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Risk Stratification for Bleeding Complications in Patients With Venous Thromboembolism: Application of the HAS-BLED Bleeding Score During the First 6 Months of Anticoagulant Treatment

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Title:
Risk Stratification for Bleeding Complications in Patients With Venous Thromboembolism: Application of the HAS-BLED Bleeding Score During the First 6 Months of Anticoagulant Treatment
Series Title:
Brown, J. D., Goodin, A. J., Lip, G. Y., & Adams, V. R. (2018). Risk Stratification for Bleeding Complications in Patients With Venous Thromboembolism: Application of the HAS‐BLED Bleeding Score During the First 6 Months of Anticoagulant Treatment. Journal of the American Heart Association, 7(6), e007901.
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Brown, Joshua
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American Heart Association
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English
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Journal Article

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Abstract:
Background-—The Hypertension, Abnormal renal/liver function, Stroke, Bleeding, Labile International Normalized Ratio (INR), Elderly, Drugs or alcohol use (HAS-BLED) score has strong predictive validity for major bleeding complications, but limited validation has been conducted in venous thromboembolism (VTE). This study evaluates the HAS-BLED score in a large cohort of VTE patients. Methods and Results-—A retrospective cohort of adults ≥18 years with primary diagnosis of VTE between January 1, 2010 and November 31, 2013 were identified in an insurance claims database. Patients were tracked until death, any bleed event, or end of study period. HAS-BLED score and components were evaluated via proportional hazard models. Cumulative incidence functions were reported at 30, 60, 90, and 180 days. N=132 280 patients with a VTE were identified, with 73.8% having HAS-BLED scores of 0 to 2, 3.6% score ≥4, and 4789 bleeding events (3.6% all patients). A 1-point HAS-BLED score increase was associated with 20% to 30% bleeding rate increase overall, but in a cancer cohort only the increase from 3- to 4-points was significant for all bleeds (csHR=1.41, 95% CI: 1.17–1.69; sdHR=1.40, 95% CI: 1.17–1.69) and major bleeds (csHR=1.66, 95% CI: 1.26–2.20; sdHR=1.66, 95% CI: 1.25–2.19). Adding cancer to the model as an independent covariate provided the strongest association among all covariates, with csHR=2.25 (95% CI: 1.98–2.56) and sdHR=2.11 (95% CI: 1.85–2.41) in the model for major bleeds. Conclusions-—The HAS-BLED score has good predictive validity for bleeding risks in patients with VTE. The addition of cancer as an independent bleeding risk factor merits consideration, possibly as part of the “B” criterion (“bleeding tendency or predisposition”).
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Collected for University of Florida's Institutional Repository by the UFIR Self-Submittal tool. Submitted by Joshua Brown.

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RiskStrati cationforBleedingComplicationsinPatientsWithVenous Thromboembolism:ApplicationoftheHAS-BLEDBleedingScore DuringtheFirst6MonthsofAnticoagulantTreatmentJoshuaD.Brown,PharmD,PhD;AmieJ.Goodin,PhD,MPP;GregoryY.H.Lip,MD,FRCP,DFM,FACC,FESC;ValR.Adams,PharmD,BCOPBackground- TheHypertension,Abnormalrenal/liverfunction,Stroke,Bleeding,LabileInternationalNormalizedRatio(INR), Elderly,Drugsoralcoholuse(HAS-BLED)scorehasstrongpredictivevalidityformajorbleedingcomplications,butlimited validationhasbeenconductedinvenousthromboembolism(VTE).ThisstudyevaluatestheHAS-BLEDscoreinalargecohortof VTEpatients. MethodsandResults- Aretrospectivecohortofadults 18yearswithprimarydiagnosisofVTEbetweenJanuary1,2010and November31,2013wereidenti edinaninsuranceclaimsdatabase.Patientsweretrackeduntildeath,anybleedevent,orendof studyperiod.HAS-BLEDscoreandcomponentswereevaluatedviaproportionalhazardmodels.Cumulativeincidencefunctions werereportedat30,60,90,and180days.N = 132280patientswithaVTEwereidenti ed,with73.8%havingHAS-BLEDscoresof 0to2,3.6%score 4,and4789bleedingevents(3.6%allpatients).A1-pointHAS-BLEDscoreincreasewasassociatedwith20%to 30%bleedingrateincreaseoverall,butinacancercohortonlytheincreasefrom3-to4-pointswassigni cantforallbleeds (csHR = 1.41,95%CI:1.17 1.69;sdHR = 1.40,95%CI:1.17 1.69)andmajorbleeds(csHR= 1.66,95%CI:1.26 2.20;sdHR = 1.66, 95%CI:1.25 2.19).Addingcancertothemodelasanindependentcovariateprovidedthestrongestassociationamongall covariates,withcsHR = 2.25(95%CI:1.98 2.56)andsdHR = 2.11(95%CI:1.85 2.41)inthemodelformajorbleeds. Conclusions- TheHAS-BLEDscorehasgoodpredictivevalidityforbleedingrisksinpatientswithVTE.Theadditionofcancerasan independentbleedingriskfactormeritsconsideration,possiblyaspartofthe B criterion( bleedingtendencyorpredisposition ). ( JAmHeartAssoc .2018;7:e007901.DOI:10.1161/JAHA.117.007901.) KeyWords: HAS-BLEDscore riskstrati cation venousthromboembolism Venousthromboembolism(VTE),includingbothdeepvein thrombosisandpulmonaryembolismaffectsaround1to 2adultsper1000everyyear.1ThemostrecentAmerican CollegeofChestPhysicians(ACCP)guidelinesrecommend treatmentwithnon-vitaminKantagonistoralanticoagulants overvitaminKantagonists(eg,warfarin)inpatientswithout cancerforatleast3months.2Inpatientswithcancer,lowmolecularweightheparins(LMWH)arerecommendedover othertreatments.Thegoalofanticoagulationistotreatthe currentVTEandtopreventrecurrentVTE.However,anticoagulationalsoimposesanincreasedriskforbleedingevents andthisriskmustbeassessedtodetermineappropriateness ofagiventreatmentplanforeachpatient. Inananalogoustreatmentparadigm,individualswithatrial brillation(AF)oftenreceivelong-termanticoagulationfor preventionofcerebrovascularevents.IntheAFpopulation, riskscoresarenowcommonlyusedasclinicaldecision supporttoolstoinitiateanticoagulationbasedonstrokerisk (eg,CHADSsandCHA2DS2-VASc).3Morerecently,bleeding riskscoreshavebeendevelopedtogohand-in-handwith strokeriskscorestodeterminethepotentialnetclinical bene tofanticoagulationandtoguidepatientfollow-up throughouttherapy.3TheHypertension,Abnormalrenal/liverfunction,Stroke, Bleeding,LabileInternationalNormalizedRatio(INR),Elderly, Drugsoralcoholuse(HAS-BLED)scoreisonesuchscoreand FromtheDepartmentofPharmaceuticalOutcomes&Policy,Universityof FloridaCollegeofPharmacy,Gainesville,FL(J.D.B.,A.J.G.);Instituteof CardiovascularScience,UniversityofBirmingham,UnitedKingdom(G.Y.H.L.); AalborgThrombosisResearchUnit,DepartmentofClinicalMedicine,Aalborg University,Aalborg,Denmark(G.Y.H.L.);DepartmentofPharmacyPractice& Science,UniversityofKentuckyCollegeofPharmacy,Lexington,KY(V.R.A.). Correspondenceto: JoshuaD.Brown,PharmD,PhD,UniversityofFlorida CollegeofPharmacy,1225CenterDr.HPNP#3320,Gainesville,FL32611. E-mail:joshua.brown@u .edu ReceivedNovember25,2017;acceptedJanuary30,2018. 2018TheAuthors.PublishedonbehalfoftheAmericanHeartAssociation, Inc.,byWiley.ThisisanopenaccessarticleunderthetermsoftheCreative CommonsAttribution-NonCommercial-NoDerivsLicense,whichpermitsuse anddistributioninanymedium,providedtheoriginalworkisproperlycited, theuseisnon-commercialandnomodi cationsoradaptationsaremade. DOI:10.1161/JAHA.117.007901 JournaloftheAmericanHeartAssociation1 ORIGINALRESEARCH by guest on March 7, 2018 http://jaha.ahajournals.org/ Downloaded from

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hasbeenshowntohavestrongpredictivevalidityformajor bleedingcomplications.4HAS-BLEDhasbeenvalidatedacross severalAFcohorts4,5andhasrecentlybeenappliedto patientswithVTEtodetermineitsabilitytoidentifythoseat thehighestrisk.6ThesepriorstudiesofVTEcohortshave beenlimitedinsizeandnumberofevents,andhavethusbeen unabletoestablishaclearabilityoftheHAS-BLEDscoreto assessbleedingriskinaVTEpopulation. Thisstudy sprimaryobjectivewastoevaluatetheHASBLEDscoreinalargecohortofVTEpatientsreceiving outpatientanticoagulationtreatment.Second,theHAS-BLED scorewasevaluatedinasubgroupofVTEpatientswith cancer.Thelatterobjectiveful llsacrucialgapinthe literature,giventhatcancerisoneofthestrongestrisk factorsforVTEandpresentsamorecomplicatedpatient populationinregardstoadditionalriskfactorsforadverse bleedingevents.MethodsThisretrospectivecohortstudyusedtheTruvenHealth MarketScanCommercialClaimsandMedicareSupplemental Databasesfromtheyears2010 2014.TheMarketScandata include 40millionindividualsfrom > 160largeemployers andhealthplansacrosstheUnitedStates.Thedatarepresent anindividual shealthcareutilizationincludingmedicalclaims withdiagnosisandprocedurecodesformedicalencounters andallprescriptionmedication lls,aswellasin-hospital mortality.Thesedataarede-identi edincompliancewiththe HealthInsurancePortabilityandAccountabilityActregulations (HIPAA)andtheUniversityofKentuckyInstitutionalReview Boardapprovedtheuseofthedatabaseforthisstudy.Thedata arelicensedandarenotavailableforpublicdissemination. Codesforanalyticmethodsareavailablefromtheauthorson requestforpurposesofreproducingthestudyresults.CohortSelectionAdultsaged 18yearsdiagnosedwithaVTEeventbetween January1,2010andNovember31,2013wereidenti ed.The dateofthe rstqualifyingdiagnosisofVTEwasde nedasthe indexdate,requiringthatthediagnosiswasintheprimary positiononaninpatienthospitalrecord.VTEwasidenti edby InternationalClassi cationofDisease,9threvision ( ICD-9 ) codesbasedonpreviouslyvalidatedcodingalgorithms.7Patientswerefurtherrequiredtohaveatleast12monthsof pre-indexanda1-monthminimumofpost-indexcontinuous enrollmentwithmedicalandoutpatientpharmacyinformation includedinthedatabase.Patientswerealsorequiredtobe treatment-na ve(ie,noanticoagulanttherapyduringthe baselineperiod),topresentananticoagulanttreatmentna ve cohort.CohortCharacteristicsThecohortwasdescribedbyage(18 64,65 74, 75years) andsex.AllcategoriesfortheHAS-BLEDscorewereidenti ed by ICD-9 codesincluding:hypertension,liverdisease,history ofstroke,historyofbleeding,8alcoholabuse,anddrug abuse.9NSAIDsorantiplateletmedicationswereidenti ed frompharmacyrecords.The labileINR criterionofHASBLEDwasnotassessedgiventhatthecohortwasrequiredto beanticoagulanttreatment-na veandnosuchrecordswould exist. PatientswereassignedatotalHAS-BLEDscoreof1-point eachforhypertension,renaldisease,liverdisease,historyof stroke,historyofbleeding,aged > 65years,medicationuse predisposingtobleeding(NSAIDsandantiplatelets),and alcoholand/ordrugabuse.Patientswithmalignantneoplasmsand/ormetastaticdiseaseduringthebaselineperiod werealsoidenti edusing ICD-9 codes140.xto209.x. Anticoagulanttreatmentwasidenti edasthe rstobserved LMWH,non-vitaminKantagonistoralanticoagulant,or warfarin,allowingforbridgetherapyfromLMWHtowarfarin.PatientFollow-UpandOutcomesAllbleedingeventsweretrackedduringthe180days followingtheinitialVTEdiagnosis.Patientswerefollowedup untiltheyexperiencedableedingevent,werecensoreddueto ClinicalPerspectiveWhatIsNew? TheHAS-BLEDscorehasbeenwidelyusedforrisk strati cationinpatientswithatrial brillationreceiving anticoagulation. ThisstudyshowsthatHAS-BLEDhashighpredictivevalidity forbleedingeventsinvenousthromboembolism(VTE) patientsreceivinganticoagulation. Further,weshowthatcancerisastrongindependentrisk factorforbleedinginthispopulationandshouldbeincluded intheriskscore.WhatAretheClinicalImplications? HAS-BLEDcanbeusedinpatientswithVTEtopredictthe riskofableedingeventwhilebeinganticoagulated. Bleedriskstrati cationscoresshouldnotbeusedto withholdtreatment. Rather,riskscorescanbeusedtoidentifypatientsfor monitoringormodi edtherapeuticapproachesaswellas identi cationofsomemodi ableriskfactors(eg,blood pressure,medicationuse). DOI:10.1161/JAHA.117.007901 JournaloftheAmericanHeartAssociation2 ApplicationofHAS-BLEDforBleedinginVTE BrownetalORIGINALRESEARCH by guest on March 7, 2018 http://jaha.ahajournals.org/ Downloaded from

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droppingoutofthedatabase,theydied,oruntiltheendofthe studyperiodorfollow-uptime.Bleedingeventswereclassi ed as all iftheymetthecodingalgorithmusedor major if theyoccurredduringaninpatientstay,wereassociatedwitha criticalsite,resultedinneedfortransfusion,orleadtodeath whileinthehospital.10StatisticalAnalysisAtime-to-event,survivalanalyticapproachwastaken.Given thatthereisahighriskofdeathintheoverallcohort,andan especiallyelevatedriskinthecancersub-group,itwas deemednecessarytoassessoutcomesinacompetingrisks framework,takingdeathintoaccountasacompetingeventto theprimarybleedingoutcome.11Thecumulativeincidencefunction(CIF)ofallbleeding eventsandmajorbleedingeventsweremodeledusingFine andGray smethodforcompetingriskswhichreportedthe incidenceproportionatmultipletimeperiods(30,60,90, 180days).12CIFplotswerestrati edbyHAS-BLEDscores andshowtheincidenceofbleedingcomplications,takinginto accountbothcensoringandcompetingeventsduringfollowup.Gray sstatisticaltestsfortheequalityofCIFcurves betweenHAS-BLEDstrati cationswereconducted. Table1. DemographicandClinicalCharacteristicsofPatientsWithanIndexVenousThromboembolismDVTOnly PEWithorWithoutDVT Overall N%N%N%Total 6093046.171350 53.9 132280100 Age,y 18to64 3673160.347520 66.6 8425163.7 65to74 7793 12.88978 12.6 1677112.7 75 1640626.914852 20.8 3125823.6 Sex(male) 2773452.032257 51.5 5999145.4 Hypertension 2868253.830127 48.1 5880944.5 Renaldisease 6365 11.93770 6.0 101357.7 Liverdisease 3826 7.23733 6.0 7559 5.7 Historyofstroke 6943 13.05470 8.7 124139.4 Historyofbleeding 8076 15.27405 11.8 1548111.7 Medicationuse(NSAIDs,antiplatelets)1644330.819908 31.8 3635127.5 Alcoholordruguse 827 1.6843 1.4 1670 1.3 Cancer 1258623.612329 19.7 2491518.8 Metastaticcancer 4197 7.94317 6.9 8514 6.4 HAS-BLEDScore 0 1256423.618023 28.8 3058723.1 1 1642430.820858 33.3 3728228.2 2 1453627.315282 24.4 2981822.5 3 7048 13.26389 10.2 1343710.2 4 2320 4.41786 2.9 4106 3.1 5 397 0.7251 0.4 648 0.5 6 28 0.119 0.0 47 0.0 7 2 0.0 2 0.0 Anticoagulation LMWH 5955 11.23980 6.4 9935 7.5 NOAC 8465 15.912100 19.3 2056515.5 Warfarin 3889973.046528 74.3 8542764.6DVTindicatesdeepveinthrombosis;HAS-BLED,Hypertension,Abnormalrenal/liverfunction,Stroke,Bleeding,LabileInternationalNormalizedRatio(INR),Elderly,Drugsoralcoholuse; LMWH,lowmolecularweightheparin;NOAC,non-vitaminKantagonistoralanticoagulant;PE,pulmonaryembolism. DOI:10.1161/JAHA.117.007901 JournaloftheAmericanHeartAssociation3 ApplicationofHAS-BLEDforBleedinginVTE BrownetalORIGINALRESEARCH by guest on March 7, 2018 http://jaha.ahajournals.org/ Downloaded from

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Twoproportionalhazardregressionmodelsspeci cations wereused.Acause-speci cmodelwasusedwhichtreatsthe competingriskasacensoringevent.Thismodelsthe instantaneousrateofbleedingeventsamongsubjectswho areeventfreeatagiventimepoint(nobleeding,nodeath). Thecause-speci cmodeliscomparabletoatypicalCox proportionalhazardmodel.Asub-distributionmodelwasalso usedwhichaccountsdirectlyfordeathasacompetingriskby retainingthosethatdiewithinagiventimepointintherisk set.Suchamodelprovidesanestimateoftheinstantaneous rateofbleedingeventsinthosewhohavenotexperienceda bleedorhavediedwithinthetimeinterval.Includingboth modelsallowedforbroaderinterpretationofresultsaseach hasuniqueimplicationsandapplications.11Speci cally,using bothapproachesallowsforanassessmentofhowtheriskof deathinterplayswiththeriskofbleedingandtheassociation ofeachwiththeincludedcovariates. Fromeachmodel,cause-speci c(csHR)andsub-distribution(sdHR)hazardratiosand95%con denceintervals(CI)are reportedfortheHAS-BLEDscore,individualcomponentsof theHAS-BLEDscore,andforcancer.TobettercompareHASBLEDscoresandpotentiallow/highriskcut-offs,hazard Table2. CumulativeIncidenceProportionofBleedingEventsat30,60,90,and180DaysofFollow-UpbyHAS-BLEDScoreTimetoBleedingEvent HAS-BLEDScore 0123 4(A)Majorbleeds,overall 30d0.5%(0.4 0.5%)0.5%(0.5 0.6%)0.6%(0.5 0.7%)0.6%(0.5 0.8%)1.1%(0.9 1.4%) 60d0.6%(0.5 0.7%)0.7%(0.6 0.8%)0.8%(0.8 0.9%)0.8%(0.7 1.0%)1.7%(1.4 2.0%) 90d0.7%(0.6 0.8%)0.9%(0.8 1.0%)1.1%(1.0 1.2%)1.1%(1.0 1.3%)2.3%(2.0 2.7%) 180d0.9%(0.8 1.1%)1.3%(1.1 1.4%)1.7%(1.5 1.8%)2.0%(1.8 2.3%)3.4%(3.0 3.9%) (B)Majorbleeds,nocancer 30d0.4%(0.3 0.5%)0.5%(0.4 0.5%)0.5%(0.4 0.6%)0.6%(0.5 0.8%)1.0%(0.7 1.3%) 60d0.5%(0.4 0.6%)0.6%(0.5 0.7%)0.7%(0.6 0.8%)0.8%(0.6 0.9%)1.5%(1.2 1.9%) 90d0.6%(0.5 0.7%)0.8%(0.7 0.9%)0.9%(0.8 1.0%)1.0%(0.9 1.2%)2.1%(1.7 2.6%) 180d0.7%(0.6 0.8%)1.0%(0.9 1.2%)1.3%(1.2 1.5%)1.8%(1.6 2.1%)3.1%(2.6 3.7%) (C)Majorbleeds,canceronly 30d0.9%(0.7 1.3%)0.7%(0.6 0.9%)0.9%(0.7 1.1%)0.7%(0.5 0.9%)1.3%(0.9 1.9%) 60 d 1.3%(1.0 1.7%)1.1%(0.8 1.3%)1.3%(1.1 1.6%)1.0%(0.8 1.3%)1.9%(1.4 2.6%) 90d 1.7%(1.3 2.1%)1.3%(1.1 1.6%)1.7%(1.5 2.0%)1.3%(1.1 1.7%)2.7%(2.1 3.4%) 180d 2.4%(1.9 2.9%)2.1%(1.8 2.5%)2.6%(2.2 2.9%)2.5%(2.1 3.0%)4.1%(3.3 5.0%) (D)Allbleeds,overall 30d 1.2%(1.1 1.4%)1.4%(1.3 1.5%)1.5%(1.4 1.6%)1.5%(1.4 1.7%)2.5%(2.2 2.9%) 60d 1.6%(1.5 1.8%)1.9%(1.8 2.1%)2.1%(1.9 2.2%)2.2%(2.0 2.4%)3.7%(3.2 4.2%) 90d 1.9%(1.8 2.1%)2.4%(2.2 2.5%)2.7%(2.6 2.9%)3.1%(2.8 3.3%)5.0%(4.5 5.6%) 180d 2.6%(2.4 2.8%)3.4%(3.2 3.6%)4.2%(4.0 4.4%)5.3%(4.9 5.6%)8.0%(7.3 8.7%) (E)Allbleeds,nocancer 30d 1.0%(0.9 1.2%)1.3%(1.1 1.4%)1.3%(1.2 1.5%)1.6%(1.4 1.8%)2.3%(1.9 2.8%) 60d 1.4%(1.2 1.5%)1.7%(1.6 1.9%)1.8%(1.7 2.0%)2.1%(1.9 2.4%)3.5%(3.0 4.1%) 90 d 1.6%(1.4 1.8%)2.1%(1.9 2.2%)2.3%(2.1 2.5%)2.9%(2.6 3.2%)4.8%(4.2 5.5%) 180d 2.1%(2.0 2.3%)2.9%(2.7 3.1%)3.6%(3.4 3.9%)4.8%(4.4 5.2%)7.6%(6.8 8.5%) (F)Allbleeds,canceronly 30d 2.5%(2.0 3.0%)1.9%(1.6 2.2%)1.9%(1.6 2.1%)1.4%(1.2 1.8%)2.9%(2.2 3.6%) 60d 3.3%(2.7 3.8%)2.8%(2.4 3.1%)2.8%(2.5 3.2%)2.4%(2.1 2.9%)4.1%(3.3 4.9%) 90d 4.2%(3.6 4.9%)3.5%(3.1 3.9%)3.8%(3.4 4.2%)3.5%(3.0 4.0%)5.4%(4.5 6.4%) 180d 5.9%(5.2 6.7%)5.4%(4.9 6.0%)5.8%(5.4 6.3%)6.3%(5.6 7.0%)8.6%(7.4 9.9%)HAS-BLEDindicatesHypertension,Abnormalrenal/liverfunction,Stroke,Bleeding,LabileInternationalNormalizedRatio(INR),Elderly,Drugsoralcoholuse. DOI:10.1161/JAHA.117.007901 JournaloftheAmericanHeartAssociation4 ApplicationofHAS-BLEDforBleedinginVTE BrownetalORIGINALRESEARCH by guest on March 7, 2018 http://jaha.ahajournals.org/ Downloaded from

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ratiosarepresentedincrementally(ie,comparingthelevel withthepreviouslevel,ratherthanhavingacommon referencegroup).Anticoagulanttreatmentwasincludedasa covariatetocontrolforanyselectionbiasintreatment selection.C-indices,ametricofmodelconcordanceor,the abilityofthemodeltoidentifythosewhowillhaveoutcomes, arereported. AlldataanalysiswasperformedusingSASEnterprise Guide(SASInstitute,Cary,NC)version7.1withanapriori alphaof0.05forstatisticalsigni cance.ResultsOverthestudyperiod,N = 132280patientswithVTEwere identi edincluding60930(46.1%)withdeepveinthrombosis and71350(53.9%)withpulmonaryembolism(Table1). Nearlytwo-thirdswereaged18to64years(63.7%),and 45.4%weremale.ThemostcommonHAS-BLEDcomponent washypertension(44.5%),followedbyNSAIDorantiplatelet medicationuse(27.5%),cancer(18.8%),andahistoryof bleeding(11.7%).ThelargemajorityofpatientshadHAS-BLED scoresof0to2,10.2%hadascoreof3,and3.6%hadascore 4.Themajorityofpatientsreceivedwarfarin(64.6%),15.5% receivednon-vitaminKantagonistoralanticoagulants,and 7.5%receivedLMWH.Treatmentdidnotdifferbasedonthe HAS-BLEDscoreintheoverallcohortbutcancerpatients weremorelikelytoreceiveLMWHthannon-cancerpatients, whichisconsistentwithUStreatmentguidelines.2,13Therewereatotalof4789(3.6%ofallpatients)bleeding eventsofwhich,1847(38.6%)wereclassi edasmajor bleeds.Mediantimetobleedwas50days(mean62days)for allbleedsaswellasmajorbleeds.Anadditional2739patients (2.1%ofallpatients)diedinthehospitalduringfollow-upwith amediantimetodeathof66daysafterindex.Theremainder ofpatientswerecensoredwithmeanfollow-upof160 32 days. Table2showsthe30,60,90,and180-dayCIFestimates ofallbleedsandmajorbleedsstrati edbytheHAS-BLED scoreswiththecorrespondingCIFplotsinFigure.The incidenceofbleedingeventsincreasedwithincreasingHASBLEDscoreswithstatisticallysigni cantdifferencesbetween HAS-BLEDscores( P < 0.001).DirectlycomparingtheHASBLEDscoresof3and4,whichhavebeeninvestigated previouslyascutpointsfordistinguishinghighrisk,at180daysascoreof4hadcumulativeincidenceformajorbleeding of3.1%(2.7 3.6%)andallbleedingof7.3%(6.6 8.0%).AHASBLEDscoreof3wasassociatedwithacumulativeincidence of5.3%(4.9 5.6%),whichwassigni cantlylowerthanthe HAS-BLED 4group( P < 0.001).Thecancercohorthada higherriskofbleedingthantheoverallandnon-cancercohort andtherewasaconsistentcorrelationbetweenincreasesin HAS-BLEDscoresandtheriskofbleedingevents. Figure.Cumulativeincidencefunctionplotsofmajor(AthroughC)andall(DthroughF)bleedingeventsstrati edbyHAS-BLEDscoresfor overall(AandD),non-cancer(BandE),andcancergroups(CandF).HAS-BLEDindicatesHypertension,Abnormalrenal/liverfunction, Stroke,Bleeding,LabileInternationalNormalizedRatio(INR),Elderly,Drugsoralcoholuse.GraphlablelofHAS-BLEDscoreof 4 indicates HAS-BLED 4. DOI:10.1161/JAHA.117.007901 JournaloftheAmericanHeartAssociation5 ApplicationofHAS-BLEDforBleedinginVTE BrownetalORIGINALRESEARCH by guest on March 7, 2018 http://jaha.ahajournals.org/ Downloaded from

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Theresultsoftheregressionanalysesareprovidedin Table3fortheHAS-BLEDscoreandTable4forindividual componentsandcancervariables.Overall,anincreaseof1 pointintheHAS-BLEDscoreincreasedtherateofbleedingby 20%to30%.Inthecanceronlycohort,increasesfrom0 pointsto3pointswerenotstatisticallysigni cant.Forcancer, onlyincreasingfrom3pointsto4pointstotalwassigni cant. InTable4,mostoftheHAS-BLED sindividualcomponents weresigni cantpredictorsofmajorandallbleedingwith hazardratiosrangingfrom1.35to1.90.Ageandhighbleed riskmedicationusewerenotfoundtobesigni cantly predictiveintheseresults. Addingcancertothemodelasanindependentcovariate providedthestrongestassociationofallincludedcovariates, withhazardratiosof2.25(95%CI:1.98 2.56)inthecausespeci cmodelformajorbleedsand2.11(95%CI:1.85 2.41) inthesub-distributionmodelformajorbleeds.Similarresults wereobservedforallbleeds,withhazardratiosof2.07(95% CI:1.91 2.25)inthecause-speci cmodeland1.94(95%CI: 1.78 2.11)inthesub-distributionmodel.C-indicesranged between0.66to0.73andwerehighestforthenon-cancer cohortversusthecancercohort.DiscussionToourknowledgethisisthelargestandmostcomprehensive analysisusingtheHAS-BLEDscoretoassessbleedingin patientswithVTE.Ourprincipal ndingsarethattheHASBLEDscorehasgoodpredictivevalidityforbleedingrisksin patientswithVTE,whereaHAS-BLEDscoreof 4indicateda cleardelineationforthoseathighriskformajorbleeding amongthetotalcohort.Thisobservationremainedconsistent whencomparingriskformajorbleedingamongcancerand non-cancerpatients.Second,theadditionofcancerasan independentriskfactortobleedingriskmeritsconsideration, possiblyaspartoftheBcriterion( bleedingtendencyor predisposition )oftheHAS-BLEDscore. TheuseoftheHAS-BLEDscore,oranyriskstrati cationtool, inpatientswithVTEshouldbeappropriatelyappliedandnot misused.14Adesignationof highrisk inthispopulationshould beusedto agup highriskpatientsforadditionalreviewand follow-up.Moreimportantly,themanagementofreversible bleedingriskfactors(andtheHAS-BLEDscorecontainsmostof themorecommonmodi ablebleedingriskfactors)shouldbe performedinallpatients,andthedesignationofhighbleedrisk isnotintendedforthewithholdingofanticoagulationtherapyin manypatientswithVTE. TheHAS-BLEDscorehasbeenmostvalidatedinpatients withAF,whereitwaspredictiveofbleedinginpatientsonno antithrombotictherapy,aspirinandanticoagulants(whether warfarinornon-warfarinanticoagulants).4,15DatainVTE patientsaremorelimited.Forexample,Kooiman,etalfound anincreasedriskofmajorbleedingataHAS-BLEDscoreof 3inacohortof537acuteVTEpatients.6Thepresentstudy greatlyextendstheworkbyKooimanetalbyreplicatingthe studydesignusingasubstantiallylargercohort,where Table3. SurvivalRegressionModelShowingtheIncremental Cause-Speci candSub-DistributionHazardRatiosComparing HAS-BLEDScoresRiskofBleedingEventsHAS-BLEDScore Comparison CoxPHCompetingRisks csHR95%CIsdHR95%CI(A)Majorbleeds,overall HAS-BLED1vs01.341.15to1.561.341.15to1.55 HAS-BLED2vs11.311.16to1.491.311.16to1.48 HAS-BLED3vs21.221.06to1.391.211.06to1.39 HAS-BLED 4vs31.711.44to2.041.711.44to2.03 (B)Majorbleeds,nocancer HAS-BLED1vs01.441.20to1.731.441.20to1.72 HAS-BLED2vs11.261.08to1.471.261.08to1.47 HAS-BLED3vs21.371.16to1.631.371.15to1.63 HAS-BLED 4vs31.721.38to2.141.711.38to2.14 (C)Majorbleeds,canceronly HAS-BLED1vs00.880.67to1.140.890.68to1.15 HAS-BLED2vs11.220.99to1.491.231.00to1.50 HAS-BLED3vs20.950.77to1.190.950.77to1.19 HAS-BLED 4vs31.661.26to2.201.661.25to2.19 (D)Allbleeds,overall HAS-BLED1vs01.291.18to1.411.281.17to1.41 HAS-BLED2vs11.241.15to1.331.241.14to1.33 HAS-BLED3vs21.241.14to1.351.241.14to1.35 HAS-BLED 4vs31.551.38to1.731.541.38to1.73 (E)Allbleeds,nocancer HAS-BLED1vs01.351.21to1.501.341.21to1.50 HAS-BLED2vs11.241.13to1.361.241.13to1.36 HAS-BLED3vs21.331.20to1.481.331.20to1.48 HAS-BLED 4vs31.621.41to1.861.611.40to1.86 (F)Allbleeds,canceronly HAS-BLED1vs00.890.76to1.050.900.76to1.06 HAS-BLED2vs11.070.94to1.221.080.95to1.23 HAS-BLED3vs21.050.92to1.211.050.92to1.21 HAS-BLED 4vs31.411.17to1.691.401.17to1.69C-indices(95%CI)forCoxPHandcompetingrisksmodels,respectively:A = 0.710(0.698 0.723),0.700(0.690 0.710);B = 0.730(0.712 0.748),0.720(0.710 0.730);C = 0.685 (0.665 0.705),0.670(0.658 0.682);D = 0.725(0.715 0.735),0.715(0.705 0.725); E = 0.735(0.728 0.742),0.730(0.720 0.740);F= 0.670(0.650 0.690),0.660(0.635 0.685).CIindicatescon denceinterval;csHR,cause-speci chazardratio;HAS-BLED, Hypertension,Abnormalrenal/liverfunction,Stroke,Bleeding,LabileInternational NormalizedRatio(INR),Elderly,Drugsoralcoholuse;PH,proportionalhazards;sdHR, sub-distributionhazardratio. DOI:10.1161/JAHA.117.007901 JournaloftheAmericanHeartAssociation6 ApplicationofHAS-BLEDforBleedinginVTE BrownetalORIGINALRESEARCH by guest on March 7, 2018 http://jaha.ahajournals.org/ Downloaded from

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estimatescouldbestabilizedandindividualelementsofthe riskscorecouldbeexamined. Theimplicationsofthese ndingsarethatthecurrent designationof highrisk formajorbleedsmayperhapsbe betterattributedtothoseVTEpatientswithaHAS-BLEDscore 4asKooiman,etalpostulated.6Asmentionedabove,we shouldnotfocusondesignatingacutpointforwhatishighrisk, buttoprovidefurtherevidenceforcontinuedrevieworfor followupandactiontoreducetheelementsoftheHAS-BLED scorethataremodi able(eg,alcoholexcess,concomitant NSAIDsorantiplatelets,uncontrolledhypertension,etc).14In thecurrentanalysis,utilizingahigh-riskcut-offofHAS-BLED 4 wouldhaveasensitivityof < 5%foridentifyingtruepositive casesgiventhedistributionoftheHAS-BLEDscoresinthe cohortstudied( 5%ofpatientshadaHAS-BLED 4).Thus,to preventthemostbleedeventsinapatientpopulation,therange ofHAS-BLEDscoresshouldbeconsidered,andmodi ablerisk factorsconsidered,forclinicalintervention. Cancerwasincludedasameanstostratifythecohort giventhepossibledifferenceinbaselinehazardforthecancer populationandalsoincludedasacovariateintheregression models.Cancerisamongthestrongestriskfactorsfor VTE,16,17andwaspresentinroughly20%ofthecohort studied.Whenincludedasanindividualcovariatealongwith componentsoftheHAS-BLEDscore,cancerwasthestrongest predictorofmajorandoverallbleeding.Inthecancercohort, theHAS-BLEDscorewithoutconsiderationofcancer appearedtobelesspredictiveofbleedingeventscompared withthenon-cancercohort(Table3).Alongwiththe nding thatageandmedicationusewerenotstrongpredictors,a bleedingriskscorespeci callytailoredtoacancerpopulation withVTEasriskfactorscouldinherentlybedifferent comparedwithanAFpopulationorageneralVTEpatient group.Alternatively,cancercouldbeaddedasanadditional riskfactorinamodi edHAS-BLEDscorespeci cforpatients withVTE,whereitcouldbepartoftheBcriterion( bleeding tendencyorpredisposition )oftheHAS-BLEDscore.Further workisneededtoevaluatecancerasariskfactorforbleeding, itssuitabilityinamodi edHAS-BLEDscore,andthe developmentofotherriskscoresspeci callyfortheVTE patientpopulation.Ofnote,cancerhasbeenincludedasan independentriskfactorinarecentlydeveloped,VTE-speci c bleedriskstrati cationscore,VTE-BLEED.18Validatinganexistingriskstrati cationtoollikeHAS-BLED acrossmultipleindicationsmayhelpimproveclinicaladoption andencourageitsuptakeinpractice.19Someurgecautionin applyingbleedingriskscoresintheclinicalenvironment,due tothedevelopmentofthesescoresbasedoninitialclinical decisionstoprescribeanticoagulantswhichnecessitatedthat thepatientswereconsideredlowerbleedrisk.20Additionally, bleedriskscoreshaveonlybeenmodestlypredictiveof bleedinginanticoagulatedpatientswithVTEinaprior validationstudy.21Also,thereistheperceptionthatbleeding riskscoresareinappropriatelyusedtodenypatientsanticoagulationbecauseoftheirperceived highrisk although bleedingriskishighlydynamicandmodi able,andthe reversibleriskfactorsforbleedingshouldbeaddressedinall patientsratherthanjustthoseathighrisk.14HAS-BLEDhas beenusedwidelyinclinicalandresearchsettings,20and performsbetterthanotherbleedingriskscores(including ATRIA).19HAS-BLEDshouldbecomparedwithotherbleed scoresspeci callydevelopedintheVTEpopulation18to determinethecomparativepredictivevalidityofthesesimilar clinicaltools. Table4. SurvivalRegressionModelResultsShowingIndividualHAS-BLEDComponentsandCancerVariablesVariable MajorBleeds AllBleeds CoxPH(c-Index = 0.722)CompetingRisks(c-Index = 0.690)CoxPH(c-Index = 0.710)CompetingRisks(c-Index = 0.685) csHR95%CI sdHR95%CI csHR95%CI sdHR95%CIAge65to74vs 64,y0.930.81to1.070.940.82to1.080.880.81to0.970.890.82to0.98 Age75 + vs 64,y0.870.78to0.980.880.79to0.990.850.79to0.910.850.80to0.92 Hypertension1.351.22to1.501.351.21to1.491.291.21to1.371.281.21to1.37 Renaldisease1.551.36to1.761.541.35to1.751.591.46to1.721.581.45to1.71 Liverdisease1.401.20to1.621.381.19to1.601.431.31to1.571.411.29to1.55 Priorstroke1.871.66to2.101.861.65to2.091.471.36to1.591.461.36to1.58 Priorbleeding1.691.51to1.881.691.51to1.881.911.78to2.041.911.78to2.04 Highriskmedicationuse0.920.83to1.020.920.84to1.020.970.92to1.040.980.92to1.04 Alcohol/drugabuse1.551.16to2.081.551.16to2.071.591.33to1.901.581.32to1.89 Cancer2.251.98to2.562.111.85to2.412.071.91to2.251.941.78to2.11CIindicatescon denceinterval;csHR,cause-speci chazardratio;HAS-BLED,Hypertension,Abnormalrenal/liverfunction,Stroke,Bleeding,LabileInternationalNormalizedRatio(INR), Elderly,Drugsoralcoholuse;PH,proportionalhazards;sdHR,sub-distributionhazardratio. DOI:10.1161/JAHA.117.007901 JournaloftheAmericanHeartAssociation7 ApplicationofHAS-BLEDforBleedinginVTE BrownetalORIGINALRESEARCH by guest on March 7, 2018 http://jaha.ahajournals.org/ Downloaded from

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LimitationsThereareseverallimitationswithinthisstudy.First,administrativeclaimsdatamaynotreliablycapturealldiagnoses andprocedureswithinthepatientpopulation.22Second, previousexaminationofcumulativeincidenceinHAS-BLED scoringofmajorbleedriskhavenotincorporatedthedeathas acompetingriskinthecohort,whichsuggeststhatour analysisresultsmaynotbedirectlycomparabletoprevious studies.Ourmeasureofdeathincludedonlyin-hospitaldeath asdeathdataarenotreadilyavailableintheMarketScan data.Thiswillhavecausedanunderestimationofthenumber ofmajorbleedingeventsdetectedinthisstudyandsome misclassi cationoffollow-upstatusascensoredratherthan thecompetingriskofdeath.Misclassi cationofdeathis unlikelytohaveimpactedthemagnitudeofeffectbetween theHAS-BLEDscorecategoriesgivenhowfew( 2%)patients diedduringfollow-up.Misclassifyingdeathwouldhave underestimatedtheeffectsizebetweenhigherHAS-BLED scoresversuslowerscoresasthelowerscoreslikelyhavea smallerproportionofin-hospitaldeathsand,thus,an overestimatedcumulativeincidenceofbleeding.11,23Further, therewerenocleardifferencesbetweenCoxandcompeting risksregressionmodelswhichsuggestedlittleeffectof missingdeathdata.Lastly,thedatabaseprimarilycontains patientswithemployer-sponsoredhealthinsuranceplans, whichmeansthatlowerincomepatients,whotendtohave worsehealthoutcomes,arelikelyunder-represented.ConclusionsTheHAS-BLEDscorehasgoodpredictivevalidityforbleeding risksinpatientswithVTE.Theadditionofcancerasan independentriskfactortobleedingriskmeritsconsideration, possiblyaspartoftheBcriterion( bleedingtendencyor predisposition )oftheHAS-BLEDscore.SourcesofFundingThisstudywaspartiallyfundedbyagrantfromthe Hematology/OncologyPharmacyAssociation(V.R.A.and J.D.B.).Publicationofthisarticlewasfundedinpartbythe UniversityofFloridaOpenAccessPublishingFund.DisclosuresDrLipreportsreceivingconsultingfeesfromBayer/Janssen, BMS/P zer,Biotronik,Medtronic,BoehringerIngelheim, Novartis,VerseonandDaiichi-Sankyoandspeakerfeesfrom Bayer,BMS/P zer,Medtronic,BoehringerIngelheim,and Daiichi-Sankyo.Nofeesweredirectlyreceivedpersonally. Otherauthorsreportnocon ictsofinterest.References1.HeitJA,SpencerFA,WhiteRH.Theepidemiologyofvenousthromboembolism. JThrombThrombolysis.2016;41:3 14. 2.KearonC,AklEA,OrnelasJ,BlaivasA,JimenezD,BounameauxH,Huisman M,KingCS,MorrisTA,SoodN,StevensSM,VintchJRE,WellsP,WollerSC, MooresL.AntithrombotictherapyforVTEdisease. Chest .2016;149:315 352. 3.YouJJ,SingerDE,HowardPA,LaneDA,EckmanMH,FangMC,HylekEM, SchulmanS,GoAS,HughesM,SpencerFA,ManningWJ,HalperinJL,Lip GYH.Antithrombotictherapyforatrial brillation:antithrombotictherapy andpreventionofthrombosis,9thed:AmericanCollegeofChest PhysiciansEvidence-BasedClinicalPracticeGuidelines. Chest .2012;141: e531S e575S. 4.PistersR,LaneDA,NieuwlaatR,deVosCB,CrijnsHJ,LipGY.Anovel user-friendlyscore(HAS-BLED)toassess1-yearriskofmajorbleedingin patientswithatrial brillation:theEuroHeartSurvey. Chest .2010;138:1093 1100. 5.LipGY,FrisonL,HalperinJL,LaneDA.Comparativevalidationofanovelrisk scoreforpredictingbleedingriskinanticoagulatedpatientswithatrial brillation:theHAS-BLED(Hypertension,AbnormalRenal/LiverFunction, Stroke,BleedingHistoryorPredisposition,LabileINR,Elderly,Drugs/Alcohol Concomitantly)score. JAmCollCardiol .2011;57:173 180. 6.KooimanJ,vanHagenN,IglesiasDelSolA,PlankenEV,LipGY,vanderMeer FJ,CannegieterSC,KlokFA,HuismanMV.TheHAS-BLEDscoreidenti es patientswithacutevenousthromboembolismathighriskofmajorbleeding complicationsduringthe rstsixmonthsofanticoagulanttreatment. PLoS One.2015;10:e0122520. 7.WhiteRH,GarciaM,SadeghiB,TancrediDJ,ZrelakP,CunyJ,SamaP, GammonH,SchmaltzS,RomanoPS.EvaluationofthepredictivevalueofICD9-CMcodedadministrativedataforvenousthromboembolismintheUnited States. ThrombRes .2010;126:61 67. 8.GrahamDJ,ReichmanME,WerneckeM,HsuehYH,IzemR,SouthworthMR, WeiY,LiaoJ,GouldingMR,MottK,ChillarigeY,MaCurdyTE,WorrallC,Kelman JA.Stroke,bleeding,andmortalityrisksinelderlyMedicarebene ciaries treatedwithdabigatranorrivaroxabanfornonvalvularatrial brillation. JAMA InternMed .2016;176:1662 1671. 9.QuanH,SundararajanV,HalfonP,FongA,BurnandB,LuthiJC,SaundersLD, BeckCA,FeasbyTE,GhaliWA.Codingalgorithmsforde ningcomorbiditiesin ICD-9-CMandICD-10administrativedata. MedCare .2005;43:1130 1139. 10.HernandezI,ZhangY.Comparingstrokeandbleedingwithrivaroxabanand dabigatraninatrial brillation:analysisoftheUSMedicarePartDdata. AmJ CardiovascDrugs .2017;17:37 47. 11.AustinPC,LeeDS,FineJP.Introductiontotheanalysisofsurvivaldatainthe presenceofcompetingrisks. Circulation .2016;133:601 609. 12.FineJP,GrayRJ.Aproportionalhazardsmodelforthesubdistributionofa competingrisk. JAmStatAssoc .1999;94:496 509. 13. LymanGH,BohlkeK,KhoranaAA,KudererNM,LeeAY,ArcelusJI,BalabanEP, ClarkeJM,FlowersCR,FrancisCW,GatesLE,KakkarAK,KeyNS,LevineMN, LiebmanHA,TemperoMA,WongSL,Somer eldMR,FalangaA;American SocietyofClinicalOncology.Venousthromboembolismprophylaxisand treatmentinpatientswithcancer:AmericanSocietyofClinicalOncology clinicalpracticeguidelineupdate2014. JClinOncol .2015;33:654 656. 14.LipGYH,LaneDA.Bleedingriskassessmentinatrial brillation:observations ontheuseandmisuseofbleedingriskscores. JThrombHaemost 2016;14:1711 1714. 15.RoldanV,MarinF,FernandezH,Manzano-FernandezS,GallegoP,Valdes M,VicenteV,LipGY.PredictivevalueoftheHAS-BLEDandATRIA bleedingscoresfortheriskofseriousbleedingina real-world population withatrial brillationreceivinganticoagulanttherapy. Chest .2013;143:179 184. 16.HisadaY,GeddingsJE,AyC,MackmanN.Venousthrombosisandcancer: frommousemodelstoclinicaltrials. JThrombHaemost .2015;13:1372 1382. 17.TimpJF,BraekkanSK,VersteegHH,CannegieterSC.Epidemiologyofcancerassociatedvenousthrombosis. Blood .2013;122:1712 1723. 18.KlokFA,H oselV,ClemensA,YolloWD,TilkeC,SchulmanS,LankeitM, KonstantinidesSV.Predictionofbleedingeventsinpatientswithvenous thromboembolismonstableanticoagulationtreatment. EurRespirJ. 2016;48:1369 1376. DOI:10.1161/JAHA.117.007901 JournaloftheAmericanHeartAssociation8 ApplicationofHAS-BLEDforBleedinginVTE BrownetalORIGINALRESEARCH by guest on March 7, 2018 http://jaha.ahajournals.org/ Downloaded from

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19.ZhuW,HeW,GuoL,WangX,HongK.TheHAS-BLEDscoreforpredicting majorbleedingriskinanticoagulatedpatientswithatrial brillation:a systematicreviewandmeta-analysis. ClinCardiol .2015;38:555 561. 20.ParksAL,FangMC.Scoringsystemsforestimatingtheriskofanticoagulantassociatedbleeding. SeminThrombHemost .2017;43:514 524. 21.RivaN,BellesiniM,DiMinnoMN,MumoliN,PomeroF,FranchiniM,FantoniC, LupoliR,BrondiB,BorrettaV,BonfantiC,AgenoW,DentaliF.Poorpredictive valueofcontemporarybleedingriskscoresduringlong-termtreatmentof venousthromboembolism.Amulticentreretrospectivecohortstudy. Thromb Haemost .2014;112:511 521. 22.JohnsonEK,NelsonCP.Utilityandpitfallsintheuseofadministrative databasesforoutcomesassessment. JUrol .2013;190:17 18. 23.BrownJD,AdamsVR.Incidenceandriskfactorsofthromboembolismwith multiplemyelomainthepresenceofdeathasacompetingrisk:an empiricalcomparisonofstatisticalmethodologies. Healthcare(Basel) 2016;4:E16. DOI:10.1161/JAHA.117.007901 JournaloftheAmericanHeartAssociation9 ApplicationofHAS-BLEDforBleedinginVTE BrownetalORIGINALRESEARCH by guest on March 7, 2018 http://jaha.ahajournals.org/ Downloaded from

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Joshua D. Brown, Amie J. Goodin, Gregory Y. H. Lip and Val R. Adams Treatment BLED Bleeding Score During the First 6Months of Anticoagulant Application of the HAS Risk Stratification for Bleeding Complications in Patients With Venous Thromboembolism: Online ISSN: 2047-9980 Dallas, TX 75231 is published by the American Heart Association, 7272 Greenville Avenue, Journal of the American Heart Association The doi: 10.1161/JAHA.117.007901 2018;7:e007901; originally published March 7, 2018; J Am Heart Assoc. http://jaha.ahajournals.org/content/7/6/e007901 World Wide Web at: The online version of this article, along with updated information and services, is located on the for more information. http://jaha.ahajournals.org Access publication. Visit the Journal at is an online only Open Journal of the American Heart Association Subscriptions, Permissions, and Reprints: The by guest on March 7, 2018 http://jaha.ahajournals.org/ Downloaded from