肺血栓栓塞症的抗凝治疗策略

肺血栓栓塞症的抗凝治疗策略StrategyofanticoagulanttherapyforPulmonarythromboembolism北京医院呼吸与危重症医学科PulmonaryandCriticalCareMedicineDivision,BeijingHospital方保民FangBaomin03/06/2012 内容 财务内部控制制度的内容财务内部控制制度的内容人员招聘与配置的内容项目成本控制的内容消防安全演练内容 肺栓塞流行病学（发病率）肺栓塞分类：传统分类现在分类治疗：分类治疗：抗凝治疗：溶栓后治疗起始抗凝治疗when?长期抗凝治疗howlong?抗凝监测howmonitor?抗凝时间howlong?抗凝药物（新型）what?newdrugs?副作用sideeffect？特殊情况下的处理specialmanagement?家庭管理：familymanagement?停药指证indicationofstopusedrug?ConceptEpidemiologyofPTEPulmonaryembolism(PE)isacommonproblem,thoughitsexactincidenceisdifficulttoassessduetoitsnon-specificclinicalpresentationandfrequentlysuboptimaldiagnosticmanagementaffectingthequalityofreporting.Datacollected3decadesagointheUSAsuggestedaprevalenceofPEof0.4%amonghospitalisedpatients,whiletheoverallannualincidencewasestimatedat600 000cases.ClinicalandpostmortemdatacollectedintheMalmoarea,aregionofSwedenwithaparticularlyhighautopsyrate,suggestedanincidenceofPEofapproximately20/10 000inhabitants/year.1OldandnewclinicalclassificationofPEOldATS1999,ESC2000,BTS2003,ACEP2003,ACCP2004,ACCP2008MASSIVE(cardiacarrest,shock,hypotension)SUB-MASSIVE(normotensivePEwithRHD)NONMASSIVE(normotensivePEwithoutRHD)NewESC2008HIGHRISK(cardiacarrest,shock,hypotension)NONHIGHRISKINTERMEDIATERISK(normotensivePEwithRHDand/orhighBNPand/orhightroponins)LOWRISK(normotensivePEwithoutRHDandlowBNPandlowtroponins)MortalityandClassificationIndicationofAnticoagulationMechanismofAnticoagulantinIntrinsicandExtrinsicPathwayRivaroxabanDabigatranAnticoagulationdrugsAnticoagulatewithLMWH,IV/Sub-QUFH,orfondaparinux(IA)Enoxaparin(依诺肝素)Dalteparin(达肝素钠)Tinzaparin(亭扎肝素)VitaminKantagonists(VKAs):WarfarinDirectThrombinInhibitors:DabigatranEtexilateDirectFactorXaInhibitors:RivaroxabanwarfarinDirectThrombinInhibitors:DabigatranEtexilateDabigatranisaselective,reversible,directthrombininhibitorgivenasdabigatranetexilate,anorallyabsorbableprodrug,sincedabigatranitselfisastronglypolarmoleculethatisnotabsorbedfromthegut.Phase3clinicalstudiesreportedtodatehaveevaluatedtheuseofdabigatranetexilateforthepreventionofVTEafterelectivetotalkneeorhiparthroplasty,fortherapyofVTE,andtopreventstrokeorsystemicemboisminnonvalvularAF.ThedrugisapprovedinmanycountriesforthepreventionofVTEinpatientsundergoingtotalhiporkneereplacementsurgeryandintheUnitedStatesandCanadaforthepreventionofstrokeorsystemicembolisminnonvalvularAFDirectFactorXaInhibitors:RivaroxabanRivaroxabanisadirectfactorXainhibitorandiscurrentlyapprovedinmanycountries,includingtheUnitedStates,forthepreventionofVTEinpatientsundergoingtotalhiporkneereplacementsurgery.Thedrugisundergoinganextensiveclinicaldevelopmentprograminotherclinicalsettings,IncludingthetreatmentofVTEandthepreventionofacuteischemicstrokeinpatientswithAF.AnticoagulationisthemainstayoftreatmentforPE.BecauseoftherisksofhypoxemiaandhemodynamicinstabilityassociatedwithPE,closemonitoringandsupportivetherapyarenecessary.Therefore,outpatienttreatmentofPEisnotadvised.UnfractionatedheparinmostcommonlyisusedtotreatpatientswithPE,althoughLMWheparinalsoissafeandeffective.OnlyenoxaparinandtinzaparinhavereceivedformalFDAapprovalforuseinthetreatmentofPE.ThrombolysisThrombolysisclearlyisindicatedinpatientswithmassivePEandassociatedhemodynamicinstability.However,theroleofthrombolysisinpatientswithsubmassivePEremainscontroversial.Inthelargeststudytodate,19improvedsurvivalwasobservedinpatientstreatedwithalteplaseplusheparincomparedwithheparinalone.Usingdeathandmajorcomplicationsastheendpoint,thenumberneededtotreatwas7.3.Onefewerdeathwasobservedforevery82patientstreatedwiththecombinationtherapy.10InpatientswithPE,theusualdoseofalteplase(Activase)is50mggivenbyintravenousinfusionoveraperiodoftwohours.Streptokinase(Streptase)isgivenina250,000-IUloadingdose,followedby100,000IUperhourfor24hours.Deliveryofthrombolyticsdirectlyintothethrombusbycatheterhasbeendescribedbuthasnotbeenshowntobesuperiortoperipheralinfusion.ThevitaminKantagonists(VKAs):warfarinAnticoagulationwithwarfarinshouldfollowheparintherapy.ThesameregimensareusedforDVTandPEWeight-BasedHeparinTherapywithAdjustmentsBasedontheAPTTInitialdosageBolusof80unitsperkg,then18unitsperkgperhourbyinfusionAPTT<35seconds(<1.2timescontrol)Bolusof80unitsperkg,then4unitsperkgperhourbyinfusionAPTT=35to45seconds(1.2to1.5timescontrol)Bolusof40unitsperkg,then2unitsperkgperhourbyinfusionAPTT=46to70seconds(1.5to2.3timescontrol)NochangeAPTT=71to90seconds(2.3to3.0timescontrol)Decreaseinfusionrateby2unitsperkgperhour.APTT>90seconds(>3.0timescontrol)Holdinfusionfor1hour,thendecreaseinfusionrateby3unitsperkgperhour.InitiationofWarfarinTherapyat5mgperDayDayINRWarfarindosage(mgperday)15253<1.5101.5to1.952.0to2.92.5>3.004<1.5101.5to1.97.52.0to2.95>3.005<2.0102.0to2.95>3.006<1.5101.5to1.97.52.0to2.95>3.00InitiationofWarfarinTherapyat10mgperDay*Warfarindosage(mgperday)Warfarindosage(mgperday)Day3INRDay3Day4Day5INRDay5Day6Day7<1.31515<2.01515151.3to1.410102.0to3.07.557.53.1to3.505>3.5002.51.5to1.6105<2.07.57.57.51.7to1.9552.0to3.05553.1to3.52.52.52.5>3.502.52.52.0to2.22.52.5<2.05552.3to3.002.52.0to3.02.552.53.1to3.502.50>3.5002.5>3.000<2.02.52.52.52.0to3.02..502.53.1to4.0002.52.50>4.000002.5SPECIALSITUATIONSWarfarintherapyiscontraindicatedduringpregnancy.Therefore,long-termtreatmentwithLMWheparinisusedwhenPEoccursinapregnantwoman.AntithromboticTherapyandPreventionofThrombosis,9thed:AmericanCollegeofChestPhysiciansEvidence-BasedClinicalPracticeGuidelines,2012AcutePE,Recommendinitialtreatmentwithparenteralanticoagulation(LMWH,fondaparinux,IVUFH,orSCUFH)overnosuchinitialtreatment(Grade1B).1HighclinicalsuspicionofacutePE,Suggesttreatmentwithparenteralanticoagulantscomparedwithnotreatmentwhileawaitingtheresultsofdiagnostictests(Grade2C).2.IntermediateclinicalsuspicionofacutePE,Suggesttreatmentwithparenteralanticoagulantscomparedwithnotreatmentiftheresultsofdiagnostictestsareexpectedtobedelayedformorethan4h(Grade2C).3.LowclinicalsuspicionofacutePE,Suggestnottreatingwithparenteralanticoagulantswhileawaitingtheresultsofdiagnostictests,providedtestresultsareexpectedwithin24h(Grade2C).5.3.AcutePE,RecommendearlyinitiationofVKA(eg,samedayasparenteraltherapyisstarted)overdelayedinitiation,andcontinuationofparenteralanticoagulationforaminimumof5daysanduntiltheINRis2.0oraboveforatleast24h(Grade1B).AntithromboticTherapyandPreventionofThrombosis,9thed:AmericanCollegeofChestPhysiciansEvidence-BasedClinicalPracticeGuidelines,20125.4.1.AcutePE,SuggestLMWHorfondaparinuxoverIVUFH(Grade2CforLMWH;Grade2Bforfondaparinux)andoverSCUFH(Grade2BforLMWH;Grade2Cforfondaparinux).Remarks:Localconsiderationssuchascost,availability,andfamiliarityofusedictatethechoicebetweenfondaparinuxandLMWH.LMWHandfondaparinuxareretainedinpatientswithrenalimpairment,whereasthisisnotaconcernwithUFH.InpatientswithPEwherethereisconcernabouttheadequacyofSCabsorptionorinpatientsinwhomthrombolytictherapyisbeingconsideredorplanned,initialtreatmentwithIVUFHispreferredtouseofSCtherapies.5.4.2.AcutePEtreatedwithLMWH,Suggestonce-overtwice-dailyadministration(Grade2C).AntithromboticTherapyandPreventionofThrombosis,9thed:AmericanCollegeofChestPhysiciansEvidence-BasedClinicalPracticeGuidelines,20125.5.low-riskPEandwhosehomecircumstancesareadequate,Suggestearlydischargeoverstandarddischarge(afterfirst5daysoftreatment)(Grade2B).5.6.1.1AcutePEassociatedwithhypotension(eg,systolicBP<90mmHg)whodonothaveahighbleedingrisk,wesuggestsystemicallyadministeredthrombolytictherapyovernosuchtherapy(Grade2C).5.6.1.2.AcutePEnotassociatedwithhypotension,Recommendagainstsystemicallyadministeredthrombolytictherapy(Grade1C).5.6.1.3.AcutePEnotassociatedwithhypotensionandwithalowbleedingriskwhoseinitialclinicalpresentation,orclinicalcourseafterstartinganticoagulanttherapy,suggestsahighriskofdevelopinghypotension,Suggestadministrationofthrombolytictherapy(Grade2C)5.6.2.1.AcutePE,whenathrombolyticagentisused,Suggestshortinfusiontimes(a2-hinfusion)overprolongedinfusiontimes(a24-hinfusion)(Grade2C).5.6.2.2.AcutePEwhenathrombolyticagentisused,Suggestadministrationthroughaperipheralveinoverapulmonaryarterycatheter(Grade2C).AntithromboticTherapyandPreventionofThrombosis,9thed:AmericanCollegeofChestPhysiciansEvidence-BasedClinicalPracticeGuidelines,20125.7.AcutePEassociatedwithhypotensionandwhohave(i)contraindicationstothrombolysis,(ii)failedthrombolysis,or(iii)shockthatislikelytocausedeathbeforesystemicthrombolysiscantakeeffect(eg,withinhours),ifappropriateexpertiseandresourcesareavailable,Suggestcatheter-assistedthrombusremovalovernosuchintervention(Grade2C).5.8.AcutePEassociatedwithhypotension,Suggestsurgicalpulmonaryembolectomyovernosuchinterventioniftheyhave(i)contraindicationstothrombolysis,(ii)failedthrombolysisorcatheter-assistedembolectomy,or(iii)shockthatislikelytocausedeathbeforethrombolysiscantakeeffect(eg,withinhours),providedsurgicalexpertiseandresourcesareavailable(Grade2C).5.9.1.AcutePEwhoaretreatedwithanticoagulants,RecommendagainsttheuseofanIVCfilter(Grade1B).5.9.2.AcutePEandcontraindicationtoanticoagulation,RecommendtheuseofanIVCfilter(Grade1B).5.9.3.AcutePEandanIVCfilterinsertedasanalternativetoanticoagulation,Suggestaconventionalcourseofanticoagulanttherapyiftheirriskofbleedingresolves(Grade2B).AntithromboticTherapyandPreventionofThrombosis,9thed:AmericanCollegeofChestPhysiciansEvidence-BasedClinicalPracticeGuidelines,20126.1.InpatientswithPEprovokedbysurgery,werecommendtreatmentwithanticoagulationfor3monthsover(i)treatmentofashorterperiod(Grade1B),(ii)treatmentofalongertime-limitedperiod(eg,6or12months)(Grade1B),or(iii)extendedtherapy(Grade1Bregardlessofbleedingrisk).6.2.InpatientswithPEprovokedbyanonsurgicaltransientriskfactor,werecommendtreatmentwithanticoagulationfor3monthsover(i)treatmentofashorterperiod(Grade1B),(ii)treatmentofalongertime-limitedperiod(eg,6or12months)(Grade1B),and(iii)extendedtherapyifthereisahighbleedingrisk(Grade1B).Wesuggesttreatmentwithanticoagulationfor3monthsoverextendedtherapyifthereisalowormoderatebleedingrisk(Grade2B).6.3.InpatientswithanunprovokedPE,werecommendtreatmentwithanticoagulationforatleast3monthsovertreatmentofashorterduration(Grade1B).After3monthsoftreatment,patientswithunprovokedPEshouldbeevaluatedfortherisk-benefitratioofextendedtherapy.6.3.1.InpatientswithafirstVTEthatisanunprovokedPEandwhohavealowormoderatebleedingrisk,wesuggestextendedanticoagulanttherapyover3monthsoftherapy(Grade2B).AntithromboticTherapyandPreventionofThrombosis,9thed:AmericanCollegeofChestPhysiciansEvidence-BasedClinicalPracticeGuidelines,20126.3.2.FirstVTEthatisanunprovokedPEandwhohaveahighbleedingrisk,Recommend3monthsofanticoagulanttherapyoverextendedtherapy(Grade1B).6.3.3.SecondunprovokedVTE,Recommendextendedanticoagulanttherapyover3monthsoftherapyinthosewhohavealowbleedingrisk(Grade1B),suggestextendedanticoagulanttherapyinthosewithamoderatebleedingrisk.6.3.4SecondunprovokedVTEhaveahighbleedingrisk,wesuggest3monthsoftherapyoverextendedtherapy(Grade2B).6.4.InpatientswithPEandactivecancer,ifalowormoderatebleedingrisk,Recommendextendedanticoagulanttherapyover3monthsoftherapy(Grade1B),andifahighbleedingrisk,Suggestextendedanticoagulanttherapy(Grade2B).6.5.PEtreatedwithVKA,RecommendatherapeuticINRrangeof2.0to3.0(targetINRof2.5)overalower(INR<2)orhigher(INR3.0-5.0)rangeforalltreatmentdurations(Grade1B).6.6.PEandnocancer,SuggestVKAtherapyoverLMWHforlong-termtherapy(Grade2C).ForPEandnocancerwhoarenottreatedwithVKAtherapy,SuggestLMWHoverdabigatranorrivaroxabanforlong-termtherapy(Grade2C).AntithromboticTherapyandPreventionofThrombosis,9thed:AmericanCollegeofChestPhysiciansEvidence-BasedClinicalPracticeGuidelines,20126.7.PEandcancer,SuggestLMWHoverVKAtherapy(Grade2B).PEandcancerwhoarenottreatedwithLMWH,SuggestVKAoverdabigatranorrivaroxabanforlong-termtherapy(Grade2C).6.8.PEwhoreceiveextendedtherapy,Suggesttreatmentwiththesameanticoagulantchosenforthefirst3months(Grade2C).6.9.InpatientswhoareincidentallyfoundtohaveasymptomaticPE,Ruggestthesameinitialandlong-termanticoagulationasforcomparablepatientswithsymptomaticPE(Grade2B).7.1.1.Inpatientswithchronicthromboembolicpulmonaryhypertension(CTPH),Recommendextendedanticoagulationoverstoppingtherapy(Grade1B).7.1.2.InselectedpatientswithCTPH,suchasthosewithcentraldiseaseunderthecareofanexperiencedthromboendarterectomyteam,Suggestpulmonarythromboendarterectomyovernopulmonarythromboendarterectomy(Grade2C).