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E ffective a N ticoa G ulation with factor x A next G E neration in

E ffective a N ticoa G ulation with factor x A next G E neration in. A trial F ibrillation – TIMI 48 P r imary Results Robert P. Giugliano, MD, SM, FAHA, FACC O n b e h a lf o f t h e E N G A G E AF - TIMI 48 Executive Committee and Investigators. Background.

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E ffective a N ticoa G ulation with factor x A next G E neration in

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  1. EffectiveaNticoaGulationwith factorxA next GEnerationin AtrialFibrillation–TIMI 48 Primary Results Robert P.Giugliano,MD, SM,FAHA,FACC On behalfoftheENGAGEAF-TIMI48 ExecutiveCommittee andInvestigators

  2. Background • Warfarin inAF:↓stroke64%vsplacebo • Warfarin ↑bleedingand haswell-known limitations • 3NOACsat leastaseffective;↓hem. strokeby 51%1 • Edoxabanseatedin FactorXa catalyticcenter Directoral FXa inhibitor 62%oral bioavailability Oncedaily ~50% renal clearance • Dose↓50%2if: • CrCl 30-50mL/m • Weight≤ 60kg • StrongP-gpinhib Peak 1-2h t1/2 ~10-14h AF=atrial fibrillation; CrCl=creatinineclearance;FXa=Factor Xa; 1. Dogliiotti A etal. ClinCardiol2013;36:61-7. 2 NOAC=neworal anticoagulant; P-gp=p-glycoprotein 2.Salazar DEetal. ThrombHaemost 2012;107:925-36.

  3. Study Design 21,105PATIENTS AF onelectricalrecording within last 12 mCHADS2 ≥2 RANDOMIZATION 1:1:1randomizationisstratifiedbyCHADS2 score2–3versus 4–6 andneedfor edoxabandosereduction* Warfarin (INR2.0–3.0) High-dose Edoxaban 60*mgQD Low-dose Edoxaban 30*mgQD 1ºEfficacyEP=Stroke or SEE 2º EfficacyEP=Stroke orSEE orCV mortality 1º SafetyEP=MajorBleeding(ISTH criteria) • *Dose reducedby50% if: • CrCl30–50mL/min • weight≤60kg • strongP-gp inhibitor Non-inferiority Upper97.5%CI<1.38 CI =confidence interval; CrCl= creatinine clearance;ISTH=International Society on 3 Ruff CR etal.AmHeart J 2010; 160:635-41. Thrombosis and Haemostasis; P-gp = P-glycoprotein; SEE=systemicembolicevent

  4. TrialOrganization TIMIStudyGroup EugeneBraunwald (StudyChair) ElliottM.Antman(PrincipalInvestigator) RobertP.Giugliano(Co-Investigator) Christian T.Ruff(Co-Investigator) SuzanneMorin(Director) StephenD.Wiviott(CEC) SabinaA.Murphy(Statistics) NaveenDeenadayalu(Statistics) LauraGrip(ProjectDirector) AbbyCange(ProjectManager) ExecutiveCommittee EugeneBraunwald ElliottM.Antman RobertP.Giugliano MicheleMercuri Stuart Connolly JohnCamm MichaelEzekowitz JonathanHalperin Albert Waldo Sponsor:DaiichiSankyo MicheleMercuri HansLanz IndravadanPatel Minggao Shi JamesHanyok CRO:Quintiles Maureen Skinner ShiraliPatel DeanOtto JoshuaBetcher CarmenReissner DataSafety MonitoringBoard FreekW.A.Verheugt (Chair) JeffreyAnderson J.DonaldEaston Allan Skene(Statistician) ShinyaGoto KennethBauer 4

  5. Population/AnalysisDefinitions Populations Analyses Primaryefficacy (Non-inferiority) mITT*,On-Treatment† Intent-to-Treat (ITT) Allrandomized Superiority Allevents Principal Safety MajorBleeding (ISTHdefinition) Safety,On-Treatment† *mITT =Allpatients who tookatleast1 dose † On-Treatment =1st doselast dose+3 daysorendofdouble-blindtreatment 5 ISTH=InternationalSociety onThrombosisand Haemostasis

  6. BaselineCharacteristics 6 CHF=congestiveheartfailure; IQR=interquartile range; TIA=transientischemicattack;VKA=vitaminK antagonist

  7. 21,105Patients,1393Centers,46Countries 7

  8. Key TrialMetrics Receiveddrug/ enrolled Completenessof follow-up Finalvisit or died/enrolled Offdrug(patientsper yr) Withdrewconsent,no data Lost tofollow-up Mediantime in therapeuticrange [Interquartilerange] 99.6% 99.5% 99.1% 8.8% 0.9% n=1 68.4% [56.5-77.4] 8

  9. PrimaryEndpoint:Stroke /SEE (2.8yearsmedianf/u) NoninferiorityAnalysis(mITT,OnTreatment) Hazardratio(97.5%CI) P Values Warfarin TTR68.4% Non-inferiority Superiority 0.79 Edoxaban60*mg QD P<0.0001 P=0.017 vs warfarin 1.07 P=0.005 P=0.44 Edoxaban30*mg QD vs warfarin 1.38 0.50 1.00 2.0 edoxabannoninferior SuperiorityAnalysis(ITT,Overall) Hazardratio(97.5%CI) P Value forSuperiority 0.87 Edoxaban60*mg QD vs warfarin P=0.08 1.13 Edoxaban30*mg QD vs warfarin P=0.10 0.50 1.00 2.0 *Dose reducedby 50% inselectedpts edoxabansuperior edoxabaninferior 9

  10. KeySecondaryOutcomes Pvs Edoxaban60*mg QD vs warfarin Edoxaban30*mg QD vs warfarin Warfarin TTR68.4% HR(95%CI) 1.00 1.4 Hem. Stroke Ischemic Stroke 2° EP:Stroke, SEE,CV death Deathor ICH All-causemortality CV death Myocardialinfarction 0.54 0.33 0.87 0.95 0.87 0.82 0.92 0.87 0.86 0.85 0.94 1.19 0.5 edoxabansuperior 0.25 1.00 2.0 *Dose reducedby 50% inselectedpts edoxabaninferior 10

  11. MainSafetyResults -SafetyCohorton Treatment- P Value vswarfarin Edoxaban 60*mg QD Edoxaban 30*mg QD vswarfarin vswarfarin ISTHMajorBleeding WarfarinTTR 68.4% HR(95%CI) 0.80 P<0.001 0.47 P<0.001 0.55 Fatal Bleeding P=0.006 0.35 P<0.001 0.47 Intracranial Hemorrhage 0.30 GastrointestinalBleeding P<0.001 P<0.001 1.23 P=0.03 0.67 P<0.001 0.5 2.0 1.0 0.25 *Dose reducedby edoxabansuperior 50% inselectedpts edoxabaninferior 11 Safetycohort=allpatientswhoreceivedat least1doseby treatmentactuallyreceived

  12. NetClinicalOutcomes P Value vswarfarin Edoxaban60*mg QD vs warfarin Edoxaban30*mg QD vs warfarin Hazardratio (95%CI) WarfarinTTR 68.4% 0.89 P=0.003 Stroke, SEE,death, majorbleeding 0.83 P<0.001 0.88 Disablingstroke,life-threatening P=0.008 bleeding, death 0.83 P<0.001 0.88 Stroke, SEE,life-threatening P=0.003 bleeding, death 0.89 P=0.007 0.71 1.0 0.5 *Dose reducedby50% in selectedptsSEE=systemicembolicevent edoxabansuperior edoxabaninf12

  13. TolerabilityandAdverseEvents %pts %pts %pts *Dose reducedby 50% inselectedpts P<0.001foreach edoxabandose vswarfarin P=NS P=NS 13

  14. TransitionPeriod Outcomes • AllptstransitionedVKA orNOAC • IfVKA: FrequentINRs, overlapped VKA + edox(30or 15mg) for≤ 2 wksuntilINR≥2.0 • IfNOAC:startwhen INR< 2.0 Datashownincludeall patientson blindedstudy drugattheend ofthetreatmentperiod 14 SEE=systemicembolicevent. NoSEEsoccurredduringthe30-daytransitionperiod.

  15. Summary • Comparedto well-managedwarfarin(TTR68.4%)once-dailyedoxaban: • Non-inferior for stroke/SEE(bothregimens) • -Highdose↓stroke/SEEonRx(trendITT) • Bothregimens significantlyreduced: • -Majorbleeding(20%/53%)-ICH(53%/70%) • -Hem.stroke(46%/67%) -CVdeath(14%/15%) • Superiornetclinicaloutcomes • Noexcessinstrokeor bleeding during transitionoralanticoagulantatend oftrial

  16. www.nejm.comDOI:10.1056/NEJMoa1310907 Ruff CT,etal.[in press] LeftAtrialStructure and FunctioninAtrial Fibrillation:ENGAGEAF-TIMI 48 GuptaDet al. EHJ(in press)

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