LITERATUREREVIEW

1. COMPARATIVERISKOFGASTROINTESTINALBLEEDINGWITHDABIGATRAN,
RIVAROXABAN,ANDWARFARIN:POPULATIONBASEDCOHORTSTUDY.

NeenaSAbraham,SonalSingh,GCalebAlexander,HerbertHeien,LindseyRHaas,
WilliamCrown,NilayDShah

ARetrospective,propensitymatchedcohortstudywasconductedtodeterminetherealworldriskof
gastrointestinalbleedingassociatedwiththeuseofthenoveloralanticoagulantsdabigatranand
rivaroxabancomparedwithwarfarin.Theincidenceofgastrointestinalbleedingassociatedwith
dabigatranwas2.29(95%confidenceinterval1.88to2.79)per100patientyearsandthatassociated
withwarfarinwas2.87(2.41to3.41)per100patientyearsinpatientswithatrialfibrillation.In
nonatrialfibrillationpatients,theincidenceofgastrointestinalbleedingwas4.10(2.47to6.80)per
100patientyearswithdabigatranand3.71(2.16to6.40)per100patientyearswithwarfarin.With
rivaroxaban,2.84(2.30to3.52)gastrointestinalbleedingeventsper100patientyearsoccurredin
atrialfibrillationpatients(warfarin3.06(2.49to3.77)/100patientyears)and1.66(1.23to2.24)per
100patientyearsinnonatrialfibrillationpatients(warfarin1.57(1.25to1.99)/100patientyears).
Inpropensityscorematchedmodels,therisk
ofgastrointestinalbleedingwithnoveloralanticoagulantswassimilartothatwithwarfarininatrial
fibrillationpatients(dabigatranvwarfarin,hazardratio0.79(0.61to1.03);rivaroxabanvwarfarin,
0.93(0.69to1.25))andinnonAFpatients(dabigatranvwarfarin,hazardratio1.14(0.54to2.39);
rivaroxabanvwarfarin,0.89(0.60to1.32)).Theriskofgastrointestinalbleedingincreasedafterage
65,suchthatbyage76theriskexceededthatwithwarfarinamongatrialfibrillationpatientstaking
dabigatran(hazardratio2.49(1.61to3.83))andpatientswithandwithoutatrialfibrillationtaking
rivaroxaban(2.91(1.65to4.81)and4.58(2.40to8.72),respectively).

2.COMPARATIVEEFFECTIVENESSOFDABIGATRAN,RIVAROXABAN,APIXABAN
ANDWARFARININTHEMANAGEMENTOFPATIENTSWITHNONVALVULAR
ATRIALFIBRILLATION.

JoshuaPink,MunirPirmohamed,andDyfrigA.Hughes

Theyevaluatedalternativeanticoagulantstowarfarin(dabigatran,rivaroxabanandapixaban)using
adiscreteeventsimulationwithalifetimehorizonofanalysis,basedonanindirectcomparisonof
theRELY,ROCKETAFandARISTOTLEtrialresultsforpatientswiththecharacteristicsofthe
USatrialfibrillationpopulation.Theresultsofthesimulationsat2yearsmatchedtheresultsof
eachtrial.Novaluedeviatedbymorethan3.2%(datanotpresented),alevelofvariabilitythat
wouldbeexpectedgiventhestochasticnatureofthesimulation.At2years,apixabanaccrued0.15
morequalityadjustedlifeweeksthandabigatran,0.26morethanrivaroxaban,and0.78morethan
warfarin.
3.COMPARATIVEEFFICACYANDSAFETYOFNEWORALANTICOAGULANTSIN
PATIENTSWITHATRIALFIBRILLATION

SebastianSchneeweiss,MD,ScD;JoshuaJ.Gagne,PharmD,ScD;AmandaR.Patrick,MS;
NiteeshK.Choudhry,MD,PhD;JerryAvorn,MD

Theyincludedfindingsfrom44535patientsenrolledin3trialsoftheefficacyofdabigatran
(RandomizedEvaluationofLongTermAnticoagulationTherapy[RELY]),apixaban(Apixabanfor
ReductioninStrokeandOtherThromboembolicEventsinAtrialFibrillation[ARISTOTLE]),and
rivaroxaban(RivaroxabanOnceDailyOralDirectFactorXaInhibitionComparedWithVitaminK
AntagonismforPreventionofStrokeandEmbolismTrialinAtrialFibrillation[ROCKETAF]),
eachcomparedwithwarfarin.Theprimaryefficacyendpointwasstrokeorsystemicembolism;the
safetyendpointtheystudiedwasmajorhemorrhage.Toaddressalackofcomparabilitybetween
trialpopulationscausedbytherestrictionofROCKETAFtohighriskpatients,theyconducteda
subgroupanalysisinpatientswithaCHADS2score3.theyfoundnostatisticallysignificant
efficacydifferencesamongthe3drugs,althoughapixabananddabigatranwerenumerically
superiortorivaroxaban.Apixabanproducedsignificantlyfewermajorhemorrhagesthandabigatran
andrivaroxaban.Anindirectcomparisonofnewanticoagulantsbasedonexistingtrialdata
indicatesthatinpatientswithaCHADS2score3dabigatran150mg,apixaban5mg,and
rivaroxaban20mgresultedinstatisticallysimilarratesofstrokeandsystemicembolism,but
apixabanhadalowerriskofmajorhemorrhagecomparedwithdabigatranandrivaroxaban.Until
headtoheadtrialsorlargescaleobservationalstudiesthatreflectroutineuseoftheseagentsare
available,suchadjustedindirectcomparisonsbasedontrialdataareonetooltoguideinitial
therapeuticchoices.

4.CARDIOVASCULAR,BLEEDING,ANDMORTALITYRISKSINELDERLY
MEDICAREPATIENTSTREATEDWITHDABIGATRANORWARFARINFORNON
VALVULARATRIALFIBRILLATION

DavidJ.Graham,MD,MPH;MarshaE.Reichman,PhD;MichaelWernecke,BA;Rongmei
Zhang,PhD;MaryRossSouthworth,PharmD;MarkLevenson,PhD;TingChangSheu,
MPH;KatrinaMott,MHS;MargieR.Goulding,PhD;

WeformednewusercohortsofpropensityscorematchedelderlypatientsenrolledinMedicare,
whoinitiateddabigatranorwarfarinfortreatmentofnonvalvularAFbetweenOctober2010and
December2012.Among134,414patientswith37,587personyearsoffollowup,therewere2,715
primaryoutcomeevents.Thehazardratios(95%confidenceintervals)comparingdabigatranwith
warfarin(reference)wereischemicstroke:0.80(0.670.96);intracranialhaemorrhage:0.34(0.26
0.46);majorgastrointestinalbleeding:1.28(1.141.44);acutemyocardialinfarction:0.92(0.78
1.08);anddeath:0.86(0.770.96).Inthesubgrouptreatedwithdabigatran75mgtwicedaily,there
wasnodifferenceinriskcomparedwithwarfarinforanyoutcomesexceptintracranial
haemorrhage,wheredabigatranriskwasreduced.Mostpatientstreatedwithdabigatran75mgtwice
dailysubgroupthemagnitudeofeffectforeachoutcomewasgreaterthaninthecombineddose
analysis.Ingeneralpracticesettings,dabigatranwasassociatedwithreducedriskofischemic
stroke,intracranialhaemorrhageanddeath,andincreasedriskofmajorgastrointestinal
haemorrhagecomparedwithwarfarininelderlypatientswithnonvalvularAF.Theseassociations
weremostpronouncedinpatientstreatedwithdabigatran150mgtwicedaily,whereasthe
associationof75mgtwicedailywithstudyoutcomeswasindistinguishablefromwarfarinexcept
foralowerriskofintracranialhemorrhagewithdabigatran.

5.STABILITYOFHIGHQUALITYWARFARINANTICOAGULATIONINA
COMMUNITYBASEDATRIALFIBRILLATIONCOHORT:THEANTICOAGULATION
ANDRISKFACTORSINATRIALFIBRILLATION(ATRIA)STUDY.

LianeO.Dallalzadeh,BS;AlanS.Go,MD;YuchiaoChang,PhD;LeilaH.Borowsky,
MPH;MargaretC.Fang,MD,MPH;DanielE.Singer,MD

WithinthecommunitybasedAnticoagulationandRiskFactorsinAF(ATRIA)cohortfollowed
from1996to2003,theyidentified2841newwarfarinuserswhocontinuedwarfarinover9months.
Theyexcludedmonths1to3toachieveastabledose.Forthe987patientswithTTR70%inan
initial6monthperiod(TTR1;months49),TheydescribedthedistributionofTTR2(months10
15)andassessedmultivariablecorrelatesofpersistentTTR70%.OfpatientswithTTR170%,
57%persistedwithTTR270%and16%deterioratedtoTTR2<50%.OnlyinitialTTR190%
(adjustedoddsratio1.47,95%CI1.072.01)independentlypredictedTTR270%.Heartfailure
wasmoderatelyassociatedwithmarkeddeterioration(TTR2<50%);adjustedoddsratio1.45,95%
CI1.002.10.Nearly60%ofAFpatientswithhighqualityTTR1onwarfarinmaintainedTTR
70%overthenext6months.AminoritydeterioratedtoverypoorTTR.Patientfeaturesdidnot
stronglypredictTTRinthesecond6monthperiod.TheiranalysessupportwatchfulwaitingforAF
patientswithinitialhighqualitywarfarinanticoagulationbeforeconsideringalternative
anticoagulants.