房颤治疗新型抗凝药物进展课件

房颤新型抗凝药物进展杨新春首都医科大学附属北京朝阳医院心脏中心

阵发性房颤持续性房颤年中风率(%)房颤与中风房颤增加中风危险4-5倍中风是非常最常见和灾难性的后果房颤患者全因中风率5%房颤是中风的独立危险因素美国大约15%的中风由房颤引起中风危险随年龄增长无症状房颤患者中风危险同样存在即使是节律控制的患者中风发现同样存在(AFFIRM,RACE研究)RACEII=RateControlEfficacyinPermanentAtrialFibrillation.FusterV,etal.JAmCollCardiol.2006;48(4):e149-e246.KannelWB,etal.MedClinNorthAm.2008;92(1):17-42.PageRL,etal.Circulation.2003;107(8):1141-1145.HartRG,etal.JAmCollCardiol.2000;35(1):183-187.DulliDA,etal.Neuroepidemiology.2003;22(2):118-123.低危中危高危1086420房颤并发脑卒中的机制血流缓慢、内皮功能障碍及血液的高凝状态等使血液易发生淤滞左心耳的栓子可引发栓塞，导致脑卒中或全身动脉栓塞Wolfetal.Stroke1991;22:983-9881/6的中风归因于房颤FraminghamStudy%年龄组(岁)010203050–5960–6970–7980–89房颤患病率归因于房颤的中风中国住院房颤病人抗血小板和抗凝治疗现状阿司匹林华发林不用房颤-中风危险分层CHADS2CHA2DS2-VASc危险因素积分Cardiacfailure心力衰竭1HTN高血压1Age≥75y年龄1Diabetes糖尿病1Stroke中风2危险因素积分Cardiacfailure心力衰竭1HTN高血压1Age≥75y年龄2Diabetes糖尿病1Stroke中风2Vascdz(MI,PAD,aorticath)血管病变1Age65-74y年龄1Sexcategory(female)女性1LipGY,HalperinJL.AmJMed.2010;123(6):484-488.012345605101520中风率%01.32.23.24.06.79.8CHA2DS2-VASc积分7899.615.26.7CHA2DS2-VASc积分与年中风率积分

年中风率(%)

0 1.9

1 2.8

2 4.0 3 5.9 4 8.5 5 12.5 6

18.2HAS-BLED出血危险积分ESCAFGuidelinesEHJ2010字母临床特征分值HHypertension高血压1AAbnormalrenalandliverfunction肝肾功能异常1或2SStroke中风1BBleeding出血1LLabileINRINR易变1EElderly老年1DDrugsoralcohol药物或酗酒1或29华法林—预防房颤缺血性脑卒中不可取代的药物华法林面临的问题起效/停药可逆性慢剂量反应难于预测治疗剂量范围窄药物和食物相互反应监测麻烦高出血率OddsRatio05.06.08.0INR1.02.03.04.07.05.015.010.0—中风—颅内出血1.0Fusteretal.JAmCollCardiol.2001;38:1231-1266.缺血性中风与颅内出血校正的OR与抗凝强度的关系房颤应用华法林现状

局限性导致治疗不足SamsaGP,etal.ArchInternMed2000;160:967.INR超过目标

6%未达到治疗剂量INR

13%INR在目标范围15%无华法林65%房颤患者抗凝治疗一级预防的现状治疗窗内时间TTR

(TimeinTherapeuticRange)

口服华法林期间达到目标INR时间的百分比分析评价口服抗凝剂的疗效差异

SPORTIFIII和V华法林组与对照组患者结果事件差异

TTR<60%

TTR60-75%

TTR>75%结果TTR<60%TTR60-75%TTR>75%死亡率,%4.21.841.69严重出血,%3.851.961.58中风/外周栓塞,%2.101.341.07ArchInternMed.

2007.WhiteHD,GruberM,FeyziJ,KaatzS,TseH,HustedS,AlbersG研究中的新型抗凝剂TFPI(tifacogin)IdraparinuxRivaroxaban

Apixaban

EndoxabanBetrixabanLY517717

YM150TAK42Dabigatran口服胃肠外DX-9065a

OtamixabanXaIIaTF/VIIaXIXIXaVIIIaVaII(thrombin)FibrinFibrinogenATAPC(drotrecoginalfa)sTM(ART-123)AdaptedfromWeitzJI.ThrombHaemost2007;5Suppl1:65-7.TTP889APC活化蛋白CAT抗凝血酶sTM可溶性血栓调节素TF组织因子TFPI组织因子途径抑制物关于新型抗凝剂的试验ARISTOTLE–Apixaban（阿司匹林）RELY–Dabigatran（华发林）ROCKET–Rivaroxaban（华发林）ENGAGE–Edoxaban（华法林）AVERROES–Apixaban（华法林）与warfarin相比，AFIII期临床试验Re-LYROCKET-AFARISTOTLEENGAGEAF-TIMI48DrugDabigatranRivaroxabanApixabanEdoxabanDose(mg)Freq150,110BID20(15*)QD5(2.5*)BID60*,30*QDN18,11314,26618,206>21,000DesignPROBE2xblind2xblind2xblindCHADS2≥1≥2≥1≥1AFcriteriaAF<6mthsAF(>1in<30d)AForAFl<12mthsAF<12mths%VKAnaive50%38%43%40%goal*Doseadjustedinpatientswith↓drugclearance.**Maxof10%withCHADS-2score=2andnostroke/TIA/SEEPROBE=prospective,randomized,open-label,blindedendpointevaluation VKA=VitaminKantagonistApixaban5mgBIDASA(81-324mg/d)AF合并≥1危险因素,不适合服用VKA主要终点:StrokeorSystemicEmbolicEvent(SEE)5,600病人AVERROES设计2.5mgBID（在选择的病人）R36个国家,522个中心双盲NEnglJMed2011;364:806-817.CumulativeRisk0.00.010.030.050369121821ASAApixabanNo.atRiskASAApix2791272025412124154162632928092761256721271523617353MonthsRR=0.4695%CI=0.33-0.64p<0.001Strokeor

SystemicEmbolicEvent54%ACTIVEA,NEnglJMed2009;360:1-13HartRG,etal.AnnInternMed.2007;146:857-867AVERROES;ESCHotline2010,NEnglJMed2011;364:806-817从SPAF试验我们对使用抗血小板得到什么启发在AF与ASA抗栓治疗相比Clopidogrel+ASAVKAApixabanFavorstreatmentFavorsASA100%50%050%100%Relativeriskreduction(95%CI)FavorstreatmentFavorsASA50%050%100%Relativeriskincrease(95%CI)StrokeReductionIncreaseinIntracranialBleeding-28%-38%-54%+87%+128%-15%100%AVERROES结论对不适合VKA治疗,相对于ASA，apixaban

减少卒中>50%,并不增加大出血与ASA相比，Apixaban

可以很好耐受，尚没有肝毒性的证据对不适合VKA的房颤病人,apixaban有可能降低危险从SPAF试验我们对使用抗血小板药物得到什么启发?

summary

在预防AF卒中，对不适合华法林时，ASA

仍然是目前仅有的替代药物,但仅是中等有效联合

ASA

和clopidogrel比ASA更有效，但仍不如warfarin有效，且可以引起出血增加在AVERROES

试验，对较广范围的不适合warfarin的AF病人，Apixaban显示比ASA更有效，安全相似，更好耐受RE-LY:非劣效性检验设计ROpen•房颤伴≥1危险因素•没有禁忌症•患者来自44国家的951中心华法林调整INR2.0–3.0N=6000Dabigatranetexilate110mgBIDN=6000Dabigatranetexilate150mgBIDN=6000盲法结果判定开放双盲RRE-LY:中风或周围血管栓塞0.500.751.001.251.50Dabigatran110vs.华法林Dabigatran150vs.华法林非劣效性p-值<0.001<0.001优效性p-值

0.34<0.001Margin=1.46HR(95%CI)华法林更好Dabigatran更好Connollyetal.,NEJM,2009RR0.40(95%CI:0.27–0.60)p<0.001(sup)RE-LY:颅内出血RR0.31(95%CI:0.20–0.47)p<0.001(sup)Numberofevents0,23%0,74%0,30%RRR69%RRR60%Connollyetal.,NEJM,2009CammJ.:OralpresentationatESConAug30th2009.缺血性中风与周围血管栓塞荟萃分析WvsplaceboWvsWlowdoseWvsASAWvsASA+clopidogrelWvsdabigatran15000.30.60.91.21.51.82.0倾向华法林倾向其他治疗150mgBIDMODERNERA:RE-LY

StuartConnollyMD,MichaelD.EzekowitzMD,SalimYusuf MD,…..Wallentin.DabigatranversusWafarininPatientswith AtrialFibrillation.NEJM2009,361.c&NEJM2010,363RE-LY结论与传统的华法林相比，达比加群两种剂量均显示出优势达比加群150mg更有效而达比加群110mg有更好的安全性两种有效剂量各有其优缺点，在临床上对不同特点的患者可做不同的治疗选择Warfarin(targetINR2-3)Apixaban5mgoraltwicedaily(2.5mgBIDinselectedpatients)Primaryoutcome:strokeorsystemicembolismHierarchicaltesting:non-inferiorityforprimaryoutcome,superiorityforprimaryoutcome,majorbleeding,deathRandomizedoubleblind,doubledummy(n=18,201)InclusionriskfactorsAge≥75yearsPriorstroke,TIAorSEHForLVEF≤40%DiabetesmellitusHypertensionWarfarin/warfarinplaceboadjustedbyINR/shamINRbasedonencryptedpoint-of-caretestingdevice

ExclusionMechanicalprostheticvalveSevererenalinsufficiencyNeedforaspirinplusthienopyridineAtrialFibrillationwithatLeastOneAdditionalRiskFactorforStrokeARISTOTLEMainTrialResults

21%RRR31%RRRISTHmajorbleedingStrokeorsystemicembolismMedianTTR66%Apixaban212patients,1.27%peryearWarfarin265patients,1.60%peryearHR0.79(95%CI,0.66–0.95);P=0.011Apixaban327patients,2.13%peryearWarfarin462patients,3.09%peryearHR0.69(95%CI,0.60–0.80);P<0.001Warfarin(targetINR2-3)Apixaban5mgoraltwicedaily(2.5mgBIDinselectedpatients)Primaryoutcome:strokeorsystemicembolismHierarchicaltesting:non-inferiorityforprimaryoutcome,superiorityforprimaryoutcome,majorbleeding,deathRandomizedoubleblind,doubledummy(n=18,201)InclusionriskfactorsAge≥75yearsPriorstroke,TIA,orSEHForLVEF≤40%DiabetesmellitusHypertensionWarfarin/warfarinplaceboadjustedbyINR/shamINRbasedonencryptedpoint-of-caretestingdeviceMajorexclusioncriteriaMechanicalprostheticvalveSevererenalinsufficiencyNeedforaspirinplusthienopyridineAtrialFibrillationwithatLeastOneAdditionalRiskFactorforStrokePrimaryOutcome

Stroke(ischemicorhemorrhagic)orsystemicembolismApixaban212patients,1.27%peryearWarfarin265patients,1.60%peryearHR0.79(95%CI,0.66–0.95);P(superiority)=0.011No.atRiskApixaban 9120 8726 8440 6051 3464 1754Warfarin 9081 8620 8301 5972 3405 1768P(non-inferiority)<0.00121%RRRMajorBleeding

ISTHdefinitionApixaban327patients,2.13%peryearWarfarin 462patients,3.09%peryearHR0.69(95%CI,0.60–0.80);P<0.001No.atRiskApixaban 9088 8103 7564 5365 3048 1515Warfarin 9052 7910 7335 5196 2956 149131%RRRMODERNERA:ARISTOTLEGranger,Alexander,MacMurray….Wallentin.,NEJM2011ConnollySetalNEJM2009;PatelMetalNEJM2011;GrangerCetalNEJM2011NewantithrombotictherapiescomparedtowarfarinStrokeorsystemicembolism

Dabigatran150mgb.i.d. Dabigatran110mgb.i.d. Rivaroxaban20mgo.d. Abixaban5mgb.i.d.0.512NewantithrombotictherapiescomparedtowarfarinHemorrhagicstroke

Dabigatran150mgb.i.d. Dabigatran110mgb.i.d. Rivaroxaban20mgo.d. Abixaban5mgb.i.d.

0.1ConnollySetalNEJM2009;PatelMetalNEJM2011;GrangerCetalNEJM201112ConnollySetalNEJM2009;PatelMetalNEJM2011;GrangerCetalNEJM2011NewantithrombotictherapiescomparedtowarfarinStrokeofischemicorunknownorigin

Dabigatran150mgb.i.d. Dabigatran110mgb.i.d. Rivaroxaban20mgo.d. Abixaban5mgb.i.d.0.512ConnollySetalNEJM2009;PatelMetalNEJM2011;GrangerCetalNEJM2011NewantithrombotictherapiescomparedtowarfarinAll-causemortality

Dabigatran150mgb.i.d. Dabigatran110mgb.i.d. Rivaroxaban20mgo.d. Abixaban5mgb.i.d.0.512ConnollySetalNEJM2009;PatelMetalNEJM2011;GrangerCetalNEJM2011NewantithrombotictherapiescomparedtowarfarinMajorbleeding

Dabigatran150mgb.i.d. Dabigatran110mgb.i.d. Rivaroxaban20mgo.d. Abixaban5mgb.i.d.0.512ConnollySetalNEJM2009;PatelMetalNEJM2011;GrangerCetalNEJM2011NewantithrombotictherapiescomparedtowarfarinMajor+clinicallyrelevantbleeding

Dabigatran150mgb.i.d. Dabigatran110mgb.i.d. Rivaroxaban20mgo.d. Abixaban5mgb.i.d.0.512ConnollySetalNEJM2009;PatelMetalNEJM2011;GrangerCetalNEJM2011NewantithrombotictherapiescomparedtowarfarinGastrointestinalbleeding

Dabigatran150mgb.i.d. Dabigatran110mgb.i.d. Rivaroxaban20mgo.d. Abixaban5mgb.i.d.0.512NewantithrombotictherapiescomparedtowarfarinIntracranialhemorrhage

Dabigatran150mgb.i.d. Dabigatran110mgb.i.d. Rivaroxaban20mgo.d. Abixaban5mgb.i.d.

0.1ConnollySetalNEJM2009;PatelMetalNEJM2011;GrangerCetalNEJM201112ConnollySetalNEJM2009;PatelMetalNEJM2011;GrangerCetalNEJM2011NewantithrombotictherapiescomparedtowarfarinMyocardialinfarction

Dabigatran150mgb.i.d. Dabigatran110mgb.i.d. Rivaroxaban20mgo.d. Abixaban5mgb.i.d.0.512NewanticoagulantscomparedtowarfarininAF2011EffetonoutcomeeventD150D110RivaApixNoninferioritystrokeReductionhemorrhagicstroke√√√√√√√√Reductionischemicstroke√√√√ReductionmortalityReductionmajorbleedingIncreasegastrointestinalbleeding(√)

√√(√)(√)IncreasemyocardialinfarctionFewertreatmentdiscontinuationsValidationinasecondrandomizedtrial√√ConnollySetalNEJM2009&NEJM2011;PatelMetalNEJM2011;GrangerCetalNEJM2011从SPAF试验我们对使用抗凝药物得到什么启发?-summaryDabigatran,rivaroxaban,apixaban都提供比warfarin重要的优势，包括方便，至少有相似预防卒中的效果，少的颅内出血ARISTOTLE发现在预防卒中和系统性栓塞，使用单剂量的apixaban比warfarin有效，且发生出血减少，死亡率降低，期望新的药物对房颤病人提供改善机会，包括有适应症,但目前又未服用任何口服抗凝药物的病人

Warfarin RiskforstrokeandIntracranialbleeding

Apixaban DabigatranRivaroxabansideeffectse.g.otherbleedings Survival Patientpreferences Healtheconomy

ThreenewanticoagulantssuperiortoWarfarinforpreventionofstrokeandintracranialbleedinginAF available2011在2011年，与warfarin相比，EffetonoutcomeeventD150D110RivaApixStrokeorsystemicembolism(Noninferiority)√√√√Reductionischemicstroke√√√√ReductionmortalityReductionmajorbleedingIncreasegastrointestinalbleeding(√)

√√(√)(√)IncreasemyocardialinfarctionFewertreatmentdiscontinuationsValidationinasecondrandomizedtrial√√ConnollySetalNEJM2009&NEJM2011;PatelMetalNEJM2011;GrangerCetalNEJM2011新抗凝剂Apixaban对房颤病人提供全面保护作用ReductionhemorrhagicstrokeStrokeorsystemicembolism(superiority)√√√√√√谢谢！RELYDabigatran110mgDabigatran150mgWarfarinCHADS2

Mean0-1(%)2(%)3+(%)2.132.634.732.72.232.235.232.62.130.937.032.1C.MichaelGibson,M.S.,M.D.ROCKETAFRivaroxabanWarfarinCHADS2Mean2(%)3(%)4(%)5(%)6(%)3.51343291323.5134428122ARISTOTLERivaroxabanWarfarinCHADS2Mean0-1(%)2(%)3+(%)2.13435.830.22.13435.830.2PatelMRetal,NEJM2011;ConnollySJ,etal.NEnglJMed.2009;361:1139-1151;GrangerCetal,NEngJMed;20113+86%ARISTOTLECOVERACROSSCHADS2SCORE临床试验中TTR的情况RE-LYROCKETAFARISTOTLETimeinTherapeuticRange(TTR)64%67%warfarin-experienced61%warfarin-naïveMean55%Median58%Mean62%Median66%C.MichaelGibson,M.S.,M.D.PatelMRetal,NEJM2011;ConnollySJ,etal.NEnglJMed.2009;361:1139-1151;GrangerCetal,NEngJMed;2011Theinternationalnormalizedratio(INR)testisthelaboratorytestusedtodeterminethedegreetowhichthepatient'scoagulationhasbeensuccessfullysuppressedbythevitaminKantagonist(VKA).Formostpatients,thegoalistokeeptheINRbetween2and3,whichroughlycorrespondstothebloodtaking2to3timesaslongtoclotaswouldanormalperson'sblood.Thislevelofanticoagulationhasbeenshowntomaximizebenefit(i.e.,protectpatientsfrombloodclots)whileminimizingrisk(i.e.,riskofhemorrhageattributabletoexcessiveanticoagulation).TherapeuticINRrange(TTR)isawayofsummarizingINRcontrolovertimeRE-LYDabigatran110mg 1.53%/yrDabigatran150mg 1.11%/yrWarfarin 1.69%/yrROCKETAFRivaroxaban20mg 2.1%/yrWarfarin 2.4%/yrARISTOTLEApixaban5mg 1.27%/yrWarfarin 1.60%/yr主要终点

StrokeorSystemicEmbolism:非劣效性分析

p<0.001p<0.001

p<0.001NonInferiorirtypvswarfarinITTAnalysisModifiedITTNoITTanalysisisavailablefornon-inferiorityinRocketAF.Anontreatmentorper-protocolanalysisisgenerallyperformedintheassessmentofnon-inferiority.Ifnumerouspatientscomeoffofstudydrug,thisbiasesthetrialtowardsanon-inferiorresultinanITTanalysis.Thisisthebasisforperformingaper-protocolanalysisinanon-inferiorityassessment.C.MichaelGibson,M.S.,M.D.

p<0.001ITTAnalysisPatelMRetal,NEJM2011;ConnollySJ,etal.NEnglJMed.2009;361:1139-1151;GrangerCetal,NEngJMed;2011HR=0.88HR=0.79HR=0.91HR=0.66superiority

p=0.12p<0.001

p=0.34ITTAnalysisModifiedITT

P=0.01ITTAnalysis出血性卒中Dabigatran110mg 0.12%/yr 0.31 <0.001Dabigatran150mg 0.10%/yr 0.26 <0.001Warfarin 0.38%/yrHRITTP-valueRivaroxaban20mg 0.26%/yr 0.59 0.024*Warfarin 0.44%/yrROCKETRELYC.MichaelGibson,M.S.,M.D.*InanontreatmentanalysisinRocketAFHemorrhagicStokerateswere0.26%/yrforrivaroxabanand0.44%/yrforwarfarin,p=0.024.NoontreatmentanalysisisavailablefromRE-LY.Apixaban5mg 0.24%/yr 0.51 <0.001Warfarin 0.47%/yrARISTOTLEPatelMRetal,NEJM2011;ConnollySJ,etal.NEnglJMed.2009;361:1139-1151;GrangerCetal,NEngJMed;2011缺血性卒中Dabigatran110mg 1.34%/yr 1.11 0.35Dabigatran150mg 0.92%/yr 0.76 0.03

Warfarin 1.20%/yrHRITTP-valueRivaroxaban20mg 1.62%/yr 0.99 0.92*Warfarin 1.64%/yrROCKETRELYC.MichaelGibson,M.S.,M.D.*InanontreatmentanalysisinRocketAFIschemicStokerateswere1.34%/yrforrivaroxabanand1.42%/yrforwarfarin,p=0.58.NoontreatmentanalysisisavailablefromRE-LYandAristotle.Aoixaban5mg 0.97%/yr 0.92 0.42Warfarin 1.05%/yrARISTOTLEPatelMRetal,NEJM2011;ConnollySJ,etal.NEnglJMed.2009;361:1139-1151;GrangerCetal,NEngJMed;2011Dabigatran110mg 2.71%/yr 0.8 0.003Dabigatran150mg 3.11%/yr 0.93 0.31Warfarin 3.36150mgDabigatranvs110mgDabigatran=HRof1.16(1.00–1.34)p=0.052大出血MajorBleedingHRITTP-valueRE-LYRivaroxaban20mg 3.60%/yr 1.04 0.58*Warfarin 3.4%/yrROCKETC.MichaelGibson,M.S.,M.D.*ThereisnoITTanalysisofsafetyinRocketAF.ThereisnoontreatmentanalysisofsafetyfromRE-LY.OnTreatmentP-valueP-valueApixaban5mg 2.13%/yr 0.69 <0.001Warfarin 3.09%/yrARISTOTLEPatelMRetal,NEJM2011;ConnollySJ,etal.NEnglJMed.2009;361:1139-1151;GrangerCetal,NEngJMed;20112gdropin24hours2gdropAllCauseMortalityDabigatran110mg 3.75%/yr 0.91 0.13Dabigatran150mg 3.64%/yr 0.88 0.051Warfarin 4.13%/yrHRITTp-valueRivaroxaban20mg 4.5%/yr 0.92 0.15*Warfarin 4.9%/yrROCKETRELYC.MichaelGibson,M.S.,M.D.*Inanontreatment