老年冠心病治疗策略的演变精品PPT课件.ppt

老年冠心病治疗策略的演变TheStrategicChangesofElderlyCoronaryHeartDiseaseTreatment,2,老年冠心病临床特点ClinicalFeaturesofElderlyCHD,严重心绞痛多/多支血管病变多/复杂病变多/弥漫和钙化病变多/陈旧心梗多/左室功能受累多/并存病多/无症状多/合并糖尿病多/严重心律失常多/病死率高(高龄者三支病变60%-TIME/APPROACH试验)(75岁CHD发病率:男18.6%,女6.1%)(PCI,出血并发症16.6%)治疗目的:缓解症状/改善功能/提高生活质量,3,冠心病治疗观念的改变NovelChangesinConceptofElderlyCHDTreatment,Luminalstenosistovulnerableplaqueformation从重视管腔狭窄到易损斑块Lipiddeposittoinflammatoryresponse从注意脂质沉积到炎症反应Vulnerableplaquetovulnerablepatient从重视易损斑块到易损病人Epicardialvesselopentomyocardialperfusion从注意心外膜冠脉开通到心肌组织水平灌注Outshineotherstotrio从一枝独秀到三驾马车SingleRFcontroltomulti-RFintervention从单一危险因素控制到多个危险因素联合干预Standardizedtreatmenttoindividualizedtherapy从注重规范化治疗到个体化治疗,4,LuminalStenosis管腔狭窄,VulnerablePlaque易损斑块,冠心病治疗观念改变之一FirstChangeinConceptofCHDTreatment,5,DegreeofCoronaryStenosis冠脉狭窄程度,RiskofCHD冠心病严重度,动脉粥样硬化的传统观念TraditionalConceptofAtherosclerosis,?,6,急性心梗前的冠脉狭窄程度CoronaryArteryStenosispre-AMI,70%,%ofDiameterStenosis,%ofthePatients,BargraphshowsseverityofcoronaryarterystenosisbeforeAMI(n=195,4studies)68%patientshadstenosislessthan50%atbaseline86%patientshadstenosislessthan70%atbaselineFalketal.Circulation.1995;92:657.,7,降脂疗法降低心脏事件但并不改变管腔狭窄Lipid-loweringTherapiesDecreaseCardiacEventsbutNotStenosis,LevineGN,KeaneyJFJr,VitaJA.Cholesterolreductionincardiovasculardisease:clinicalbenefitsandpossiblemechanisms.NEnglJMed.1995;332:512-521.PhilbinEF,PearsonTA.Howdoeslipid-loweringtherapyrapidlyreduceischemicevents?JMyocardIschemia.1994;6:13-18.PittB,ManciniGBJ,EllisSG,RosmanHS,ParkJ-S,McGovernME,forthePLACIinvestigators.Pravastatinlimitationofatherosclerosisinthecoronaryarteries(PLACI):reductioninatherosclerosisprogressionandclinicalevents.JAmCollCardiol.1995;26:1133-1139,8,CoronaryArteryStenosisAndCardiacEvents冠脉狭窄与心脏事件,Plaquevolumeorseverityofcoronaryarterystenosismaynotbethekeyfactorforinducingcardiacevents.提示:冠脉狭窄并非心血管事件关键原因,9,ConceptofVulnerablePlaque易损斑块概念的提出,In1989,Mullerandcolleaguesfirstused“vulnerableplaques”todescriberupture-proneplaquesastheunderlyingcauseofmostclinicalcoronaryevents.首倡易损斑块破裂观念Avulnerableplaqueoftenhasalargelipidpool,athincap,andmacrophage-denseinflammationonorbeneathitssurface.特征Vulnerableplaqueruptureordisruptioncausesbleedingintotheplaque,luminalthrombosis,and/orvasospasmthatmaycausesuddenflowobstructionandischemicinjury.破裂致血栓形成,MullerJ,ToflerG,StoneP.Circadianvariationandtriggersofonsetofacutecardiovasculardisease.Circulation.1989;79:733743.,11,多方位策略演变Manysidedstrategicchanges,诊断进步：由以CAG为主导，到重视斑块检测技术的发展如IVUS、OCT；基础研究方向：逐渐以稳定易损斑块以及减少斑块破裂后血栓形成为方向；二级预防重点：也将由治疗冠脉狭窄转为易损斑块的干预。,12,CHDdevelopsin2030years冠心病慢性病程Plaqueruptureoccursin23hrs斑块破裂快过程,Dyslipidemia,Atherosclerosis,Plaqueformation,CHD,ACS,Heartfailure,LVdysfunction,心脏事件的发生ProgressionofCardiacEvents,AMI,LVreconstruction,13,冠脉介入治疗的短处LimitationsofPCI,AlthoughPCIcouldrelieveseverestenosisofcoronaryartery,itwouldntchangethebiologiccourseofAS,thustheproblemof“unstable”isstillunresolved.尚未能解决斑块不稳定问题,14,COURAGE临床试验,BodenWE,etal.OptimalMedicalTherapywithorwithoutPCIforStablecoronaryDisease(NEJM.356:1503-1516;April12,2007),15,COURAGE研究设计StudydesignofCOURAGEtrial,加PCI组,不加PCI组,死亡率/MACE/ACS,2287例稳定型心绞痛患者(他汀类,抗血小板,ACEI/ARB,-受体阻滞剂),随机化,随访2.5-7Y,16,两组主要终点比较Thecomparisonofendpointswithtwogroups,平均随访4.6年所有原因死亡或非致死性心肌梗死数单纯优化药物治疗组:18.5%优化药物治疗+PCI组:19.0%P=0.62,17,随访心绞痛缓解率FreedomfromAnginaDuringLong-TermFollow-up,ThecomparisonbetweenthePCIgroupandthemedical-therapygroupwassignificantat1year(P0.001)and3years(P=0.02)butnotatbaselineor5years.,18,震撼全球心血管病学界Grobalimpactoncardiologicalfield,慢性稳定性冠心病/临界狭窄病变者:现代药物治疗效果理想/病人依从性好COURAGEtrial:医生应该有信心面对这些病人保护病人效果和利益的最大化在病人身上做有证据的治疗中西医结合应受理解和提倡,19,两组总生存率OverallSurvival,NumberatRisk,MedicalTherapy11381073102991771746830238PCI11491094105192973348831244,Years,0,1,2,3,4,5,6,0.0,0.5,0.6,0.7,0.8,0.9,1.0,PCI+OMT,OMT,7,Hazardratio:0.8795%CI(0.65-1.16)P=0.38,20,稳定易损斑块的重要作用StabilizationofVulnerablePlaques,Thevascularpathophysiologicalresearchhasfocusedonstabilizingthevulnerableplaqueandinhibitingthrombosisafterplaquerupture.ThesecondarypreventionofCHDalsofocusedoninterventionofthevulnerableplaqueinadditiontotreatingluminalstenosisofcoronaryartery.防治重点应是易损斑块+狭窄问题,KulloIJ,EdwardsWD,SchwartzRS.Vulnerableplaque:pathobiologyandclinicalimplications.AnnInternMed1998;129(12):1050-60.OzerK,CilingirogluM.Vulnerableplaque:definition,detection,treatment,andfutureimplications.CurrAtherosclerRep.2005;7(2):121-6,21,LipidDeposit脂质沉积,InflammatoryReaction炎症反应,冠心病治疗观念改变之二SecondChangeinConceptofCHDTreatment,22,逾百年之脂质沉积学说LipidDepositionTheory,“Lipiddepositiontheory”ofatherosclerosishasbeenputforwardfor150yearsbasedonthecausalrelationshipbetweenhyperlipidemiaandAS.高脂血症与动脉粥样硬化关系ThistheoryholdsthatlipiddepositiononthearterywallleadstotheASplaques,andithasbeendominatedthepathogenesisofASforalongtime.,SteinbergD,JosephL，WitztumJL.Lipoproteinsandatherogenesis:Currentconcepts.JAMA1990;264(23):3047-3052.,23,InflammatorytheoryofASwasfirstpresentedbyVirchowin1856.炎症理论的提出“Endarteritisdeformans”oratheroma-aproductofaninflammatoryprocesswithintheintimawiththefibrousthickeningevolvedasaconsequenceofareactivefibrosisinducedbyproliferatingconnectivetissuecellswithintheintima.Thetheorydidnotraisegreatattentionatthattime.当年未获关注,动脉粥样硬化炎症学说InflammationTheory,24,Inrecentyears,ASwasshowntohavethebasicmanifestationofinflammation炎症反应的基本表现DegenerationExudationProliferationThecell-cellinteractionissimilartootherchronicinflammationdiseasessuchasrheumatoidarthritis,chronicpancreatitisandhepaticcirrhosis.ASwasnolongerregardedasasimplediseaseoflipiddepositioninthevesselwall,butalsoanadvancedinflammatoryreaction.InASplaqueofhuman,therewasalsoevidenceofseveralpathogens病原ChlamydiapneumoniaeCytomegalovirusHerpesvirusHelicobacterpylori,动脉粥样硬化炎症学说InflammationTheory,25,动脉粥样硬化炎症学说InflammationTheory,In1999,acenturylater,RossdeclaredthatASisoneofchronicinflammatorydisease,basedonhisinjuryreactiontheory.损伤反应理论的提出(Ross,1999),26,动脉粥样硬化的新概念TheNewConceptofAS,Traditional-“Rustinapipe”(管腔生锈)Passivelipiddepositionontovesselwall,Current-“Afirewithin”(管壁着火)Activeinflammatoryreactioninsidevesselwall,27,InflammatoryBiomarkersAS炎症生物学标志物InflammatoryBiomarkers,白介素-6反应蛋白单核细胞趋化因子-1血清淀粉样蛋白肿瘤坏死因子白介素-18白介素-10,细胞间黏附分子血管细胞黏附分子E-选择素血管性假血友病因子,髓过氧化物酶磷脂酶血浆脂蛋白相关性磷脂酶,血管内皮生长因子胎盘生长因子肝细胞生长因子,基质金属蛋白酶1，2，9妊娠相关血浆蛋白-A,CD40配体P-选择素,28,AS炎症生物学标志物Hs-CRPC-ReactiveProteininCVD,Elevatedhs-CRPlevelsinhealthypopulationspredictvasculareventssuchasMIandstrokeaswellasthedevelopmentofdiabetes.Hs-CRPisausefulbiomarkerinriskpredictionandtreatmentoutcomeassessment.Hs-CRPwasalsoimplicateddirectlyinatherogenesis.CRPhasbeenfoundinhumanatheroscleroticplaqueandshowntocauseendothelialcelldysfunction,oxidantstressandintimalhypertrophyinexperimentalmodels.ItcouldalsobeapotentialtargetofAStreatmentandprevention.高敏C反应蛋白增高,WilsonAM,RyanMC,BoyleAJ.ThenovelroleofC-reactiveproteinincardiovasculardisease:riskmarkerorpathogen.IntJCardiol.2006;106(3):291-7.,29,基于几种生化标记物的心血管事件相对风险,0,1.0,2.0,4.0,6.0,Lipoprotein(a),LDLC,Homocysteine,TC,ApolipoproteinB,TC:HDLC,hs-CRP,hs-CRP+TC:HDLC,RelativeRiskofFutureCVEvents,CV,cardiovascular;TC,totalcholesterol;LDLC,low-densitylipoproteincholesterol;HDL-C,high-densitylipo-proteincholesterol;CRP,C-reativeprotein;hs-CRP,high-sensitivityC-reactiveprotein;TC,totalcholesterol.AdaptedfromRifaiN,etal.ClinChem.2001;47:28-30.,30,hs-CRP(mg/L),他汀治疗6周对hs-CRP水平的影响TheinfluenceofStatinsonhs-CRPlevel,JialalIetal.Circulation2001;103:1933-1935.,6543210,Baseline,Prava(40mg/d),Simva(20mg/d),Atorva(10mg/d),*p0.025vs.Baseline,31,ENHANCE试验的启示EnlightenmentfromENHANCEtrial,Kastelein,JJ.NEJM.April3,2008;P.1431-1443,32,冠心病治疗策略的更新TherapeuticStrategiesforCHD,EvidencebasedapproachDespiteregulatingbloodlipidmetabolism,statinsshouldberecommendedinitsanti-inflammationandotherprotectiveeffectsoncardiovasculardiseases.推荐他汀药物的应用Anti-inflammation-severalstrategiesthatinterferewithinflammationareinprogress.一些干予炎症治疗策略在发展中,OzerK,CilingirogluM.Vulnerableplaque:definition,detection,treatment,andfutureimplications.CurrAtherosclerRep.2005;7(2):121-6.,33,VulnerablePlaque易损斑块,VulnerablePatient易损病人,冠心病治疗观念改变之三ThirdChangeinConceptofCHDTreatment,34,易损病人概念的提出DefinitionofVulnerablePatient,Vulnerableplaquesarenottheonlyculpritfactors.Vulnerablebloodandvulnerablemyocardiumplayanimportantroleinforthedevelopmentofacutecoronarysyndromes,myocardialinfarction,andsuddencardiacdeath.“Vulnerablepatientisproposedtodefinesubjectssusceptibletoanacutecoronarysyndromeorsuddencardiacdeathbasedonplaque,blood,ormyocardialvulnerability.NaghaviM.etal.Circulation2003;108(14):1664-72.,易损病人=易损斑块+易损血液+易损心肌,35,Aquantitativemethodforcumulativeriskassessmentofvulnerablepatientsneedstobedevelopedthatmayincludevariableslistedbelow.Vulnerableplaques易损斑块pronetorupture易于破裂withhighlikelihoodofthromboticcomplicationsandrapidprogressionPlaqueruptureaccountsfornearly70%offatalAMIand/orsuddencoronarydeathsVulnerableplaqueisthemain,butnottheuniquecauseforacutecardiovasculareventsVulnerableblood易损血液pronetothrombosis易于血栓形成Vulnerablemyocardium易损心肌pronetofatalarrhythmia易发生致命性心律失常,易损病人VulnerablePatient,36,治疗上的创新性发展DevelopmentofInnovativeTherapies,脂质沉积Lipiddeposit,调节血脂RegulatingBloodLipid,药物:扩冠Drugs：Nitrates,CaA手术Surgery：PCI、CABG,稳定斑块StabilizingPlaque,抗炎anti-inflammatory，抗栓(抗血小板、抗凝)Anti-thrombosis(anti-platelet,anticoagulation),早期识别；重预防EarlyIdentificationandPrevention,冠脉狭窄CoronaryStenosis,易损斑块、破裂、血栓形成VulnerablePlaque,Rupture,Thrombosis,易损患者VulnerablePatients,37,血脂康现代中药XuezhikangModernChineseHerbalMedicine,Material:specialproducedredyeastrice原料：特制红曲Method:redyeastrice(OrizaSativeL.)isgrownonnutrientagarandspecialredyeastadded,thenfermentedusingmodernbiologicaltechnologytomaketheeffectivecompound.方法：粳米加入培养液，接入特殊的红曲霉菌种，运用现代生物技术发酵而成。,38,CAREvs.CCSPS,39,CCSPS亚组分析血脂康广泛适用于特殊人群的调脂治疗,合理积极谨慎老年人群高血压人群糖尿病人群,40,日本MEGASTUDY结果表明:东方人群温和调脂即可明显获益,与CCSPS结果一致MEGAStudysresult:similartoCCSPS,对日本人的一级预防:服用10-20mg的pravastatin可使冠心病危险33%;与美欧用20-40mg效益相当对轻中度Tc增高的东方人群低剂量是安全有效的,AtherosclerSuppl.2007Aug;8(2):13-7.Epub2007Jun22.LinksPrimarypreventionofcardiovasculardiseasesamonghypercholesterolemicJapanesewithalowdoseofpravastatin.NakamuraH;MEGAStudyGroup.,Tokyo,Japan-ResultsoftheManagementofElevatedCholesterolinthePrimaryPreventionGroupofAdultJapanese(MEGA)study,thefirstlarge-scaleprimary-preventiontrialinaJapanesepopulationthatshowedstatintherapyreducestheriskofcoronaryheartdisease(CHD),havenowbeenpublishedintheSeptember30,2006issueoftheLancet.MEGA,firstpresentedbyleadauthorDrHaruoNakamura(NationalDefenseMedicalCollege,Saitama,Japan)attheAmericanHeartAssociationScientific(AHA)Sessions2005inDallas,TX,showedthattheadditionofpravastatin10mgtoalow-fatdietrichinomega-3fattyacidsreducestheriskofCHDinJapaneseindividualswithmoderatelyelevatedcholesterollevelsby33%,approximatelythesamereductionobservedinUSandEuropeanprimary-preventiontrialsthathaveusedlargerstatindoses.,41,Plateletsareinflammatorycells血小板实乃炎症细胞,42,EBM研究所得(Aspirin)ExperiencefromEBM,43,抗血小板治疗的困惑Certainpuzzledproblemonanti-platelettherapy,颅内出血胃肠道出血鼻腔出血胸膜腔出血皮下出血（aspirin75-100mg/d,clopidogril75mg/d)高龄尤多见;远超1.8-2.1（CURE研究）可适当减量（包括首剂负荷量）,44,Aspirinresistance概念的争议,临床Aspirinresistance:减少事件/未能消除事件AA基因多态性/无效或不利结果生化Aspirinresistance:出血时间延长/TXA2抑制合成/刺激血小板聚集0.4-83.0%DalenJE,etal:AmJMed,2007,120:1-4LoordkipandizeM,etal:PharmacoTher,2006,112:733-743,45,川芎嗪抗血小板作用Anti-plateletEffectsofLigustrazine,TheactivecomponentofABCherb-LigusticumChuanxiong活血化瘀药川芎主要成分Alkaloids生物碱类(Tetramethypyrazine,Ligustrazine)Lactones内酯类四甲基吡嗪Phenols酚性化合物Ferulicacid阿魏酸Others其它,46,活血药抗TXA2生成InhibitoryEffectsofABC-herbsonTXA2Production,芎芍胶囊干预治疗研究XS0601ReducestheIncidenceofRestenosisPost-PCI(RIRETrial,NationalProject),川芎有效部位Paeoniflorin赤芍有效部位Chuanxingol(国家十五攻关课题),安贞医院同仁医院中日友好医院西苑医院广东省中医院,48,临床研究流程SurveyofStudy,335casesenrolled335例入选,Controlgroup对照组169cases,Treatmentgroup治疗组166cases,308casescompletedwith147repeatangiography308例完成试验，147例重复冠脉造影,Randomized随机,3caseslost脱落,12casesexclude剔除,3caseslost脱落,9casesexclude剔除,154cases,154cases,(47.4%),49,Comparisonofclinicalend-pointevent两组临床终点事件的比较,Note:Therewassignificantdifferencebetweenthetwogroups(p0.05).,干预PCI术后再狭窄临床结果比较,注:两组比较有显著性差异(p0.05).,50,XS0601TreatmentStandardTreatment,P0.05,生存率比较XS0601ImprovesCumulativeNo-EventSurvival,51,IntegrativeMedicine:TheExperiencefromChina结合医学经验：来自中国,52,Hs-CRP:HypersensitiveC-reactionProtein;MCP-1:MonocyteChemoattractantProtein;TNF-:TumorNecrosisFactor-,ABC+D药物对炎症指标变化比较Results:InflammatoryMarkerChanges,53,老年冠心病治疗多元模式MultiplePatternsforElderlyCHDTreatment,优化药物治疗(证据和达标问题)PCI(Cypher/TAXUS,安全性/适应症的长期考察)CABG(搭桥与药物支架不能相互替代/在左主干和/或多支病变/或一支多处病变/钙化比较严重的治疗中有优势)心理干预多元模式互补,54,心外膜冠脉开通,心肌组织水平灌注,冠心病治疗观念改变之四FourthChangeinConceptofCHDTreatment,55,再灌注治疗是AMI治疗的里程碑，从被动、保守转为主动、积极的血运重建，挽救了无数患者的生命但临床发现，约10-30%患者PCI成功后，心肌组织水平无再灌注，即无复流现象无复流是PCI后死亡和心梗的独立预测因素,无复流现象的反思Askinginreplyonno-flow,FredericSR,etal.AmHeartJ2003;145:42-46.,56,可能的机制Possiblemechanism,可能的机制微血管结构完整性破坏微栓子栓塞白细胞聚集微血管功能完整性损伤，主要是痉挛所致血小板激活氧自由基,57,策略演变Strategicchange,回顾再灌注历史：过去20年基本上是心外膜冠状动脉再灌注的20年，相信未来的10年将是微循环灌注的10年检测手段：冠脉微循环灌注评价：心肌声学造影成为热点防治手段：无复流防治：腺苷、CaA，活血化瘀中药等微循环改善剂：未来冠心病研究方向之一？,DiabetesCare29:202206,2006,CircJ2006;70:10991104),58,一枝独秀,三驾马车,冠心病治疗观念改变之五FifthChangeinConceptofCHDTreatment,59,“药物支架时代”来临？ThetrendoftheDEStimes?,DES的出现，使心血管介入技术向前迈进了一大步，成为冠心病介入治疗的第3个里程碑。BMS、冠脉搭桥术以及传统药物治疗是否真的要淡出舞台,60,Stenting(includingdrug-elutingstents)reducesrestenosisandrepeatedintervention,butdoesnotreducemortalityormyocardialinfarction.支架不降低心脏病死率或心梗,SerruysPW,KutrykMJB,OngATL.Coronary-arterystents.NEnglJMed2006;354:483-495.,61,FDA05/12/2006:药物支架要求一万例验证三年,FDA:Heartpatientswithdrug-coatedstentsfaceblood-clotriskByAssociatedPressTuesday,December5,2006WASHINGTON-Patientsimplantedwithdrug-coatedstentstoholdopentheirchokedarteriesfaceasmallbutsignificantriskofbloodclots,healthofficialssaidTuesday,andanewstudyrecommendedtheytakeclot-bustingmedicationsindefinitely.Growingconcernsaboutthelong-termsafetyofdrug-coatedstentscomestoaheadthisweek,whentheFoodandDrugAdministrationconvenesatwo-daymeetingtodiscussclottingrisksassociatedwiththedevices.IndocumentsreleasedTuesday,theFDAsaiditisunknownwhetherthereisanincreasedriskofdeathorheartattackinpatientsfittedwiththeso-calleddrug-elutingstents.However,thosepatientsdofaceanincreasedriskofbloodclotsayearormoreaftersurgerycomparedwiththosefittedwithbare-metalstents,theagencysaidincitingrecentstudies.Natick,Mass.-basedBostonScientificCorp.andNewBrunswick,N.J.-basedJohnson在美国，只有18%的左主干和/或三支病变患者选择支架植入;在欧洲，在复杂病变血运重建中，CABG仍占有主导优势。,65,关注冠心病Hybrid技术PayattentiontoHybridtreatment,冠心病杂交手术(Hybrid技术)：联合应用介入治疗/搭桥手术,优势互补,一站式完成再血管化,是冠心病治疗的重要发展方向。,66,LifeWideOpen开放生命,67,危险因素单一控制,危险因素复杂干预,冠心病治疗观念改变之六SixthChangeinConceptofCHDTreatment,68,Diabetes,Dyslipidemia,Hypertension,Obesity,69,多重危险因素的干预Interventionsformulti-RF,单一危险因素的治疗常可使病人心脑血管病危险下降20%30%，意味着还有70%80%的剩余危险需要降低,70,Polypill:心脏病一/二级予防PolypillApproachforClassIComposition:Simvastatin40mg,Lisinopril,half-doseAtenolol,lowdoseaspirin,folicacid(BMJ2003;326:1407,1419,1423,1427)目标:55岁以上使用,可降低心脑血管事件80%;Target:forthoseaged55orabove,couldlowercardiocerebralincidenceby80%争议:激烈;Dispute:FierceAstrategytoreducecardiovasculardiseasebymorethan80%,71,Caduet二合一复方已在美作为新药临床应用CaduetCombines2Drugsin1TabletasaNewDrughasbeenMarketedintheUS,Company:Pfizer；络加喜片RegulatoryStatus:ApprovedbyFDAinJanuary2004Treatment:HBP/Angina/HighcholesterolTabletStrengths(mg):Amiodipine(Novasc)/atrovastatin(Lipitor)=2.5/10,20,40;5/10,20,40,80;10/10,20,40,80.(ASCOTtrial,Anglio-ScandinavianCardiac