房顫治療新型抗凝藥物進(jìn)展課件

房顫新型抗凝藥物進(jìn)展楊新春首都醫(yī)科大學(xué)附屬北京朝陽(yáng)醫(yī)院心臟中心

陣發(fā)性房顫持續(xù)性房顫年中風(fēng)率(%)房顫與中風(fēng)房顫增加中風(fēng)危險(xiǎn)4-5倍中風(fēng)是非常最常見(jiàn)和災(zāi)難性的后果房顫患者全因中風(fēng)率5%房顫是中風(fēng)的獨(dú)立危險(xiǎn)因素美國(guó)大約15%的中風(fēng)由房顫引起中風(fēng)危險(xiǎn)隨年齡增長(zhǎng)無(wú)癥狀房顫患者中風(fēng)危險(xiǎn)同樣存在即使是節(jié)律控制的患者中風(fēng)發(fā)現(xiàn)同樣存在(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房顫并發(fā)腦卒中的機(jī)制血流緩慢、內(nèi)皮功能障礙及血液的高凝狀態(tài)等使血液易發(fā)生淤滯左心耳的栓子可引發(fā)栓塞，導(dǎo)致腦卒中或全身動(dòng)脈栓塞Wolfetal.Stroke1991;22:983-9881/6的中風(fēng)歸因于房顫FraminghamStudy%年齡組(歲)010203050–5960–6970–7980–89房顫患病率歸因于房顫的中風(fēng)中國(guó)住院房顫病人抗血小板和抗凝治療現(xiàn)狀阿司匹林華發(fā)林不用房顫-中風(fēng)危險(xiǎn)分層CHADS2CHA2DS2-VASc危險(xiǎn)因素積分Cardiacfailure心力衰竭1HTN高血壓1Age≥75y年齡1Diabetes糖尿病1Stroke中風(fēng)2危險(xiǎn)因素積分Cardiacfailure心力衰竭1HTN高血壓1Age≥75y年齡2Diabetes糖尿病1Stroke中風(fēng)2Vascdz(MI,PAD,aorticath)血管病變1Age65-74y年齡1Sexcategory(female)女性1LipGY,HalperinJL.AmJMed.2010;123(6):484-488.012345605101520中風(fēng)率%01.32.23.24.06.79.8CHA2DS2-VASc積分7899.615.26.7CHA2DS2-VASc積分與年中風(fēng)率積分

年中風(fēng)率(%)

0 1.9

1 2.8

2 4.0 3 5.9 4 8.5 5 12.5 6

18.2HAS-BLED出血危險(xiǎn)積分ESCAFGuidelinesEHJ2010字母臨床特征分值HHypertension高血壓1AAbnormalrenalandliverfunction肝腎功能異常1或2SStroke中風(fēng)1BBleeding出血1LLabileINRINR易變1EElderly老年1DDrugsoralcohol藥物或酗酒1或29華法林—預(yù)防房顫缺血性腦卒中不可取代的藥物華法林面臨的問(wèn)題起效/停藥可逆性慢劑量反應(yīng)難于預(yù)測(cè)治療劑量范圍窄藥物和食物相互反應(yīng)監(jiān)測(cè)麻煩高出血率OddsRatio05.06.08.0INR1.02.03.04.07.05.015.010.0—中風(fēng)—顱內(nèi)出血1.0Fusteretal.JAmCollCardiol.2001;38:1231-1266.缺血性中風(fēng)與顱內(nèi)出血校正的OR與抗凝強(qiáng)度的關(guān)系房顫應(yīng)用華法林現(xiàn)狀

局限性導(dǎo)致治療不足SamsaGP,etal.ArchInternMed2000;160:967.INR超過(guò)目標(biāo)

6%未達(dá)到治療劑量INR

13%INR在目標(biāo)范圍15%無(wú)華法林65%房顫患者抗凝治療一級(jí)預(yù)防的現(xiàn)狀治療窗內(nèi)時(shí)間TTR

(TimeinTherapeuticRange)

口服華法林期間達(dá)到目標(biāo)INR時(shí)間的百分比分析評(píng)價(jià)口服抗凝劑的療效差異

SPORTIFIII和V華法林組與對(duì)照組患者結(jié)果事件差異

TTR<60%

TTR60-75%

TTR>75%結(jié)果TTR<60%TTR60-75%TTR>75%死亡率,%4.21.841.69嚴(yán)重出血,%3.851.961.58中風(fēng)/外周栓塞,%2.101.341.07ArchInternMed.

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

Apixaban

EndoxabanBetrixabanLY517717

YM150TAK42Dabigatran口服胃腸外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可溶性血栓調(diào)節(jié)素TF組織因子TFPI組織因子途徑抑制物關(guān)于新型抗凝劑的試驗(yàn)ARISTOTLE–Apixaban（阿司匹林）RELY–Dabigatran（華發(fā)林）ROCKET–Rivaroxaban（華發(fā)林）ENGAGE–Edoxaban（華法林）AVERROES–Apixaban（華法林）與warfarin相比，AFIII期臨床試驗(yàn)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危險(xiǎn)因素,不適合服用VKA主要終點(diǎn):StrokeorSystemicEmbolicEvent(SEE)5,600病人AVERROES設(shè)計(jì)2.5mgBID（在選擇的病人）R36個(gè)國(guó)家,522個(gè)中心雙盲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從SPAF試驗(yàn)我們對(duì)使用抗血小板得到什么啟發(fā)在AF與ASA抗栓治療相比Clopidogrel+ASAVKAApixabanFavorstreatmentFavorsASA100%50%050%100%Relativeriskreduction(95%CI)FavorstreatmentFavorsASA50%050%100%Relativeriskincrease(95%CI)StrokeReductionIncreaseinIntracranialBleeding-28%-38%-54%+87%+128%-15%100%AVERROES結(jié)論對(duì)不適合VKA治療,相對(duì)于ASA，apixaban

減少卒中>50%,并不增加大出血與ASA相比，Apixaban

可以很好耐受，尚沒(méi)有肝毒性的證據(jù)對(duì)不適合VKA的房顫病人,apixaban有可能降低危險(xiǎn)從SPAF試驗(yàn)我們對(duì)使用抗血小板藥物得到什么啟發(fā)?

summary

在預(yù)防AF卒中，對(duì)不適合華法林時(shí)，ASA

仍然是目前僅有的替代藥物,但僅是中等有效聯(lián)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

試驗(yàn)，對(duì)較廣范圍的不適合warfarin的AF病人，Apixaban顯示比ASA更有效，安全相似，更好耐受RE-LY:非劣效性檢驗(yàn)設(shè)計(jì)ROpen?房顫伴≥1危險(xiǎn)因素?沒(méi)有禁忌癥?患者來(lái)自44國(guó)家的951中心華法林調(diào)整INR2.0–3.0N=6000Dabigatranetexilate110mgBIDN=6000Dabigatranetexilate150mgBIDN=6000盲法結(jié)果判定開(kāi)放雙盲RRE-LY:中風(fēng)或周圍血管栓塞0.500.751.001.251.50Dabigatran110vs.華法林Dabigatran150vs.華法林非劣效性p-值<0.001<0.001優(yōu)效性p-值

0.34<0.001Margin=1.46HR(95%CI)華法林更好Dabigatran更好Connollyetal.,NEJM,2009RR0.40(95%CI:0.27–0.60)p<0.001(sup)RE-LY:顱內(nèi)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.缺血性中風(fēng)與周圍血管栓塞薈萃分析WvsplaceboWvsWlowdoseWvsASAWvsASA+clopidogrelWvsdabigatran15000.30.60.91.21.51.82.0傾向華法林傾向其他治療150mgBIDMODERNERA:RE-LY

StuartConnollyMD,MichaelD.EzekowitzMD,SalimYusuf MD,…..Wallentin.DabigatranversusWafarininPatientswith AtrialFibrillation.NEJM2009,361.c&NEJM2010,363RE-LY結(jié)論與傳統(tǒng)的華法林相比，達(dá)比加群兩種劑量均顯示出優(yōu)勢(shì)達(dá)比加群150mg更有效而達(dá)比加群110mg有更好的安全性兩種有效劑量各有其優(yōu)缺點(diǎn)，在臨床上對(duì)不同特點(diǎn)的患者可做不同的治療選擇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從SPAF試驗(yàn)我們對(duì)使用抗凝藥物得到什么啟發(fā)?-summaryDabigatran,rivaroxaban,apixaban都提供比warfarin重要的優(yōu)勢(shì)，包括方便，至少有相似預(yù)防卒中的效果，少的顱內(nèi)出血ARISTOTLE發(fā)現(xiàn)在預(yù)防卒中和系統(tǒng)性栓塞，使用單劑量的apixaban比warfarin有效，且發(fā)生出血減少，死亡率降低，期望新的藥物對(duì)房顫病人提供改善機(jī)會(huì)，包括有適應(yīng)癥,但目前又未服用任何口服抗凝藥物的病人

Warfarin RiskforstrokeandIntracranialbleeding

Apixaban DabigatranRivaroxabansideeffectse.g.otherbleedings Survival Patientpreferences Healtheconomy

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

√√(√)(√)IncreasemyocardialinfarctionFewertreatmentdiscontinuationsValidationinasecondrandomizedtrial√√ConnollySetalNEJM2009&NEJM2011;PatelMetalNEJM2011;GrangerCetalNEJM2011新抗凝劑Apixaban對(duì)房顫病人提供全面保護(hù)作用ReductionhemorrhagicstrokeStrokeorsystemicembolism(superiority)√√√√√√謝謝！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臨床試驗(yàn)中TTR的情況RE-LYROCKETAFARISTOTLETimeinTherapeuticRange(TTR)64%67%warfarin-experienced61%warfarin-na?veMean55%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主要終點(diǎn)

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