老年冠心病治疗策略的演变医学

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 50 50 70 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 79 733 743 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 CHDdevelopsin20 30years冠心病慢性病程Plaqueruptureoccursin2 3hrs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 itwouldn tchangethebiologiccourseofAS 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 P 0 001 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 p 0 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 Evidencebasedapproach Despiteregulatingbloodlipidmetabolism 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 Vulnerablepatient isproposedtodefinesubjectssusceptibletoanacutecoronarysyndromeorsuddencardiacdeathbasedonplaque 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Xuezhikang ModernChineseHerbalMedicine 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MEGAStudy sresult 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 p 0 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 p 0 05 50 XS0601Treatment StandardTreatment P 0 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 202 206 2006 CircJ2006 70 1099 1104 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 Johnsonaretheonlytwocompaniesapprovedtosellthedrug coatedversions TheFDAisseekingadviceonawiderangeofquestionsonthepopularstents includingwhethertoupdatetheirlabelswithnewwarnings identifypatientsforwhomtheyaren tappropriateandperhapschangefederalrecommendationsonhowlongpeopleshouldtakebloodthinnerslikePlavixandaspirinfollowingstentsurgery 62 StentvsCABG 国际上正在组织三个大规模随机对照临床研究进行多支血管病的DES和CABG疗效评估 相信这些研究将有助于明确二者各自的优势和适应证 FREDOOM 多支血管病合并糖尿病患者的DES和CABG的对比研究 SYNTAX 左主干和 或 多支血管病的DES和CABG对比研究 COMBAT 左主干和 或 多支血管病的DES和CABG的对比研究 63 目前认识Understandingatpresent DES总体是有较好效果的 但长期应用安全性仍有待大规模临床试验加以验证 DES术后更应强调坚持规范二联抗血小板治疗 至少1年以上 以减少支架血栓的发生 大约60 75 接受DES治疗的患者实际上并不一定需要DES 临床应严格掌握适应症 64 StentvsCABG 在左主干和 或多支病变中 CABG有优势 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PolypillApproachforClassI IIPreventionofCardiacDiseases 组成 辛伐他汀40mg ACEI 赖诺普利 半量噻嗪类利尿剂 或阿替洛尔25mg 低剂量阿司匹林 叶酸 Composition 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 Lipit