Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation

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Oral Anticoagulants for Stroke Prevention in Atrial FibrillationAnticoagulants in Atrial Fibrillation Keitaro Senoo MD, Deirdre A Lane PhD, Gregory YH Lip MD

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S0146-2806(14)00058-9 10.1016/j.cpcardiol.2014.07.001 YMCD280

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Curr Probl Cardiol

Cite this article as: Keitaro Senoo MD, Deirdre A Lane PhD, Gregory YH Lip MD, Oral Anticoagulants for Stroke Prevention in Atrial FibrillationAnticoagulants in Atrial Fibrillation, Curr Probl Cardiol, 10.1016/j.cpcardiol.2014.07.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

1 OralAnticoagulantsforStrokePreventioninAtrialFibrillation  KeitaroSenoo,MD1,2 DeirdreALane,PhD1 GregoryYHLip,MD1 

1

UniversityofBirminghamCentreforCardiovascularSciences,CityHospital,Birmingham,

UnitedKingdom; 2

TheCardiovascularInstitute,Tokyo,Japan

 Section:Review Shorttitle:AnticoagulantsinAtrialFibrillation  Addressforcorrespondence: ProfGregoryYHLip. Tel:+441215075080;Fax:+441215544083;[email protected]  Wordcount:4909[excludingAbstractandReferences] Tables:3 Figure:2 

2 Disclosurestatement  KeitaroSenoo:Nothingtodisclose. DeirdreALane:DrLanehasreceivedinvestigatorinitiatededucationalgrantsfromBayer HealthcareandBoehringerIngelheimandservedasaspeakerforBoehringerIngelheimand BMS/Pfizer.Inaddition,DrLaneisontheSteeringCommitteeofaPhaseIVapixabanstudy (AEGEAN). GregoryYHLip:ConsultantforBayer,Astellas,Merck,AstraZeneca,SanoAventis,Biotronik, BMS/Pfizer,DaiichiSankyo,MedtronicandBoehringherIngelheim.SpeakersbureauforBayer, BMS/Pfizer,BoehringherIngelheim,DaiichiSankyo,MedtronicandSanoAventis.

3 Tableofcontents  1. Introduction 2. Studyendpoints 3. Results 4. Discussion 5. Specificproblems 1) Renaldysfunction 2) Elderlypatients 3) Racialdifferences 4) Combinationofneworalanticoagulantsandantiplatelettherapy 6. Limitations 7. Conclusion 

4 Biographicalsketch(lessthan100words)  KeitaroSenoo Dr Senoo has a broad background in arrhythmia, with specific training and expertise in key research areas for atrial fibrillation (AF). As an electrophysiology fellow at the The Sakakibara Heart Institute of Okayama in Japan, Dr Senoo first developed his interest into AF and its management. At the Cardiovascular Institute in Japan, he expanded his research to include epidemiologicalstudiesassociatedwithAF,leadingtoseveralpeerreviewedpublications.  DeirdreALane Dr Lane is a Senior Lecturer in Cardiovascular Health at the University of Birmingham and is basedinabusyinnercityteachinghospital.Themainfocusofherrecentworkhasbeenatrial fibrillation (AF), with two major research themes: bleeding and stroke risk stratification and patientcentredresearch.SheisacoauthorofboththeCHA2DS2VAScstrokeriskstratification scoreandtheHASBLEDbleedingriskscore.HerothermainresearchinterestishowAFaffects qualityoflifeandpsychologicalwellbeing,patienteducation,andpatients’perceptionsofAF.  GregoryYHLip Professor Lip is Professor of Cardiovascular Medicine at the University of Birmingham and is based in a busy city centre teaching hospital.  Professor Lip has had a major interest into the epidemiology of AF, as well as the pathophysiology of thromboembolism in this arrhythmia. Furthermore, he has been researching stroke and bleeding risk factors, and improvements in clinical risk stratification. The CHA2DS2VASc and HASBLED scores  for assessing stroke and bleeding risk, respectively – were first proposed and independently validated following his research,andarenowincorporatedintointernationalguidelines. 

5 Abstract  The availability of four nonVitamin K oral anticoagulants (NOACs), that is, dabigatran, rivaroxaban, apixaban and edoxaban, have changed the landscape of stroke prevention in patients with atrial fibrillation. This review article provides an overview of the four phase III studiesthathavecomparedtheseNOACs,examiningmajoroutcomesofefficacyandsafety.A range of practical questions relating to the NOACs have emerged, including topics such as patient selection, treating patients with renal impairment, treating elderly patients, and combining anticoagulant therapy with antiplatelet drugs. We also address the interaction of various patient characteristics with the treatments and suggest the features can assist the physicianinthechoiceofaparticularNOACforparticularpatient(s).  KEYWORDS

Nonvalvularatrialfibrillation;oralanticoagulants;strokeprevention

Abbreviations AF=Atrialfibrillation;VKAs=vitaminKantagonists;NOACs=noveloralanticoagulants;CHADS2 score=congestiveheartfailure,hypertension,age75years,diabetesmellitus,andprevious stroke/transient ischemic attack; OD = once daily; BID = twice daily; LVEF = left ventricular ejectionfraction;TIA=transientischemicattack;ITT=intentiontotreat

6 Introduction Atrial fibrillation (AF) is a common cardiac arrhythmia and a major cause of morbidity and mortalityinclinicalpractice.AFincreasestheriskofstroke5foldandisresponsibleforatleast 20% of all strokes.1, 2 Until recently, the use of oral anticoagulation with the vitamin K antagonists(VKAs)providedthemosteffectivestandardtherapytopreventstrokeandsystemic embolisminpatientswithAF,sinceitreducestheriskofstrokeby64%andallcausemortality by26%,comparedtoplacebo/control.3,4  However,theVKAshaveimportantlimitations.5,6Thevariableanticoagulantresponse,foodand druginteractions,andthenarrowtherapeuticwindowrequirecloselaboratorymonitoringand frequent dose adjustments.7 Poor compliance and/or inadequate anticoagulation control (as reflectedbyaveragetimeintherapeuticrange,TTR)canleadtoincreasedadverseeventswhilst onVKAtherapy.8Indeed,theTTRcanbeinfluencedbymanyclinicalfactors,includingvarious comorbiditiesassociatedwithAFperse.9ThiscomplicatesthemanagementofpatientswithAF, leading to underuse of VKAs despite the focus of older guidelines on identifying ‘high risk’ patientswhoshouldbetargetedforVKAtherapy.10  In the last decade, several nonVKA oral anticoagulants (NOACs) have emerged as potential alternatives to VKAs for the prevention of ischemic stroke and systemic embolism in patients withAF.NOACspreviouslyreferredto‘novel’or‘new’oralanticoagulants,butmorerecently, theterminologybecamemoreconfusingwithEuropeansreferringto‘directoralanticoagulants (DOACs)’ and North Americans referring to ‘target specific oral ancoagulants (TSOCs) in

7 publicationsandmeetinglectures.WehaveproposedtheretentionoftheacronymNOACto referto‘nonVKAoralanticoagulants’,therebyallowingconsistencywitholderpapers.11  The four NOACs, which include the oral direct thrombin inhibitor, dabigatran, and the oral Factor Xa inhibitors, rivaroxaban, apixaban and edoxaban,have predictable pharmacokinetics, with a stable, doserelated anticoagulant effect and few drug interactions, hence allowing for fixeddosingwithouttheneedforregularmonitoringofanticoagulationstatus.12Therefore,the managementofpatientsonanyofthenewagentsisdistinctlydifferentfromthatofindividuals onwarfarin.13,14,15  ThisreviewarticleprovidesanoverviewofthefourphaseIIIstudies(ROCKETAF16,ARISTOTLE17, ENGAGEAFTIMI4818,andRELY19)thatcomparedtheseNOACs,examiningmajoroutcomesof efficacy and safety. A range of practical questions relating to the NOACs have emerged, including topics such as patient selection, treating patients with renal impairment, treating elderlypatients,andcombininganticoagulanttherapywithantiplateletdrugs.Wealsoaddress theinteractionofvariouspatientcharacteristicswiththetreatmentsandsuggestthefeatures canassistthephysicianinthechoiceofNOACforparticularpatient(s).  Trialdesigns Onetrial,theRELYtrialwasconductedasopentrial,basedonaprospectiverandomised,open blindedendpoint(PROBE)design.Theothertrials(ROCKETAF,ARISTOTLE,ENGAGEAF)wereall conducted as double blind, double dummy trials with sham INRs, which requires elaborate

8 procedurestomaintainblinding.Inarecentanalysis,O’Neiletal20reviewedtheoddsratiosof results across PROBE and double blind studies and outcomes, and found that amongst VKAcontrolsubjects,eventratesforstrokeorsystemicembolisminPROBEtrialsat1.74%/year (95% confidence interval: 1.541.95) was not significantly different from that in doubleblind trials, at 1.88 (1.732.03). Among other outcomes, O’Neil et al20 also observed VKAtreated subjects in both trial designs had similar event rates, apart from higher allcause mortality in ROCKETAF,andlowermyocardialinfarctionratesinPROBEstudypatients.

SimilaritiesanddifferencesbetweentheNOACs There are important differences in clinical pharmacology among the four NOACs, with significantimplicationsfortheirclinicaluse(Table1).Rivaroxaban,apixaban,andedoxabanare direct factor Xa inhibitors. Dabigatran reversibly inhibits the active site of thrombin (IIa). Dabigatranetexilateisaprodrugthatisrapidlyconvertedintotheactivecompounddabigatran byesterases.Dabigatranpossessesalowerbioavailability(6.5%)thanotherNOACs.  Theplasmahalflivesaresimilarforthefourdrugsrangingfrom8to14h.AllfourNOACsare substrates of the Pglycoprotein (Pgp) transporter. Dabigatran is excreted unmetabolized by the kidney (80%). Onethird of rivaroxaban is cleared unmetabolized via the kidney, and the remainingtwothirdsaremetabolizedbytheliverviaCYP3A4.Onefourthofapixabanandhalf ofedoxabanareexcretedbythekidney.Therecommendeddosageforapixabananddabigatran istwicedaily,andforrivaroxabanandedoxaban,itisoncedaily. 

9 In general, caution is needed in patients with significant renal impairment, patients concomitantlyusingpotentPgporCYP3A4inhibitorsorinducers,patients80yearsofage,and patientswithlowbodyweight.DoseadjustmentsforthefourNOACsarealsoshowninTable1. Theratesoflowerdoseusewerereportedas21%inROCKETAF,4.7%inARISTOTLEand25.3% inENGAGEAFTIMI48.IntheRELYstudy,dabigatran110mgbidand150mgbidwereseparate interventionarmsofthetrial,inanadequatelypoweredcomparisonofbothdosestowarfarin.  ThedefinitionsofmajorbleedinginthefourphaseIIItrialsareshowninTable2.Theprimary safety endpoint for all trials, except ROCKETAF, was major bleeding defined according to InternationalSocietyonThrombosisandHaemostasis(ISTH)criteria,whereasinROCKETAF,the primary safety endpoint was the composite of “major and nonmajor clinically relevant bleeding”. In ARISTOTLE, a 2g drop in haemoglobin over 24 hours was needed to fulfil one criterionfor‘majorbleeding’whilstothertrialsdidnothavesuchatimewindow.  IncontrasttotheARISTOTLE,ENGAGEAFTIMI48,andRELYstudies,patientsintheROCKETAF study wereat higher risk of stroke (meanCHADS2 score=3.5), were older, and had a previous strokeorsystemicembolismin>50%ofcases.ThestrokeriskoftheRELYandARISTOTLEtrials were broadly similar (mean CHADS2 score 2.1) whilst the stroke risk in ENGAGEAF was intermediate (mean CHADS2 score 2.8) between RELY/ARISTOTLE and ROCKETAF. Table 3 summarizes the efficacy and safety of the four NOACs compared with warfarin. The updated resultsaregivenforRELY.21 

10 RELY RELY19wasarandomized,openlabel,phaseIIItrialofstrokeorsystemicembolismprevention inpatientswithnonvalvularAF.Atotalof18,113patientswereblindlyrandomizedto2dosesof dabigatran,110or150mgbid,ortodoseadjustedwarfarin(INR2.0–3.0).PatientshadAFand 1 of the following criteria: previous stroke or TIA; symptomatic heart failure or LVEF < 40%; ages75yearsor65–74yearswithanadditionalfactorsofdiabetesmellitus,hypertension,or coronaryarterydisease.  Dabigatran at a dose of 150 mg bid showed superior primary efficacy outcome than warfarin (1.11% vs. 1.71% per year, P< 0.001 for superiority) and was associated with a similar rate of major bleeding (3.32% vs. 3.57% per year, P = 0.31). Both ischemic and hemorrhagic stroke occurredlessfrequentlyinthedabigatrangroup,atadoseof150mg (dabigatran150mg vs. warfarin0.92%vs.1.21%peryear,P=0.03;0.10%vs.0.38%peryear,P<0.001).  Dabigatran110mgbidwasnoninferiortowarfarinintheprimaryefficacyoutcomeofstrokeor systemic embolism (1.54% vs. 1.71% per year, P< 0.001 for noninferiority, P = 0.30 for superiority) and was superior with respect to the primary safety outcome of major bleeding (2.87%vs.3.57%peryear,P=0.003).Ischemicstrokewassimilarbetweenthedabigatran110 mg dose group and warfarin (1.34% vs. 1.21% per year, P = 0.35), and hemorrhagic stroke occurredlessfrequentlyinthedabigatran110mggroup(0.12%vs.0.38%peryear,P<0.001). Intracranialbleedingoccurredlessfrequentlyinthedabigatrangroups(dabigatran150mgbid and 110 mg bid vs. warfarin: 0.30% per year and 0.23% per year vs. 0.76% per year,

11 respectively).Majorgastrointestinal(GI)bleedingwasmorecommoninthedabigatran150mg bidgroup(dabigatran150mgbidvs.warfarin1.56%peryearvs.1.08%peryear).  Insummary,dabigatranatadoseof150mgbidintheRELYstudywasassociatedwithalower incidence of stroke and thromboembolism but was similar in the incidence of major bleeding compared with warfarin, whereas dabigatran at a dose of 110 mg bid was associated with a similarrateofstrokeandembolicoccurrenceandareducedincidenceofmajorbleeding.  ROCKETAF ROCKETAF16 was a randomized, doubleblind, doubledummy, phase III trial of stroke orsystemic embolism prevention in patients with nonvalvular AF. A total of 14,264 patients were randomized to receive either rivaroxaban 20 mg once daily (od) (15 mg od if creatinine clearancewas30–49mL/min)ordoseadjustedwarfarin(INR2.0–3.0).Inclusioncriteriainthe studyweredocumentednonvalvularAFoccurringwithinsixmonthspriortorandomizationand a history of previous stroke, transient ischemic attack (TIA) or systemicembolism, or 2 additional risk factors for stroke:heart failure or left ventricular ejection fraction (LVEF) 35%, hypertension,age75years,anddiabetesmellitus.  Rivaroxaban was noninferior to warfarin in the primary endpoint of stroke or systemic embolismwithanannualrateof2.12%vs.2.42%,respectively(P<0.001fornoninferiority;P= 0.12forsuperiority)bytheintentiontotreatanalysis.Therateofischemicstrokewassimilar between the rivaroxaban and warfarin groups (1.34% vs. 1.42% per year, P=0.581), and

12 hemorrhagicstrokeoccurredlessfrequentlyintherivaroxabangroup(0.26%vs.0.44%peryear, P=0.024).Theprincipalsafetyendpoint,acompositeofmajorandnonmajorclinicallyrelevant bleedingeventswasalsosimilarbetweentherivaroxabanandwarfaringroups(14.9%vs.14.5% per year, P=0.44), as was any major bleeding event (3.6% vs. 3.45% per year, P=0.576). Intracranialhemorrhageoccurredlessfrequentlywithrivaroxabanthanwithwarfarin(0.49%vs 0.74% per year; P=0.019). In general, ROCKETAF showed that rivaroxaban was noninferior towarfarin in the prevention of stroke or systemic embolism,with no difference in the risk of majorandnonmajorclinicallyrelevantbleeding.  ARISTOTLE ARISTOTLE17wasarandomizeddoubleblind,doubledummy,phaseIIItrialofstrokeorsystemic embolism prevention in patients with nonvalvular AF.A total of 18,201 patients were randomizedtoeitherapixabanatadoseof5mgtwicedaily(bid)(dosereducedto2.5mgbid with2ofthefollowingcriteria:age80years,bodyweight60kg,orserumcreatinine1.5 mg/dL), or to doseadjusted warfarin (INR 2.0–3.0). Patients had nonvalvular AF and 1 risk factorsforstroke:previousstroke,TIA,orsystemicembolism;age75years;heartfailureor leftventricularejectionfraction(LVEF<40%);diabetesmellitus;orhypertension.  Apixabanwassuperiortowarfarinintheprimaryoutcomeofstrokeorsystemicembolism,with anannualeventrateof1.27%vs.1.60%(P<0.001fornoninferiority;P=0.01forsuperiority). This impressive 21% reduction in the primary endpoint was largely driven by a reduction in hemorrhagic stroke (0.24% vs. 0.47% per year, P<0.001), with no significant difference in the

13 ischemicstrokeratebetweenapixabanandwarfarin(0.97%vs.1.05%peryear,P=0.42).Major bleeding events were lower in the apixaban (2.13% vs. 3.09% per year, P<0.001), particularly intracranial hemorrhages (0.33% vs. 0.80% per year, P<0.001). Apixaban was also associated withalowertotalmortalityrate(3.52%vs.3.94%peryear,P=0.047).Thebenefitofapixaban in the primary efficacy and safety outcomes was consistent across all age groups. Thus, the ARISTOTLEstudyshowedthatapixabanwassuperiortowarfarininthepreventionofstrokeor systemicembolism,anditresultedinlessbleedingandlowermortality.

ENGAGEAFTIMI48 ENGAGEAFTIMI4818wasarandomized,doubleblind,doubledummy,phaseIIItrialofstroke or systemic embolism prevention in patients with nonvalvular AF. A total of 21,105 patients wereblindlyrandomizedto2dosesofedoxaban,60or30mgod,ortodoseadjustedwarfarin (INR2.03.0).Forpatientsineitheredoxabangroup,thedosewashalvedifanyofthefollowing characteristics were present at the time of randomization or during the study: estimated creatinine clearance rate of 30–50 ml/min, a body weight < 60 kg, or the concomitant use of verapamilorquinidine(potentPgpinhibitors).PatientshadnonvalvularAFand2riskfactors for stroke: previous stroke or TIA, congestive heart failure, hypertension, diabetes mellitus or age75years.  Highdose(60mgod)edoxabanwasnoninferiortowarfarinintheprimaryefficacyoutcomeof stroke or systemic embolism (1.18% vs. 1.50% per year, P<0.001 for noninferiority) and was superior with respect to the primary safety outcome of major bleeding (2.75% vs. 3.43% per

14 year, P<0.001), particularly intracranial hemorrhages (0.39% vs. 0.85% per year, P<0.001). Ischemic stroke was similar between the edoxaban and warfarin (1.25% vs. 1.25% per year, P=0.97),andhemorrhagicstrokeoccurredlessfrequentlyintheedoxabangroup(0.26%vs.0.47% per year, P<0.001). Lowdose (30mg od) edoxaban was also noninferior to warfarin for the primary efficacy outcome (1.61% vs. 1.50% per year, P=0.005 for noninferiority) and was superior with respect to the primary safety outcome of major bleeding (1.61% vs. 3.43% per year, P<0.001), particularly intracranial hemorrhage (0.26% vs. 0.85% per year, P<0.001). Ischemicstrokewasmorecommonintheedoxabangroup(1.77%vs.1.42%peryear,P<0.001). Bycontrast,hemorrhagicstrokeoccurredlessfrequentlywithedoxaban(0.16% vs.0.47%per year, P<0.001). Treatment with edoxaban was associated with lower rates of death from cardiovascularcausesthanwarfarin:3.17%withwarfarincomparedwith2.74%withhighdose edoxaban(P=0.01)and2.71%withlowdoseedoxaban(P=0.008),withsimilarfindingsforthe rate of death from anycause. Theannualized rate of the primary netclinical outcome (death fromanycause,stroke,systemicembolicevent,ormajorbleeding)wassignificantlylowerwith both edoxaban regimens than with warfarin: 8.11% with warfarin compared with 7.26% with highdoseedoxaban(P=0.003)and6.79%withlowdoseedoxaban(P<0.001).Insummary,both oncedailydosesofedoxabanintheENGAGEAFTIMI48studywerenoninferiortowarfarinfor the prevention of stroke or systemic embolism and were associated with significantly lower ratesofbleedinganddeathfromcardiovascularcauses.  Comparingthetrials,andthedifferentNOACs

15 AcomparisonofthemaincharacteristicsofthefourtrialsispresentedinTable3.Thestudies differed in a number of important respects. ROCKETAF, ARISTOTLE, and ENGAGE AFTIMI 48 were blinded in both arms, but in RELY, warfarin therapy was openlabel. In ROCKETAF, the mean CHADS2 score was higher than those in the other three studies, leading to a higher primary endpoint event rate (2.4% per year in ROCKET AF vs. 1.6% in ARISTOTLE vs. 1.8% in ENGAGEAFTIMI48and1.71%inRELYperyear,respectively).  Inaddition,dataanalyseswerenotidentical.IntheARISTOTLE,ENGAGEAFTIMI48andRELY trials, primary analyses were performed in the intentiontotreat (ITT) population.  In ROCKETAF,thiswasdoneasaperprotocolanalysisandsafetywasasontreatmentanalysis. All four drugs were confirmed to be noninferior compared to warfarin. There was a general trendinfavourofstudydrugs,butthelevelofsignificanceforsuperioritywasreachedonlyfor apixabananddabigatran150mgbidbutnotforrivaroxabanandedoxabanintheITTanalysis. Apart for dabigatran 150 mg bid, no study drug showed significantly better ischemic stroke prevention than warfarin, with edoxaban 30mg even resulting in significantly more ischaemic strokescomparedtowarfarin.  Onthesafetyside,allfournewdrugssignificantlyreducedtheincidenceofhemorrhagicstroke and intracranial hemorrhage. This represents a clear advantage of all four new drugs over warfarin.Interestingly,theRELYstudyinitiallyraisedaconcernaboutanumericalincreasein the rate of myocardial infarction with dabigatran 150mg bid compared with warfarin (0.74%, 0.53%;P=0.048).Amoredetailedanalysis,includingsilentmyocardialinfarctionsbasedonthe

16 new appearance of pathological electrocardiographic Qwaves, did not show significant differences between dabigatran and warfarin. The ARISTOTLE, ENGAGE AFTIMI 48,and ROCKETAFstudiesdidnotcorroborateanincreaseinmyocardialinfarctionswiththesedrugs. Although allcause mortality was significantly reduced with apixaban and edoxaban 30mg, a similartrendwasalsoobservedintheotherstudies.  ChoosingbetweenusingaNOACorVKA HighqualityanticoagulationcontrolwithVKAsisassociatedwithbetterefficacyandsafety(with lowstrokeandbleedingrisks),andthus,effectivestrokepreventioninvariousguidelineswith oralanticoagulationreferstouseofwellcontrolledwarfarin(TTR70%)oroneoftheNOACs22. WhilstNOACsgenerallyoffermanyadvantages,aclinicaldilemmaishowtopredictthosenewly diagnosed nonanticoagulated AF patients who would do well on VKA achieving a high TTR, especiallygivencostsoftheNOACsandgiventhatthebenefitsofNOACsoverVKAsmaybeonly marginal in those with high TTRs.  An ESC position paper5 recommends use of the new SAMeTT2R2score9toaiddecisionmakingbyidentifyingthoseAFpatientslikelytodowellon warfarin (SAMeTT2R2 score 01) or those more likely to have poor anticoagulation control (SAMeTT2R2score>2).ThosepatientswithaSAMeTT2R2score>2wouldprobablybebetteroff being started on NOACs as initial therapy, or be targeted for more efforts to improve their anticoagulationcontrol.  Specificpatientgroups 

17 Renaldysfunction Patients with AF and renal impairment are at high risk of stroke/thromboembolism, bleeding, myocardial infarction and death.23,24,25,26 Nonetheless, the net clinical benefit seems to favour use of oral anticoagulation, rather than no anticoagulation. Given the age and comorbidities associated with AF, the presence of normal renal function or even mild renal impairment at baselinedoesnotprecludesomepatientsdeterioratingtosevererenalimpairment.27  Renal impairment might influence the balance between the safety and efficacy of NOACs (Figure 1). The various NOACs have different renal elimination characteristics, and this issue mayaffectthechoiceofaspecificagent.Dabigatranisthedrugthatismostdependentonthe renalfunctionforitseliminationandtheriskformajorbleedingincreaseswithdecreasingrenal function.Fordabigatran110mgtheannualeventratewas1.53%,2.89%,and5.29%forCrCl80, 50–79,and<50mL/min,respectively,andforthe150mgdosethecorrespondingeventrates were 2.09%, 3.33%, and 5.44%, respectively.28 Thus, exposure to dabigatran is increased by renal impairment, and this correlates with the severity of renal dysfunction. Despite a dose reduction,drugaccumulationandoverdosewereinitiallyreportedinelderlypatientswithalow body weight and moderate renal insufficiency, which led to severe and fatal bleeding complications.29In those with moderate renal impairment, the lower dose of dabigatran (110 mg) should be used with regular monitoring of renal function.28,30 A RELY subanalysis31 has demonstrated that the efficacy of both dosages of dabigatran was consistent with the overall trial irrespective of renal function, and the relative reduction of major bleeding with either dabigatrandosecomparedtowarfarinwasgreaterinpatientswithGFR80mL/min.

18  The excretion of rivaroxaban and apixaban is only partly dependent upon renal function, and the risk of drug accumulation in patients with renal insufficiency is lower than that observed with dabigatran (Figure 1). For rivaroxaban, the event rate was 2.06% for a CrCl 80 mL/min, 2.77%foraCrCl50–79mL/min,and3.37%forCrCl<50mL/min.16Forapixaban,theeventrate was 1.5%, 2.5%, and 3.2% for normal renal function, mild impairment, and moderatesevere impairment, respectively.17 Both drugs can be administered at fixed doses in patients with moderate renal impairment, and the current prescribing label for both drugs allows its use if creatinineclearanceis15mls/min.Forapixaban,arecentanalysisclearlyshowsthesafetyof this drug with moderate renal impairment, whilst retaining superior efficacy.32 Although the ENGAGEAFTIMI48trialhasyettoformallypublishdataregardingtheeventrateofbleedingin patientswithrenalimpairment,edoxabanisalsopartlydependentonrenalfunction(50%renal excretion).  Insummary,weshouldcheckrenalfunctioninallpatientsbeforechoosingoneoftheNOACs andshouldnotgiveanyNOACstopatientswithsevererenalimpairment(CrCl<30mLmin).In patientswithmoderaterenalimpairment(CrCl30–50mLmin),althoughdabigatran110mgbid andrivaroxabancanbeused,apixabanisprobablythesaferoption,particularlyinelderly patientswithalowbodyweight(<60kg).  Elderlypatients

19 WhileAFisuncommoninpatientsbelow65yearsofage(<2%),theprevalenceisapproximately 10%inpatientsaged85yearsorover.33Duetothehigherincidenceofstrokeintheelderly,the absolute risk reduction is higher in elderly than in younger patients.34 Oral anticoagulation is beneficialintheelderlywithasuperiorreductioninstrokeandnosignificantdifferenceinmajor bleedingbetweenwarfarinandaspirin.35  Regardlessofhighstrokeriskandagreaternetclinicalbenefitfromoralanticoagulation,elderly patients with AF (aged >75–80 years) are often denied warfarin owing to the perception of a substantially increasedbleeding risk in the presence of multiple comorbidities, impaired renal function, or cognitive impairment.36 However, due to a lower tendency for food and drug interactions,theanticoagulanteffectsofNOACsaremuchmorepredictablethanVKAs,allowing themtobegiveninfixeddoseswithoutroutinecoagulationmonitoring.  TheNOACshavemanybenefitsoverwarfarinforstrokepreventioninpatientswithAFinthe elderly. Treatment decisions also require an assessment of the practical considerations associatedwiththesetreatments,includingtheneedfordoseadjustmentinspecificpatients, costeffectiveness, limitations in monitoring the extent of anticoagulation, and the lack of specificreversalagents.Suchconsiderationsareparticularlyimportantinthetreatmentofolder patients,whomayexperiencedifferentreactionstodrugsthanyoungerpatients.Thisisoften duetoolderpatientshavingpoorrenalclearance,alowerbodyweight,andpolypharmacy.37 

20 DatafromthephaseIIIrandomized,controlledtrialsallconfirmthattheabsoluterisksofboth thrombotic events and bleeding rise with advancing age. For instance, patients aged over 75 years represented 43.1%, 31.2%, 40.2%, and 40.1% in the ROCKETAF, ARISTOTLE, ENGAGE AFTIMI48,andRELYstudies,respectively.InROCKETAF,theefficacyandsafetyofrivaroxaban appearstobeconsistentacrossagecategories.Inthevarioustrialswithrivaroxaban,apixaban and edoxaban, no interaction with age was reported for the efficacy outcome and the occurrence of major bleeding. In the RELY study, however, a highly significant interaction betweenageandmajorbleedingwasfound(Figure2).   Racialdifferences The ageadjusted prevalence of AF may be lower among Asians than among Caucasians.33 However,theprevalenceandincidenceofarterialthromboembolismmaydifferfromthoseof European and American countries.38 Specifically, Asian patients have a fivetosixfold higher stroke risk than Caucasians, but anticoagulation therapy is not commonly given to Asian patients with nonvalvular AF, probably because of the (perceived) risk of critical bleeding, which might be higher in Asian patients. Indeed, warfarinrelated intracranial hemorrhage in Asianpatientswasreportedtobe1.75per100patientyears,whichissignificantlyhigherthan thatinCaucasians(0.34per100patientyears).39Thisisfurthercomplicatedbythedifficultyof maintaining a therapeutic international normalized ratio when using VKAs. These challenges mightexplainwhyVKAsareunderusedbyphysicianswhotreatpatientsinAsia.40 

21 Moreover, in Asians, the risk of stroke and systemic embolism for warfarinanticoagulated AF patientsappearstobehighercomparedtoNonAsians,thoughAsianshadsimilarmeanCHADS2 scores.41Indeed, in the RELY Asia subanalysis42, although the mean CHADS2 score was 2.2 in Asian countries (2.1 in NonAsians), the incidence rate of stroke and systemic embolism was muchhigherinAsianscomparedtoNonAsians(3.06%/yearvs1.48%/year).IntheROCKETAF EastAsiasubanalysis16,althoughthemeanCHADS2scoreof3.2inEastAsiancountries(3.5in NonEastAsians),theincidencerateofstrokeandsystemicembolismwashigherinEastAsians comparedtoNonEastAsians(3.4%/yearvs2.4%/year).IntheARISTOTLEtrial17,43,althoughthe mean CHADS2 score was 2.1 in Asian countries (2.1 in nonEast Asians), the incidence rate of stroke and systemic embolism was higher in Asians compared to NonAsians (3.39%/year vs 1.38%/year).Also,inthesetrials,theTTRwasgenerallylowerinAsianscomparedtononAsians (RELY;56.5%inAsiansvs68.9%inNonAsians,ROCKETAF;52.4%vs55.2%,ARISTOTLE;60%vs 67%). These data would suggest that trial investigators in Asia tended to keep an INR in the lower range, perhaps to avoid bleeding. Both bleeding and thromboembolism rates are generallyhigherinAsianscomparedtononAsians,andthereforewarfarinisdifficulttomanage properlyinAsians.  TheNOACsmayprovideasafe,effective,andconvenientalternativetowarfarin,especiallyin Asians (the Asian subanalysis of edoxaban are awaited). The Asian subgroup analysis of the RELY trial demonstrated superiority of dabigatran 150 mg bid over warfarin in reducing thromboembolism. Also, the risk of major bleeding in the group of dabigatran 150 bid was significantlylowerthanthewarfaringroupinAsians,withagreaterrelativeriskreductionthan

22 thatfromnonAsians.Indeed,theannualriskofmajorbleedingindabigatran150mgbidgroup was2.17%forAsiansand3.52%fornonAsians.Theannualriskofmajorbleedingindabigatran 110mgbidgroupwas2.22%inAsiansand2.99%innonAsians.IntheAsiansubgroupanalysis of the ARISTOTLE trial43, apixaban had consistent benefits when compared with warfarin for strokeorsystemicembolisminEastAsianandnonEastAsianpatients.Theannualriskofmajor bleedingfromapixabanwas2.02%forAsiansand2.15%fornonAsians.Therateofstrokeand systemic embolism from the East Asia cohort of the ROCKETAF study were consistent with thoseofthemainstudy.Theannualriskofmajorbleedingfromrivaroxabanwas4.9%forAsians and7.6%fornonAsians.  Theuseof NOACsinpatientswithAFinAsiaprovidesanopportunityforimprovedqualityof care, since the rate of both thromboembolism and bleeding risk associated with NOACs was consistent with that observed globally. A modeling exercise suggests how use of NOACs may leadtoamajorimpactontheburdenofAFrelatedstrokeinChina.44  CombinationofnonVKAoralanticoagulantsandantiplatelettherapy The management of antiplatelet and anticoagulant therapy is challenging in patients with AF who sustain an acute coronary syndrome and/or undergo percutaneous coronary intervention/stenting,orinpatientswithcoronaryarterydiseasewhodevelopAF.Theoptimal strategytoprovideadequateantiplateletandanticoagulanttherapyiscurrentlyunclear. 

23 Observationaldatahaveshownanincreasedriskofbleedingaftertreatmentwithantiplatelet therapy together with an anticoagulant “triple therapy.”45,46 A subanalysis of the RELY trial showedanincreasedriskofbleedingandthromboemboliceventsassociatedwithantiplatelet therapy compared with no antiplatelet therapy and consistent treatment effects when compared with warfarin, regardless of aspirin use.47 Both the ATLAS ACS 2TIMI 5148 and APPRAISE249 trials confirmed a dosedependent increase in major bleeding events, including intracranial bleeding, with rivaroxaban and apixaban when they were combined with dual antiplatelettherapy(DAPT).  In the ATLAS ACS 2TIMI 51, lowdose (2.5 mg bid) rivaroxaban was associated with a significantly lower composite of cardiovascular death, myocardial infarction, or stroke (the primary efficacy endpoint), compared to placebo.  Of note, the doses were 2.5 or 5 mg bid, whichcorrespondtoonefourthandonehalf,respectively,ofthedosetestedinAFpatients.16In APPRAISE2,however,theprimarysafetyoutcomeofmajorbleedingoccurredmoreoftenwith apixaban than with the placebo. Apixaban was associated with more intracranial hemorrhage and with a numerical increase in fatal bleeding. Consequently, the trial was terminated prematurely before completing enrollment of the planned patients considering the overall efficacy/safetybalance.  In summary, the need for NOACs in combination with DAPT should be criticallyassessed, and thedurationofcombinedtherapyminimized.ThedurationofDAPTisdeterminedbytheriskof

24 bleeding,typeofstentandtheperceivedriskofstentthrombosis.Theuseofthirdgeneration drugelutingstentsmayreducethetimeDAPTisrequiredtopreventstentthrombosis.  Patient’svaluesandpreferences

Patient’s preferences for OAC therapy should be an integral part of the treatment decisionmaking process,50 as advocated by current clinical guidelines.22 To enable patients to make informed choices about whether or not to initiate OAC and to allow them to choose betweentheavailableOACdrugsrequiresthepatienttobeappropriatelyeducatedabouttheir own individual risk of stroke (hence the need for OAC) and their risk of major bleeding associated with the different OACs. The responsibility for educating AF patients and allowing them to voice their preferences for OAC treatment lies with the treating clinician.51 A recent studybyLaHayeandcolleagues52usedaniPadtopresentpatientswiththeirindividualriskof stroke(usingCHA2DS2VASc)andbleedingwithtreatment,usingavarietyofdifferentformats and elicited their preferences for antithrombotic therapy. This study corroborates previous research50whichreportsthatpatientsaremoreconcernedabouttheriskofstrokethantherisk ofbleeding;patientswerepreparedtosuffer4.4majorbleedsinordertopreventonestroke.52 Involving patients’ in discussions about treatment options and eliciting their preferences providesclinicianswiththeopportunitytoeducatepatientsaboutAFandtherisksandbenefits of treatment, to correct or allay misconceptions patients may hold about OAC, identify and overcomebarrierstoadherence,andimprovesthelikelihoodofarrivingatamutuallyagreeable treatmentdecision.51

25  Conclusion This overview has several limitations. First, each phase III trial examined different NOACs and therewasimportantheterogeneityregardingstudydesignsandincludedpopulations.Second, patients taking warfarin in reallifeclinical practice are less likely to be in a therapeutic range than those in controlled studies. Therefore, further insights into the appropriate use of these agents will become apparent when they are used in ‘realworld’ clinical settings, and some initialdatafrompostmarketingstudiesdosuggestthatthesedrugsappearsafecomparedto warfarin when used in newly diagnosed anticoagulation naïve patients.53,54 Some reports suggest need for caution amongst ‘switchers’ from warfarin to NOACs, and a high rate of bleedingandthromboembolismwasobserved.55Itisworthemphasizingthatthesedrugsare powerful anticoagulants that offer efficacy and safety compared to warfarin if used correctly accordingtoguidelinesand/orprescribingrecommendations.56  The introduction of 4 new NOAC alternatives for anticoagulation represents a major step forwardinimprovingoutcomesandqualityoflife.ComparedwithVKAs,thesenewalternatives have important advantages, such as lower risk of intracranial bleeding, no clear interactions withfood, favorable pharmacokinetic profiles, and no need for routine monitoring. Indeed, theseneworalanticoagulantswillbepreferredalternativestoVKAsformanypatientswithAF and an increased risk of stroke. Modelling analyses clearly show the potential healthcare and publichealthimpactofNOACsinreducingtheburdenofstrokeinpatientswithAF.57,58Things canonlygetbetter.

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56.

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57.

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58.

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33 Figurelegends  Figure1.Forestplotformajorbleedingaccordingtocreatinineclearance(CCr),nonVKAoral anticoagulants(NOACs)versuswarfarininpatientswithnonvalvularAF D150:dabigatran150mgbid,D110:dabigatran110mgbid  Figure2.Forestplotformajorbleedingaccordingtoage,nonVKAoralanticoagulants(NOACs) versuswarfarininpatientswithnonvalvularAF D150:dabigatran150mgbid;D110:dabigatran110mgbid Edoxabanhigh:edoxaban60mgod,Low:edoxaban30mgod

‹ Serumcreatinine





*Dependonindicate

Dose 



20mg15mg



5mg2.5mg

t1.5mg/dl

30mg15mg

Nodoseadjustment



‹ CrCl3050ml/min 60mg30mg



‹ Bodyweightd60kg



‹ Bodyweightd60kg



orquinidine



‹ Concomitantverapamil

‹ Aget80years





patients

fulfillingt2ofthefollowing



CrCl3049ml/min

criteriaatbaseline:

Twice*

80%

Pgp

1214

6.5%

Yes

IIa

Dabigatran

criteriaatbaseline:

Once

50%

Pgp

1014

62%

No

Xa

Edoxaban

Nodoseadjustment

Twice

25%

3A4/Pgp

12

50%

No

Xa

Apixaban

fulfilling1ofthefollowing

Once*

Doseadjustmentfor

Regimen

66%liver

33%kidney

3A4/Pgp

Interaction

Renalclearance

811

Halflife(h)

80100%

No

Prodrug

Oralbioavailability 

Xa

Rivaroxaban

Target



Table1:CharacteristicsofNOAC



(modifiedISTH)

㧔ISTH㧕

• Fatalbleeding • Criticalorganbleeding

• Criticalorganbleeding

packedredbloodcells

• Atransfusionoft2Uof

period

t2g/dlovera24hour



organbleeding 

• Symptomaticcritical

• Fatalbleeding

packedredbloodcells

• Atransfusionoft2Uof

t2g/dl

• AdecreaseinHblevelof • AdecreaseinHblevelof

MajorBleeding

ENGAGEAF

 Edoxaban

MajorBleeding

ARISTOTLE

Apixaban

• Fatalbleeding

wholeblood

packedredbloodcellsor

• Atransfusionoft2Uof

t2g/dl 

• AdecreaseinHblevelof

NMCRBleeding

㧔ISTH㧕

MajorBleeding

ROCKETAF

Rivaroxaban

NMCR:nonmajorclinicallyrelevantbleeding

Bleeding

Major

Primarysafety

Trial





DefinitionofMajorbleeding

Table2:ClinicalstudydesignofNOAC

organbleeding

• Symptomaticcritical

• Fatalbleeding

blood

• Transfusionoft2Uof

oft2g/dl

• ReductioninHblevel

MajorBleeding

RELY

Dabigatran

1 (2.1)

DBT

2

(3.5)

Blindness

ITT

Efficacy

Ischaemicstroke

HR;95%CI)

embolism(%/year;

0.751.17;p=0.581

1.34%vs1.42%;0.94;

Pforsuperiorityp=0.12

Pfornoninferiority<0.001,

0.751.03;

2.12%vs2.42%;0.88;

55%

TTR(mean)

Strokeorsystemic

38%

VKAnaive

CHADS2(result)

DBT

55%

Priorstroke,TIA

P=0.97

1.25%vs1.25%;

0.97%vs1.05%; p=0.42

P=0.08

p=0.01

1.00;0.83–1.19;

0.87;0.731.04;

0.79;0.660.95;

0.92;0.741.13;

1.57%vs1.80%;

ITT

65%

41%

(2.8)

2

DBT

28%

Median72

21,105

vswarfarin

Edoxaban60mg

ENGAGE AF 

1.27%vs1.60%;

ITT

62%

43%

19%

Median70

Median73

Ageyears

vswarfarin

vswarfarin 18,201

Apixaban5mg

Rivaroxaban20mg 

14,264

ARISTOTLE

ROCKETAF

Patients

Drug

Trial



P<0.001

1.41;1.19–1.67;

1.77%vs1.25%;

P=0.10

1.13;0.961.34;

2.04%vs1.80%;







vswarfarin

Edoxaban30mg



Table3:PhaseIIIstudiesofNOAC

p=0.03

0.76;0.590.97;

0.92%vs1.21%;

p<0.001

0.65;0.520.81;

1.11%vs1.71%;

ITT

64%

50.4%

(2.1)

0

Open(PROBE)

20%

Mean72

18,113

vswarfarin

p=0.35

1.11;0.891.40;

1.34%vs1.21%;

p=0.30

0.90;0.741.10;

1.54%vs1.71%







110mgvswarfarin

Dabigatran 150mg Dabigatran

RELY

0.470.93;p=0.019

bleeding



0.49%vs0.74%;0.67;

specified;p=0.576

3.6%vs3.45%;not

Ontreat

0.701.02;p=0.073

Intracranial

Majorbleeding

Safety

Allcausemortality

0.370.93;p=0.024

stroke

1.87%vs2.21%;0.85;

0.26%vs0.44%;0.59;

Haemorrhagic

1.61%vs3.43%; 0.47;0.41–0.55;

2.75%vs3.43%; 0.80;0.71–0.91; P<0.001 0.39%vs0.85%; 0.47;0.34–0.63; P<0.001

2.13%vs3.09%; 0.69;0.600.80; p<0.001 0.33%vs0.80%; 0.42;0.300.58; p<0.001

P<0.001

0.30;0.21–0.43;

0.26%vs0.85%;

P<0.001

Ontreat

Ontreat

P=0.006

0.87;0.79–0.96;

3.80%vs4.35%;

P<0.001

0.33;0.22–0.50;

0.16%vs0.47%;

Ontreat

P=0.08

3.99%vs4.35%

3.52%vs3.94% p=0.047

P<0.001

p<0.001

0.92;0.83–1.01;

0.54;0.38–0.77;

0.51;0.350.75;

0.89;0.800.998;

0.26%vs0.47%;

0.24%vs0.47%;

p<0.001

0.41;0.280.60;

0.30%vs0.76%;

p=0.31

0.93;0.811.07;

3.32%vs3.57%;

ITT

p=0.051

0.88;0.771.00;

3.64%vs4.13%;

p<0.001

0.26;0.140.49;

0.10%vs0.38%;

p<0.001

0.30;0.190.45;

0.23%vs0.76%;

p=0.003

0.80;0.700.93;

2.87%vs3.57%;

p=0.13

0.91;0.801.03;

3.75%vs4.13%;

0.170.56;p<0.001

0.31;

0.12%vs0.38%;

Figure1Majorbleedingrate(%/year)accordingtocreatinineclearance(CCr) Dabigatranversuswarfarin 7 6 5 4 3 2 1 0

5.41 3.76

PValueforinteraction Dabigatran110vswarfarinP=0.12 Dabigatran150vswarfarinP=0.68

3.33

2.89

2.36

5.44

5.29

2.09

1.53

Ccr80 Warfarin

Ccr5079 Dabigatran110

Ccr<50 Dabigatran150

 Rivaroxabanversuswarfarin 7 6 5 4 3 2 1 0

4.12

3.77 2.43

PValueforinteraction RivaroxabanvswarfarinP=0.715 3.37

2.77 2.06

Ccr80

Ccr5079 Warfarin

Ccr<50

Rivaroxaban

 Apixabanversuswarfarin 7 6 5 4 3 2 1 0

6.4

PValueforinteraction ApixabanvswarfarinP=0.03 3.2

3.2 2.5 1.8

1.5

Ccr80

Ccr5079 Warfarin

Ccr<50

Apixaban



Figure2Majorbleeding(%/year)accordingtoage Dabigatranversuswarfarin 7 6 5 4 3 2 1 0

5.1 4.43

4.37

PValueforinteraction Dabigatran110vswarfarinP=0.003 Dabigatran150vswarfarinP=0.001

3.25 2.43

2.6

2.29 0.89

0.82

Age<65

Age6574

Warfarin

Dabigatran110

Age75 Dabigatran150

 Rivaroxabanversuswarfarin 7

PValueforinteraction RivaroxabanvswarfarinP=0.107

6 5

4.03

4

2.97

2.68

3

2.67

2 1 0 Age<75

Age75 Warfarin

Rivaroxaban

 Apixabanversuswarfarin

PValueforinteraction ApixabanvswarfarinP=0.64

7 6

5.2

5 4

3.3

3 2

1.5

2

2

1.2

1 0 Age<65

Age6574 Warfarin Apixaban

Age75

 Edoxabanversuswarfarin 7 6 5 4 3 2 1 0

4.83 4.01 2.62 2.02

2.26

1.23

Age<75

Age 75

PValueforinteraction Edoxaban30vswarfarinP=0.95 Edoxaban60vswarfarinP=0.57