityDVT• Recommendations

• UEDVTofaxillaryveinormoreproximal:3months(2B)

• UEDVTwithCVC:3monthsoverlongerduration• Withoutcancer(1B)• Withcancer(2C)

• UEDVTwithCVC:ACaslongasCVCinplaceover3months• Withoutcancer(2C)• Withcancer(1C)

• UEDVTnotassociatedwithcancer/CVC:3monthsoverlongerduration(1B)

Splanchnicveinthrombosis• NoRCTs• Incidental• Anticoagulationvs.notreatment• Extentofthrombosis• Progression• Cancer• Chemotherapy• Duration?

• Provokedversusunprovoked• Surgicalormedicalfactors:3months?• Unprovoked,persistentriskfactor,myeloproliferativedisorder:indefinite?

Hepaticveinthrombosis• NoRCTs• Incidental• Anticoagulationvs.notreatment• Extentofthrombosis• Progression• Cancer• Chemotherapy• Duration?

• Provokedversusunprovoked• Surgicalormedicalfactors(eg,estrogen):3months?• Unprovoked,persistentriskfactor:indefinite?

Questions