新型抗凝剂课件

新抗凝药在房颤相关卒中的预防

-亚洲观点抗凝药在房颤相关卒中的治疗

-2014指引与共識59-year-oldmalewithoutspecificpastmedicalhistory92/03/09住院診斷1)Slurredspeechandmouthangledeviatedtorightsidefor3dayssuspectCVAinfarct2)AlcoholismCVdoctorwasconsultedandTEEwasdone.NoAf,noLAAthrombus出院診斷1)Embolicstroke,bilateralhemisphere2)Alcoholism92/03/0992/03/1363-67y/omalebusinessmanwithahistoryofoldCVA95/08/29住院診斷1.CVA,acuteinfarction,rightMCAterritory,2.Af,hypertension3.Type2DM97/03/10住院診斷1)TraumaticheadinjurywithrightF-T-PSDH2)Right3rd,4thand5thtoesamputation3)Rightribsfracture4)OldCVA100/03/16住院診斷1.LeftMCAinfarctionwithbraintissueedema.2.Pneumonia.100/03/1697/03/10MeanTTR<10%Saxagliptin-

Preferredchoiceaftermetformintreatment

處方藥物請參考衛生福利部核准仿單Saxagliptin-

Preferredchoiceaftermetformintreatment

處方藥物請參考衛生福利部核准仿單Saxagliptin-

Preferredchoiceaftermetformintreatment

處方藥物請參考衛生福利部核准仿單

DEC2011-JAN201209FEB2012世交好友蜘蛛膜下腔出血SubarachnoidHemorrhage(SAH).TaiwanStrokeRegistryMeanage57VeryPainfulLoss20122007inTaiwanCABG

2008inCanada

CCB+ACEI+Diuretic+Betablocker

Drugelutingstent

長期服用Plavix長期服用Statin

Niacin500mgprnbyOTCAged57(TSRcirculation2010SAHmeanage57)跟醫師不熟不好跟醫師太熟也不好VeryPainfulLoss2012為什麼我的大哥會從我的手中消失

我應該限制他出境

應該規定他要天天量血壓

應該想辦法說服他來做腦血管攝影

或許血管可以再多用五年十年

但為時已晩Stroke:BrainAttack這是一個會奪走我們至親好友的重症一個會如疾風迅雷讓我們悲痛至極的重症人定勝天天高地厚RealWorldPracticeStroke/SystemicEmbolism?Vascularmortality?Allcausemortality?Hemorrhagicstroke?Intra-cranialbleedingrates?Majorbleedingrates?-Lifethreatening-Non-lifethreatening-Gastrointestinal2008CAPRIEIS33.5%CHARISMAIS27.7%PRoFESSIS100%MATCHIS100%CLOASAASA+CLOASAASA+DIPCLOASA+CLOCLOAsian19185/9%15603/5%20332/32%7599/3.9%Male/Female64/36%70/30%64/36%63/37%Age65646666HTN65%80.1%74%78.2%DM26%32.3%28%68.4%Benefit/RiskMI19.2%1.9%vs2.0%6%1.7%vs1.9%10%2%vs2%-7%IS7.3%1.7%vs2.1%19%7.7%vs7.9%3%8%vs9%7%MI/IS/CVDeath0.56%8.7%6.8%vs7.3%7%13.1%vs13.1%1%0.8%5.9%ICH0.35%0.49%0.4%0.4%1.4%1.0%1.1%0.7%华法林治疗后颅内出血的

调整危害比ShenAY,etal:JAmCollCardiol50:309-315,2007Multiethniccohortof18,867patientshospitalizedwithfirst-timeAF(January1995–December2000)and173qualifyingICHeventsover3.3yearsfollow-up.21房颤相关卒中流行病学23卒中是房颤的主要并发症房颤患者卒中总体发生风险增高5倍1在对其他高危因素进行校正之后发现，房颤可使卒中发生风险翻倍2如果不采取预防治疗措施，每20名房颤患者中每年就会有将近1人（5%）发生卒中3如果将短暂性脑缺血发作和无明显临床表现的“隐性”卒中考虑在内，与非瓣膜性房颤相关的缺血性脑卒中的年发生率可达7%以上4房颤与将近三分之一的卒中发生有关，5

房颤是栓塞性卒中最主要的病因6*Stroke,transientischaemicattacksandclinically‘silent’strokes1.SavelievaIetal.AnnMed2007;39:371–91;2.ACC/AHA/HRSfocusedupdateguidelines:FusterVetal.Circulation2011;123:e269–357;3.AtrialFibrillationInvestigators.ArchInternMed1994;154:1449–57;

4.CarlsonM.MedscapeCardiol

2004;8;availableat/viewarticle/487849;

accessedFeb2010;5.HannonNetal.CerebrovascDis2010;29:43–9;

6.EmmerichJetal.EurHeartJ2005;7(SupplC):C28–3324房颤相关的卒中主要是缺血性卒中数据源于DanishNationalIndicatorProject项目39

484例因卒中住院的患者

(包括6294例伴房颤者)AndersenKKetal.Stroke2009;40:2068–72TypesofstrokeinpatientswithAF缺血性(92%)Ischaemicstroke(n=5810)Haemorrhagicstroke(n=484)出血性

(8%)26房颤相关卒中的预後27房颤相关的卒中

预後差Follow-upof501patientswithischaemicstrokeintheFraminghamstudyLinHJetal.Stroke1996;27:1760–41.01.00060卒中后天数ProbabilitySurvival0.20120180240300360伴房颤(n=103)P<0.001不伴房颤(n=398)缺血性卒中后一年内,伴房颤的患者三分之二会死亡,而不伴房颤者只有三分之一28AF患者卒中复发风险增高MariniCetal.Stroke2005;36:1115–9AF患者不伴AF的患者卒中复发首次卒中后月数累积复发概率(%)1012864200246810P=0.039830几十年来

VKAs

是唯一可用的口服抗凝药ESC=EuropeanSocietyforCardiology;FDA=USFoodandDrugAdministration;NOAC=noveloralanticoagulant;

NVAF=nonvalvularatrialfibrillation;RCT=randomizedcontrolledtrial;SE=systemicembolism;VKA=VitaminKantagonist195019601940华法林合成华法林作为灭鼠药获批(USA)198019901970200020102020RE-LY®

启动RE-LY®

完成Dabigatran进入临床阶段EUFDADabigatran获批用于NVAF卒中预防NOACs在ESC指南获得推荐华法林首批RCTs用于NVAF的卒中预防华法林获批用于人类(USA)32随机效应模型;误差范围

=95%置信区间;*P>0.2同质性;†所有卒中（缺血性和出血性）的相对危险度降幅

(RRR)华法林可显著降低房颤患者的卒中华法林更优安慰剂更优RRR(%)†100–100500–50AFASAKSPAFBAATAFCAFASPINAFEAFT所有研究RRR64%*

(95%CI:4974%)HartRGetal.AnnInternMed2007;146:857–67阿司匹林在减少房颤的卒中风险方面效果有限RRR(%)†100–100500–50AFASAKSPAFEAFTESPSIIASAbetterPlacebobetterLASAF125mg/d125mgQODUK-TIA300mg/d1200mg/dJAST所有研究RRR=19%*

(95%CI:–1to35%)HartRGetal.AnnInternMed2007;146:857–67Randomeffectsmodel.Errorbars=95%CI.*P>0.2forhomogeneity;†Relativeriskreduction(RRR)forallstrokes(ischaemicandhaemorrhagic),forischaemicstrokeonly,theRRRwas67%(95%CI:54–77%).ASA=acetylsalicylicacid;TargetsofNewOralAnticoagulantsESC2012focusedupdate:

choiceofanticoagulant35YesAtrialfibrillationValvularAF*<65yearsandloneAF(includingfemales)Assessriskofstroke

CHA2DS2-VAScscore评估出血风险

(HAS-BLEDscore)

Considerpatientvaluesandpreferences无抗栓治疗口服抗凝治疗NOACVKA01No(i.e.nonvalvular)YesNo≥2最佳选择=CHA2DS2-VASc0

=最佳选择=CHA2DS2-VASc1

=CHA2DS2-VASc≥2

=可选治疗*Includesrheumaticvalvulardiseaseandprostheticvalves;ESC=EuropeanSocietyofCardiology;

NOAC=noveloralanticoagulant;VKA=vitaminKantagonistCammAJetal.EurHeartJ2012;33:2719–4735阿司匹林地位下降.达比加群被推荐用于

CHA2DS2-VASc≥2分的房颤患者.RE-LY亚洲人群亚组分析37背景与非亚洲人相比，亚洲人报道的脑出血发生更常见RE-LY®,全部18,113受试者中有2,782来自亚洲国家亚组分析比较达比加群Vs华法林在亚洲和非亚洲人的效应

ICH=intracranialhaemorrhage;HoriM,etal.Presentedatthe2ndAsiaPacificStrokeConferenceinTokyo,Japan.September2012.Disclaimer:Dabigatranetexilateisnowapprovedforclinicaluseinstrokepreventioninatrialfibrillationincertaincountries.

Pleasechecklocalprescribinginformationforfurtherdetails38RE-LY®(n=18,113)

按地区入组Patients(n)东亚 1,648China 541HongKong 90Japan 326SouthKorea 336Taiwan 355南亚 1,134India 578Malaysia 185Philippines 157Singapore 59Thailand 155全部

2,782HoriM,etal.Presentedatthe2ndAsiaPacificStrokeConferenceinTokyo,Japan.September2012.Latin

America5%NAmerica36%Other6%Asia15%Europe38%39Asia(n=880)Non-Asia(n=4,909)INR<22-3>3<22-3>3Mean35.454.510.119.866.214.0Median30.868.911.6INR2-3Asia Mean:54.5,Median:56.5Non-Asia Mean:66.2,Median:68.9治疗窗内时间INR=internationalnormalisedratio;TTR=timeintherapeuticrange;HoriM,etal.Presentedatthe2ndAsiaPacificStrokeConferenceinTokyo,Japan.September2012.亚洲患者的平均TTR比非亚洲患者要低与非亚洲患者相比，亚洲患者高于治疗窗范围的更少，低于治疗范围的更多40Dabigatran150mgbid(25/933)Dabigatran110mgbid(44/923)Warfarin(53/926)04.0HR0.45(95%

CI:0.28–0.72)04.0Dabigatran150mgbid(109/5,143)Dabigatran110mgbid(139/5,092)Warfarin(149/5,096)2.01.02.01.0%/year亚洲非亚洲1.393.06HR0.81(95%

CI:

0.54–1.21)HR0.72(95%

CI:0.56–0.92)HR0.93(95%

CI:

0.74–1.17)1.061.483.03.02.501.37主要终点

(卒中或全身栓塞)交互作用:达比加群150mgbidvs华法林p=0.0853,达比加群110mgbidvs华法林p=0.559755%4103.0HR0.55(95%

CI:0.32–0.95)03.01.01.0%/year亚洲非亚洲HR0.82(95%

CI:0.62–1.10)2.02.0Dabigatran150mgbid(20/933)Dabigatran110mgbid(36/923)Warfarin(35/926)Dabigatran150mgbid(83/5,143)Dabigatran110mgbid(116/5,092)Warfarin(99/5,096)2.051.122.021.140.810.98缺血性卒中HR1.01(95%

CI:

0.63–1.61)HR1.17(95%

CI:

0.89–1.53)45%01.0HR0.22(95%

CI:0.06–0.77)01.0%/year亚洲非亚洲0.170.75HR0.28(95%

CI:0.13–0.58)0.090.310.12Dabigatran150mgbid(3/933)Dabigatran110mgbid(2/923)Warfarin(13/926)Dabigatran150mgbid(9/5,143)Dabigatran110mgbid(12/5,092)Warfarin(32/5,096)出血性卒中HR0.15(95%

CI:

0.03–0.66)HR0.37(95%

CI:

0.19–0.72)AsiaPacificStrokeConference201278%85%卒中或全身栓塞

亚洲

非亚洲

缺血性卒中亚洲

非亚洲

出血性卒中亚洲

非亚洲心肌梗死亚洲

非亚洲全因死亡亚洲

非亚洲Dabigatran150mgbidvs.WarfarinDabigatran110mgbidvs.WarfarinRate(%/year)110mgbidWarfarinDabigatran1.02.00WarfarinbetterHR(95%CI)Dabigatranbetter1.391.061.120.810.170.090.500.864.013.573.061.482.020.980.750.320.580.655.093.96InteractionpvalueInteractionpvalue0.08530.19770.75900.37820.4244150mgbid2.501.372.020.510.885.013.530.55970.59590.27290.37610.59291.02.00DabigatranbetterWarfarinbetterHR(95%CI)有效性终点

(亚洲vs.非亚洲)Asia:n=2,782;Non-Asia:n=15,331HoriM,etal.Presentedatthe2ndAsiaPacificStrokeConferenceinTokyo,Japan.September2012.4404.0HR0.57(95%

CI:0.38–0.84)04.02.02.0%/yearAsiaNon-AsiaHR0.57(95%

CI:

0.38–0.85)HR1.00(95%

CI:0.87–1.16)HR0.85(95%

CI:

0.73–0.99)3.03.0Dabigatran150mgbid(39/933)Dabigatran110mgbid(39/923)Warfarin(66/926)Dabigatran150mgbid(360/5,143)Dabigatran110mgbid(303/5,092)Warfarin(355/5,096)22.993.523.531.01.0大出血Interaction:Dabigatran150mgbidvsWarfarinp=0.0079,Dabigatran110mgbidvsWarfarinp=0.070543%43%4502.0HR0.68(95%

CI:0.37–1.27)02.0%/yearAsiaNon-Asia0.961.41HR1.67(95%

CI:1.31–2.14)1.691.011.01.01.151.14Dabigatran150mgbid(17/933)Dabigatran110mgbid(20/923)Warfarin(24/926)Dabigatran150mgbid(170/5,143)Dabigatran110mgbid(114/5,092)Warfarin(101/5,096)消化道大出血HR0.82(95%

CI:

0.45–1.49)HR1.13(95%

CI:

0.86–1.47)02.0HR0.40(95%

CI:0.18–0.92)02.0%/yearAsiaNon-Asia0.451.10HR0.41(95%

CI:0.27–0.63)0.290.711.01.00.230.23Dabigatran150mgbid(8/933)Dabigatran110mgbid(4/923)Warfarin(19/926)Dabigatran150mgbid(30/5,143)Dabigatran110mgbid(23/5,092)Warfarin(71/5,096)颅内出血HR0.20(95%

CI:

0.07–0.60)HR0.32(95%

CI:

0.20–0.51)60%80%0HR0.60(95%

CI:0.51–0.70)0%/yearAsiaNon-AsiaHR0.98(95%

CI:0.91–1.04)2010201013.9922.0311.72Dabigatran150mgbid(251/933)Dabigatran110mgbid(206/923)Warfarin(381/926)Dabigatran150mgbid(1,743/5,143)Dabigatran110mgbid(1,549/5,092)Warfarin(1,785/5,096)17.0217.7415.27大出血

小出血3030HR0.85(95%

CI:

0.79–0.91)HR0.48(95%

CI:

0.40–0.56)AsiaPacificStrokeConference201252%40%大出血

亚洲

非亚洲胃肠道大出血亚洲

非亚洲威胁生命的出血亚洲

非亚洲颅内出血亚洲

非亚洲小出血亚洲

非亚洲大

小出血亚洲

非亚洲Dabigatran150mgbidvs.WarfarinDabigatran110mgbidvs.WarfarinRate(%/year)150mgbid110mgbidWarfarinDabigatran1.02.00WarfarinbetterDabigatranbetterHR(95%CI)InteractionpvalueInteractionpvalue2.173.52

0.961.691.281.520.450.2912.4315.2713.9917.023.823.53

1.411.012.201.791.100.7119.6615.8122.0317.742.222.99

11.290.230.2310.1213.6911.7215.270.0079

0.00890.17490.9509<0.0001<0.00010.0705

0.33790.07380.4561<0.0001<0.00011.02.00DabigatranbetterWarfarinbetterHR(95%CI)安全性终点(亚洲vs.非亚洲)Asia:n=2,782;Non-Asia:n=15,331HoriM,etal.Presentedatthe2ndAsiaPacificStrokeConferenceinTokyo,Japan.September2012.49RE-LY:亚洲亚组分析达比加群在卒中和全身栓塞预防的效果在亚洲和非亚洲病人间是一致的与华法林相比，达比加群减少大出血，这一点在亚洲人更明显这一分析提示在亚洲人群达比加群比华法林更能获益HoriM,etal.Presentedatthe2ndAsiaPacificStrokeConferenceinTokyo,Japan.September2012.Disclaimer:Dabigatranetexilateisnowapprovedforclinicaluseinstrokepreventioninatrialfibrillationincertaincountries.

Pleasechecklocalprescribinginformationforfurtherdetails50上市后结果(FDA,EMAandDenmarkRegistry)51达比加群上市后监测数据(EMA)Availableathttp://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2012/05/WC500127771.pdfFatalbleedingwithdabigatranfoundtobelessfrequentthanpreviouslyseeninclinicaltrialsTheCommittee’srecommendationtoupdatetheproductinformationfollowstheassessmentofallavailabledata,includingfrompost-marketingsurveillance,onPradaxaandtheriskofseriousorfatalbleedings.委员会发现上市后数据观察到的达比加群相关的致命出血显著少于在其获得上市许可的临床研究中的数值butconsideredthatthisissueshouldnonethelessbekeptunderclosesurveillance.Onthebasisoftheavailableevidence,theCHMP结论认为达比加群的获益仍优于风险，其仍是其他血液稀释剂重要的替代药物.However,theadvicetodoctorsandpatientsshouldbeupdatedandstrengthenedtogiveclearerguidanceonthebestuseofthemedicine.ThisincludesmorespecificguidanceonwhenPradaxamustnotbeusedaswellasadviceonmanagingpatientsandreversingtheanticoagulanteffectofPradaxaifbleedingoccurs.在这一个“日常实践的”获批后的临床队列中，在卒中和全身栓塞的预防方面华法来呢和达比加群的效果类似（两个剂量），但是两个剂量的死亡率，肺栓塞，心肌梗死都更低。1.JACCVol.61,No.22,2013;53FDA安全报告2014-05:

MedicareanalysisIncidencerateper1000person-yearsAdjustedHR(95%CI)DabigatranWarfarin缺血性卒中11.313.90.80(0.67-0.96)颅内出血4(0.26-0.46)急性心梗15.716.90.92(0.78-1.08)死亡32.637.80.86(0.77-0.96)胃肠大出血8(1.14-1.44)与华法林相比，达比加群降低了缺血性卒中，颅内出血和死亡.

心梗的风险在两组相似.超过134,000医保病人的观察性队列研究，所有病人都是

年龄≥65岁

54Primaryfindingsfordabigatranarebasedonanalysisofboth75mgand150mgtogetherwithoutstratificationbydose.Warfarinisthereferencegroup.CI=confidenceinterval;HR=hazardratio;MI=myocardialinfarction;Availableat:/Drugs/DrugSafety/ucm396470.htm(accessedMay2014)临床实践55其他药物改换为达比加群INR=internationalnormalizedratioHuismanMetal.ThrombHaemostdoi:10.1160/TH11-10-0718华法林到达比加群

非口服转换为达比加群在预期的下一剂药物之前的2小时开始达比加群酯在停用注射的同时开始应用达比加群酯持续注射转换为达比加群56如何处理消化不良57HuismanMetal.ThrombHaemostdoi:10.1160/TH11-10-0718如何处理症状大部分在开始治疗的早期出现;多为一过性的和可控制的.推荐药物与一大杯水或者食物同时服.可以考虑H2阻滞剂,PPIs,抗酸药.在RELY中，与华法林相比大约超过5%的患者出现消化不良（这些包括腹痛，腹部不适，消化不良等）.58多数患者在采用不同缓解措施后报告症状有改善症状改善的患者比例(%)大多数RELY-ABLE病人报告在采取抑制胃酸治疗后症状改善或缓解，这些措施包括服药时与食物一起服，质子泵抑制剂，抗酸药或或H2受体拮抗剂.

2013ESCposter,ManagementofDyspepsiaSymptomsonDabigatranDuringRELY-ABLE:Long-termFollow-upStudyAfterRE-LY.腎功能不足病患可能需要較長時間清除dabigatran。使用Pradaxa的病人需進行緊急手術時該如何處置?Pradaxa®:EUSmPC,2012腎功能(CrClml/min)半衰期(小時)於進行非急需之手術前停用dabigatan高出血風險或重大手術標準風險≥80~132天前1天前79-50

~153天前2天前49-30~184天前3天前60药物相互作用Pradaxa®:EUSmPC,2012避免併用P-醣蛋白(P-gp)誘發劑(如rifampin)KetoconazoleDronedarone可併用(謹慎評估病人出血風險)QuinidineAmiodarone建議併用110mgVerapamil62出血风险检测解读:aPTT活化部分凝血活酶时间(aPTT)在测定抗凝过度方面有一定作用1,2临床相关检测：

在谷浓度时aPTT>80秒(预期的下次服药时间)提示出血风险增高1,3INR=internationalnormalizedratio1.vanRynJetal.ThrombHaemost2010;103:1116–1127;2.LiesenfeldK-Hetal.BrJClinPharmacol2006;62:527–537;3.HuismanMetal.ThrombHaemostdoi:10.1160/TH11-10-071863出血应对*Recommendationbasedonlyonlimitednon-clinicaldata;thereisnoexperienceinvolunteersorpatients

PCC=prothrombincomplexconcentrates(non-activatedoractivated);rFVIIa=recombinantactivatedFactorVIIvanRynJetal.ThrombHaemost2010;103:1116–27服用达比加群的病人出血轻度出血中到重度出血威胁生命的出血合适时延迟或停用下次的剂量对症治疗机械压迫外科干预液体替代和血流动力学支持输注血液制品口服活性炭*

(如果在服用达比加群的两小时以内)血液透析考虑rFVllaorPCC*活性碳过滤*PatientspotentiallyathigherriskofbleedingPeri-procedural&post-proceduralManagementAntidotepending,LaboratoryMonitoringAcuteischemicstrokeperiod(thrombolysis-thrombectomy)Combinationwithantiplateletdrugs65Stillchallenging

DiseaseorDrugnaturerelatedConvertingto/fromNOACBleedingcomplicationsormajorbleedsPatientCompliance,tolerabilityandadherenceMisseddose,Overdose,66Stillchallenging

PhysicianorPatientbehaviorrelated74-year-oldhousewife

hadchronicatrialfibrilationwithwarfarintreatment92/03/03病史(PresentIllness)leftupperarmswellingandechymosisfor2days.oldCVAoccurredinAUG2001.ShetookChinesemedicationwith銀杏sincetheCVAOnroutineOPDfollowINR6.75Admittedundertheimpressionofwarfarinoverdose.ThevitaminK110mgIMwasgivenandthewarfarinwasadjustedto2.5mgPOqod.住院診斷(AdmissionDiagnosis)1.Warfarinoverdose2.Hypertension3.Chronicatrialfibrilation4.OldCVAwithrightsideweakness96/06/2392/03/28MeanTTR<30%96/05/0492/01/3060-year-oldmale

s/pemergentthrombectomyofrtfemoralart,(88-10-21),DM,chronicAF,2-VCADs/pPTCA.BP127/68mmHg,HRbpm,LVheave(+),LAAthrombus96/04/1696/04/17:Dropattackon96/03/29OfficeBP119/68mmHg,P:70,96/05/04MeanTTR=30%99/01/15:Acuteappendicitiss/p99/01/15:ECG-AfwithVR73;CXR-borderlineheartsize;rece