多重心血管風(fēng)險(xiǎn)患者管理

多重心血管風(fēng)險(xiǎn)患者管理第1頁/共126頁USpopulationathighriskAHA.HeartDiseaseandStrokeStatistics–2005Update.HajjarIandKotchenTA.JAMA.2003;290:199-206.FordESetal.Circulation.2003;107:2185-9.

CDC./diabetes/pubs/pdf/ndfs_2005.pdf.*Total-C≥200mg/dL?BP≥140/90mmHg?FBG≥126mg/dLDiabetes?14.6milliondiagnosed6.2millionundiagnosedHypercholesterolemia*106.9million94millionnottreatedPatientswithCHD/stroke:

18.4million/yDirect:$105.7billion/y

Indirect:$93.2billion/y

Totalcost:$198.9billion/yHypertension?65million27millionnottreated第2頁/共126頁

AdaptedfromPepineCJ.AmJCardiol.2001;88(suppl):5K-9K.DevelopmentandprogressionofCVDRiskfactorsOxidativestressFunctionalalterationsStructuralalterationsClinicalsequelaeAge,gender,smoking,inactivity,obesity,cholesterol,BP,glucoseGeneticfactorsEndothelialfunction

EPCsEPCs=endothelialprogenitorcells第3頁/共126頁ObesityHypertensionDiabetesSTROKE/MIGENESGENESENVIRONMENTInadequateMedicalCareGENESInactivityDietPsychosocialStressCultureGeneticsaugmenteffectsofenvironmental

riskfactors第4頁/共126頁Cardiovascularriskfactors,adults55–64yearsPrevalence(%)HypertensionObesityHighcholesterolOneormoreriskfactorsHypertensionObesityHighcholesterolOneormoreriskfactorsMen020406080100Women1988–19941999–2002CDC./nchs/ppt/hus/HUS2005.ppt.第5頁/共126頁JacksonRetal.Lancet.2005;365:434-41.Synergisticinteractionoftraditional

multipleriskfactorsonCVDrisk0Reference5-year

CVDrisk

per100

peopleTC=

270mg/dLSmokerHDL=

39mg/dLMaleDiabetes60years

ofage102030405044%33%24%18%12%6%3%110SBP(mmHg)120130140150160170180<1%TC=totalcholesterolAdditiveriskfactors第6頁/共126頁

Obesitydecreaseslifeexpectancyregardless

ofsmoking

FraminghamHeartStudyPeetersAetal.AnnInternMed2003;138:24-32.ObesityandsmokingrisksareequivalentFemalenonsmokersFemalesmokers0102030401.00.20.0Proportion

aliveFollow-up(years)BMI18.5–24.9kg/m2BMI25–29.9kg/m2BMI≥30kg/m20102030401.00.20.0Follow-up(years)第7頁/共126頁Declineinsmokingvsriseinobesity:

Atrade-off?GruberJandFrakesM.JHealthEcon.

Publishedonlineaheadofprint..Proportion

ofpopulation1970Year19741978198219861990199419982002ObesityrateSmokingrate0.3500.4第8頁/共126頁DevelopmentandprogressionofCVD

AdaptedfromPepineCJ.AmJCardiol.2001;88(suppl):5K-9K.RiskfactorsFunctionalalterationsStructuralalterationsClinicalsequelaeEmergingbiomarkersOxidativestressEndothelialfunction

EPCsEPCs=endothelialprogenitorcells第9頁/共126頁TraditionalCVDriskfactors

FamilyhistoryOlderageMalegenderSmokingPhysicalinactivityOverweight/obesityTotal-C/LDL-C/HDL-C/TGBPGlucoseAdaptedfromStampferMJetal.Circulation.2004;109(suppl):IV3-IV5.第10頁/共126頁Selectedemergingbiomarkers

AdaptedfromStampferMJetal.

Circulation.2004;109(suppl):IV3-IV5.LipidsLp(a) apoA/apoBParticlesize/densityInflammationCRP SAAIL-6 IL-18TNF AdhesionmolsLp-PLA2

CD40L CSF Hemostasis/ThrombosisHomocysteine tPA/PAI-1TAFI FibrinogenD-dimer CSF=colony-stimulatingfactorOxidation

Ox-LDL

MPOGlutathioneAsp299Glypolymorphism

inTLR4geneMCP-12578GalleleCX3CR1chemokinereceptor

polymorphismV249I16Glyvariantof2-adrenergic

receptor260T/TCD14allele117Thr/ThrvariantofCSFLIGHT

GeneticMPO=myeloperoxidaseTAFI=thrombinactivatablefibrinolysisinhibitor第11頁/共126頁LDLinfiltrationtriggers

inflammatoryresponseHanssonGK.NEnglJMed.2005;352:1685-95.Coronary

arteryActivationUptakeModificationRetentionLDLEndotheliumAccumulationof

cholesterolMacrophage第12頁/共126頁Roleofox-LDLinmacrophagerecruitmentHanssonGK.NEnglJMed.2005;352:1685-95.MigrationCoronary

arteryAdhesionDifferentiationInflammation.

tissuedamageToll-like

receptorEndotheliumMonocyteEndotoxins,

heat-shockproteins,

oxidizedLDL,othersInflammatorycytokines,

chemokines,proteases,

radicalsMacrophage第13頁/共126頁HypertensionincreasesatherogeniclipoproteincontentofarterialvesselwallsSpositoAC.EurHeartJSuppl.2004;6(supplG):G8-G12.BPAtherogenicVLDL,VLDL-R,

IDL,LDLIntima-Enhanced –LPpenetrationmedia –LPretention–Pressure-induceddistension–StretchingIntima-mediaPressure-drivenconvectionLP=lipoprotein第14頁/共126頁AT1andLOX-1receptorcross-talkpromotesadhesionmoleculeexpression

AdaptedfromSinghBMandMehtaJL.

ArchInternMed.2003;163:1296-304.InteractionbetweenRAASanddyslipidemiaGrowthFactorsLOX-1FibroblastsAngiotensinIIOx-LDLLDLAT1RSmoothMuscleCellsMonocyteadhesionECNOOxygen*************SRs

AngiotensinII

LDLOxidation

CytokinesPlateletAggregationMonocyteAdhesionEC=endothelialcellSRs=scavengerreceptors第15頁/共126頁Lipoprotein-associatedphospholipaseA2

(Lp-PLA2)MacpheeCHetal.CurrOpinLipidol.2005;16:442-6.ProducedbyinflammatorycellsHydrolyzesoxidizedphospholipidstogenerateproinflammatorymolecules LysophosphatidylcholineOxidizedfattyacidsUpregulatedinatheroscleroticlesionswhereitco-localizeswithmacrophages第16頁/共126頁Studiesdemonstratingassociation

ofLp-PLA2withincidentCHDHR1.23(1.02-1.47)per1SDGeneralpopulation97cases,837controlsKoenigetal

HR1.97(1.28-3.02)

4thvs1stquartileGeneralpopulation418cases,1820controlsOeietal

HR1.78(1.33-2.38)

tertile3vstertile1Generalpopulation608cases,740controlsBallantyneetalRR1.18(1.05-1.33)per

1SDWOSCOPSsubgroupLDL-C174–232mg/dL

580cases,1160controlsPackardetal

Findings*SubjectsStudy*Adjustedrelativerisk(RR)orhazardratio(HR)PackardCJetal.NEnglJMed.2000;343:1148-55.

BallantyneCMetal.Circulation.2004;109:837-42.

KoenigWetal.Circulation.2004;110:1903-8.

OeiH-HSetal.Circulation.2005;111:570-5.第17頁/共126頁HillJMetal.NEnglJMed.2003;348:593-600.Flow-mediateddilationLowMidHighEPCs

(colony-forming

units)0102030P

<

0.001N=45healthymales,meanage50.3y,noCVDEPCnumber/functioncorrelates

withendothelialfunctionEPCs=endothelialprogenitorcells第18頁/共126頁WernerNetal.NEnglJMed.2005;353:999-1007.N=507maleswithCAD,meanage66yEPCnumberhasprognosticimportance1.000.980.960.940.920.900100200300365Group3(highEPClevel)Group2(mediumEPClevel)Group1(lowEPClevel)0Follow-up(days)Event-freesurvival(CVmortality)EPC=endothelialprogenitorcellP=0.01第19頁/共126頁Arterialstiffness:CauseandconsequenceofatherosclerosisAdaptedfromDartAMandKingwellBA.JAmCollCardiol.2001;37:975-84.Pulse

pressureCentralwavereflectionLargeartery

stiffnessAtherosclerosisEndothelial

damage&mechanical

fatigueSympatheticmodulation第20頁/共126頁CorrelationbetweennumberofriskfactorsandarterialdistensibilityUrbinaEMetal.AmJHypertens.2005;18:767-71.N=803,meanage30yBrachialarterydistensibilityoccurslongbeforeclinicalmanifestationsof

CVDappear5.5677.5031426.5≥5NumberofCVriskfactorsBrachialarterydistensibility

(%/mmHg)LineartrendP<0.0001BogalusaHeartStudy第21頁/共126頁HerringtonDMetal.Circulation.2004;110:432-7.MRIresults

QuartileofabdominalaortawallthickeningN=256Thigharterial

compliance*PeripheralarterialstiffnessisassociatedwithsubclinicalatherosclerosisQ150Q2Q4403020100Q3BrachialpulsepressureP<0.0001fortrend*MaximumvolumechangeX50第22頁/共126頁LiaoJK.AmJCardiol.2005;96(suppl1):24F-33F.MMPs=matrixmetalloproteinasesPlateletactivationCoagulationEndothelial

progenitorcells

EffectsoncollagenMMPsAT1receptorVSMCproliferationEndothelinMacrophagesInflammationImmunomodulationEndothelialfunctionReactiveoxygen

speciesNObioactivityPleiotropiceffectsofstatinsStatins第23頁/共126頁High-dosestatintreatmentreduces

Ox-LDLmarkersTsimikasSetal.

Circulation.2004;110:1406-12.OxPL=oxidizedphospholipidsIC-IgG,-IgM=immunecomplexeswithIgGandIgM,respectivelyMyocardialIschemiaReductionwithAggressiveCholesterolLoweringMIRACLstudysubgroupanalysis,N=2341withACS,atorvastatin80mg

for16weeksApoB-100AtorvastatinPlaceboTotalapoB-OxPLAtorvastatinPlaceboTotalapoB-ICIgGAtorvastatinPlaceboTotalapoB-ICIgMAtorvastatinPlacebo%change–40–2002040Mean95%CI –33.0 –34.2,–31.8 5.8 4.6,7.0 –29.7 –31.5,–28.0 –0.2 –2.3,1.9 –29.5 –31.9,–27.0 2.1 –1.1,5.4 –25.7 –28.1,–23.3 13.2 9.3,17.3第24頁/共126頁StatintreatmentreducesLp-PLA2TsimihodimosVetal.ArteriosclerThrombVascBiol.2002;22:306-11.Plasma

Lp-PLA2activity

(nmolxmL-1xmin-1)*P<0.001vsbaselineAtorvastatin20mg,4mosBaselineTypeIIAdyslipidemia(n=55)TypeIIBdyslipidemia

(n=21)87.162.2*73.542.3*204060801000第25頁/共126頁StatinsincreasecirculatingEPCsVasaMetal.Circulation.2001;103:2885-90.LiaoJK.AmJCardiol.2005;96(suppl):24F-33F.N=15withCADtreatedwithatorvastatin40mgfor4weeksPostulatedmechanism:ActivationofPI3-K/AktpathwayEndothelialNOsynthase700600500400300200100007142128n=13n=12n=14n=12Treatment(days)EPCs

(cells/mm2)*P<0.05vsbaseline****n=15第26頁/共126頁IntensivelipidloweringimprovesarterialcomplianceN=22withISHtreatedwithatorvastatin80mgfor3monthsFerrierKEetal.JAmCollCardiol.2002;39:1020-5.

P=0.03Placebo0.5AtorvastatinSystemicarterialcompliance(mL/mmHg)第27頁/共126頁ComparativeeffectsofstatinandezetimibeonEPCsandendogenousantioxidantsystemN=20withHFtreatedwithsimvastatin10mgorezetimibe10mgfor4weeksLandmesserUetal.Circulation.2005;111:2356-63.Numberperhighpowerfield4503001500P<0.05Statin

NSEzetimibe1600P<0.05Statin

NSEzetimibe

Extracellularsuperoxide

dismutaseEPCs(UxmL-1xmin-1)Endothelium-bound

ecSOD

activity1208040PreGroup:Pre=baselinePost=4weeks

PostPrePostPrePostPrePost第28頁/共126頁P(yáng)re-treatedwithstatinbeforeocclusionSimvastatinPost-treatedwithstatinafterocclusionSironiLetal.ArteriosclerThrombVascBiol.2003;23:322-7.OcclusionofmiddlecerebralarteryinratsVehicle24hrs48hrs24hrs48hrsNeuroprotectionwithstatinsinstrokemodelStatineffectaccompaniedbyeNOSupregulationincerebralbloodvesselsIschemicareasindicatedbyarrows第29頁/共126頁P(yáng)leiotropiceffectsofBP-loweringagentsLonnEetal.EurHeartJ

Suppl.2003;5(supplA):A43-A8.

WassmanSandNickenigG.EurHeartJSuppl.2004;6(supplH):H3-H9.MasonRPetal.ArteriosclerThrombVascBiol.2003;23:2155-63.ACEIs/ARBsCCBsFibrinolysisPlateletaggregationMononuclear

cellmigrationCollagenmatrix

formationEndothelialfunctionOxidativestressInflammationPlaquestabilityArterial

complianceNOMMPactivityVSMCproliferationCholesterol

deposition

inmembraneMMP=matrixmetalloproteinaseAHTN

agentsBothBP-lowering

agents第30頁/共126頁MasonRPetal.AmJCardiol.2005;96(suppl):11F-23F.HumanLDLincubatedwithO-hydroxymetaboliteofatorvastatin(100nmol/L),lovastatin(100nmol/L),andamlodipine(2.5mol/L)TBARS=thiobarbituricacid-reactive

substances*P<0.0001vsvehicletreatmentStatinmetaboliteandCCBshowadditiveantioxidanteffectAtorvastatin

metabolite*50Amlodipine

+

LovastatinAmlodipine

+

Atorvastatin

metabolite*403020100Inhibition

ofTBARSformation

(%)第31頁/共126頁FogariRetal.AmJHypertens.2004;17:823-7.*P<0.05vsplacebo

?P<0.01vsplaceboN=45withhypertension,placebo-controlled,crossovertrialAdditiveeffectsofstatin+CCB

onfibrinolyticbalanceAtorvastatin

20mgAmlodipine

5mgAtorvastatin+20mgAmlodipine

5mgChangefrombaselinePAI-1

(U/mL)t-PA

(U/mL)–9.9–0.5–10.20.080.170.26P<0.05*?**t-PA/PAI-1ratio 0.045 0.03 0.06第32頁/共126頁Beneficialeffectofstatin+ACEI

onendothelialfunction01234567KohKKetal.Hypertension.2004;44:180-5.Flow-

mediated

dilation

(%)PL=placeboRam=ramipril10mg

Sim=simvastatin20mgN=50withdyslipidemia,placebo-controlled,crossovertrialBaseline1Sim+PLBaseline2Sim+Ram4.816.026.58P<0.0014.56第33頁/共126頁ApproachestoCVDpreventionLipid

modificationLifestyle

interventionBP

loweringGlucose

loweringOptimalCVriskreduction第34頁/共126頁LifestylechangesreduceneedfordrugtherapyLifestylechangegoalsWeightreductionof≥7%initialbodyweightvia

low-fat,low-caloriedietModerate-intensityphysicalactivity≥150min/week Lifestyle Metformin Placebo16%16%12%Lipid-loweringagentsrequired31%32%23%BP-loweringagentsrequiredDiabetesPreventionProgramResearchGroup.DiabetesCare.2005;28:888-94.

*P<0.001vsothergroupsN=3234withIGTrandomizedtointensivelifestylechange,

metformin850mg2x/d,orplaceboAt3years**第35頁/共126頁≥30minutesofmoderatephysicalactivity5-7days/week≥30minutesofmoderatelyintenseexerciseeveryday60mintopreventweightgain5servings/day≥9servings/day

2000Report2005ReportHHS/USDA./dietaryguidelines.ExerciseFruitsand

vegetablesNewlifestyleguidelines:Moreexercise,fruitsandvegetables第36頁/共126頁ExercisereducesCVandall-causemortalityFangJetal.AmJHypertens.2005;18:751-8.N=9791,moderateexercisevslittleornoexercise

NHANESIEpidemiologicalFollow-upSurvey(1971-1992)0.750.760.79All-causedeathCVdeathAll-causedeathPrehypertensionCVdeathHypertensionHazardratio1.51.00.5NormalBP02.0All-causedeathCVdeath0.790.880.84HRFavorsexerciseFavorsnoexercise第37頁/共126頁P(yáng)arikhPetal.JAmCollCardiol.2005;45:1379-87.TrichopoulouAetal.BMJ.2005;330:991-7.KnoopsKTBetal.JAMA.2004;292:1433-9.2005EuropeanProspective

InvestigationintoCancer

andNutrition–elderlycohort

(N=74,607)?

*Bloodlevelsofn-3fattyacidsinversely

relatedtodeath?Greateradherenceassociatedwithlowermortality2002Nurses’HealthStudy

(N=84,688)

2004TheHealthyAging:

ALongitudinalStudyinEurope

(N=2339)

2002Physician’sHealthStudy

(N=20,551)*

2003CardiovascularHealthStudy

(N=5,201)*

2003EuropeanProspective

InvestigationintoCancer

andNutrition–Greekcohort

(N=22,043)?

Dietreducesmortalityinprimary

preventiontrials第38頁/共126頁P(yáng)otentialcardioprotectivemechanisms

ofdietarycomponentsKris-EthertonPMetal.Circulation.2002;106:2747-57.VerhaarMCetal.ArteriosclerThrombVascBiol.2002;22:6-13.Omega-3fattyacidsAntiarrhythmicAntithrombogenicAntiinflammatoryAntihypertensiveImprovedendothelialfunctionFolicacidAntioxidantNObioavailabilityImprovedendothelialfunction第39頁/共126頁Non-pharmacologicinterventions

andBPreductionAdaptedfromMesserliFHetal.In:GriffinBPetal,eds.

2004.ManualofCardiovascularMedicine.2nded.WheltonSPetal.AnnInternMed.2002;136:493-503.

CutlerJAetal.AmJClinNutr.1997;65(suppl):643S-651S.XinXetal.Hypertension.2001;38:1112-7.

WheltonPKetal.JAMA.1997;277:1624-32.BPdecrease

(mmHg)SBPDBP543210ExerciseLowsaltdietAlcohol

reductionPotassium

supplement第40頁/共126頁BenefitofmultifactorialinterventionsLipid

modificationLifestyle

interventionBP

loweringGlucose

loweringOptimalCVriskreduction第41頁/共126頁Keyfindingsfromrecentlipid-loweringtrials2002 2003 2004 2005 HPS

BenefitinCVDandDMregardlessofbaselineLDL-CASCOT-LLA

Benefitinhigh-riskHTNregardlessofbaselineLDL-CCARDS

BenefitinDM

TNT

Benefitof

intensivevs

moderate

lipidlowering

instableCADALLHAT-LLT

NeutraleffectinHTNwithmild

lipidlowering

PROVEIT-TIMI22

Earlyandlatebenefitofintensivevsmoderate

lipidloweringinACSPrimarypreventionSecondaryprevention(ACS)Secondaryprevention(stableCAD)4D

Neutraleffect

inESRDAtoZ

Latebenefitof

intensivevsmoderate

lipidloweringinACSIDEAL

Benefitofintensivevsmoderatelipidlowering

instableCAD第42頁/共126頁P(yáng)ROVEIT-TIMI22:Assessment

ofintensivelipidloweringinACSCannonCPetal.NEnglJMed.2004;350:1495-504.Design: 4162patientswithACS

randomizedtoatorvastatin80mg

orpravastatin40mgFollow-up: 2yearsPrimaryoutcome: All-causedeath,MI,hospitalizationfor UA,revascularization,strokePRavastatinOrAtorVastatinEvaluationandInfectionTherapy–ThrombolysisInMyocardialInfarction22第43頁/共126頁P(yáng)ROVEIT-TIMI22:EarlybenefitwithintensivelipidloweringRayKKandCannonCPAmJCardiol.2005;96(suppl):54F-60F.

AdaptedfromCannonCPetal.NEnglJMed.2004;350:1495-504.30203691230100151821242740mgPravastatin80mgAtorvastatinP=0.03at4mosP=0.005Follow-up(months)Deathor

major

CVevent(%)0N=4162withACSPRavastatinOrAtorVastatinEvaluationandInfectionTherapy–ThrombolysisInMyocardialInfarction22第44頁/共126頁P(yáng)ROVEIT-TIMI22:Benefitat30daysCannonCPetal.NEnglJMed.2004;350:1495-504.CensoringtimeHazardratio(95%CI)Riskreduction(%)Eventrates(%)AtorvastatinPravastatin30days90days180daysEndoffollow-up 17 1.9 2.2 18 6.3 7.7 14 12.2 14.1 16 22.4 26.30.500.751.001.251.50High-dose

atorvastatin

betterStandard-dose

pravastatin

betterNotoxicityN=4162withACSPRavastatinOrAtorVastatinEvaluationandInfectionTherapy–ThrombolysisInMyocardialInfarction22第45頁/共126頁P(yáng)ROVEIT-TIMI22:EvidenceforrapidreductioninmarkersofinflammationRidkerPMetal.NEnglJMed.2005;352:20-8.100101Randomization30days4monthsEndofstudyP<0.001P<0.001P<0.001Pravastatin

(n=1873)Atorvastatin

(n=1872)P=0.60MedianCRP(mg/L)N=4162withACSPRavastatinOrAtorVastatinEvaluationandInfectionTherapy–ThrombolysisInMyocardialInfarction22第46頁/共126頁P(yáng)ROVEIT-TIMI22:ClinicalimplicationsInpatientswithrecentACS,aggressivelipidloweringwasassociatedwithgreaterclinicalbenefitvslessaggressivelipidlowering:—

16%RRRinall-causedeath,MI,UA,revascularization,strokeBenefitevidentat30daysandmaybemediatedinpartby

anti-inflammatoryeffectNorelationshipbetweenachievedLDL-Clevelandriskofadverseevents

—Noexcessriskevenatlevels≤40mg/dLCannonCPetal.NEnglJMed.2004;350:1495-504.RayKKetal.AmJCardiol.2005;96(suppl):54F-60F.

RidkerPMetal.NEnglJMed.2005;352:20-8.WiviottSDetal.JAmCollCardiol.2005;46:1411-6.PROVEIT-TIMI22supportslowerLDL-CgoalinpatientswithACSPRavastatinOrAtorVastatinEvaluationandInfectionTherapy-ThrombolysisInMyocardialInfarction22第47頁/共126頁AtoZ:Earlyinitiationofintensiveregimen

vsdelayedinitiationofless-intensiveregimen

deLemosJAetal.JAMA.2004;292:1307-16.Population: 4497patientswithACSTreatments: Simvastatin40mg/dfor1month,followedby

80mg/d Placebofor4months,followedbysimvastatin20mg/dMedianfollow-up: 721daysPrimaryoutcome: CVdeath,nonfatalMI,ACSreadmission,strokeAggrastattoZocor第48頁/共126頁deLemosJAetal.JAMA.2004;292:1307-16.Placebo/simvastatin20mg/d060100140Baseline14824Timefromrandomization(months)LDL-C

(mg/dL)20111112122681246277638166Simvastatin40/80mg/d*P<0.001vsplacebo/simvastatin20mgAtoZ:TreatmenteffectonLDL-CAggrastattoZocorN=4497withACS****第49頁/共126頁deLemosJAetal.JAMA.2004;292:1307-16.*P<0.001vsplacebo/simvastatin20mgPlacebo/simvastatin20mg/dSimvastatin40/80mg/d0123Baseline148Timefromrandomization(months)CRP

(mg/L)20.41.521456**AtoZ:TreatmenteffectonCRPAggrastattoZocorN=4497withACS第50頁/共126頁deLemosJAetal.JAMA.2004;292:1307-16.Placebo/simvastatin20mg/dSimvastatin40/80mg/d20150510Cumulative

rate(%)4081216202411%RRR

HR=0.89(0.76-1.04)P=0.14AtoZ:Treatmenteffectonprimaryoutcome

AggrastattoZocorTimefromrandomization(months)CVdeath,MI,recurrentACShospitalization,strokeN=4497withACS11%RRR27%RRR

P=0.02第51頁/共126頁deLemosJAetal.JAMA.2004;292:1307-16.Primarycompositeoutcomerate(%)OverallstudyresultRandomization

throughmonth4Months4–24Simvastatin

40/80mg

n=2265Placebo+

simvastatin20mg

n=2232Favors

simvastatin

40/80mgFavorsplacebo

+simvastatin

20mgHazardratio(95%CI)14.41.01.5AtoZ:TreatmenteffectonprimaryoutcomeatdifferenttimeperiodsAggrastattoZocorCVdeath,MI,recurrentACShospitalization,strokeN=4497withACS第52頁/共126頁AtoZ:ClinicalimplicationsInpatientswithrecentACS,earlyinitiationofamoderate/high-dosesimvastatinregimenvsdelayedinitiationofalow-doseregimenresultedinnonsignificanttrendtowardreductioninmajorCVevents11%RRRinCVdeath,nonfatalMI,ACSreadmission,strokeNodifferencebetweenthetreatmentgroupswasobservedwithinthefirst4monthsdeLemosJAetal.JAMA.2004;292:1307-16.

RayKKetal.AmJCardiol.2005;96(suppl):54F-60F.FindingsareconsistentwithMIRACLandPROVEIT-TIMI22Earlybenefitsmaybeduetoanti-inflammatoryeffectsLatebenefitsmaybeduetolipidloweringAggrastattoZocor第53頁/共126頁TNT:AssessmentofintensivelipidloweringonclinicaloutcomesLaRosaJCetal.NEnglJMed.2005;352:1425-35.Design: 10,001patientswithstableCHDandLDL-C130-250mg/dLTreatment: Randomizedtoatorvastatin10mgor80mgFollow-up: 4.9yearsPrimaryoutcome: CHDdeath,MI,resuscitationaftercardiacarrest,fatal/nonfatalstrokeTreatingtoNewTargets第54頁/共126頁TNT:TreatmenteffectsonLDL-CLDL-C(mg/dL)LaRosaJCetal.NEnglJMed.2005;352:1425-35.01601002080120140Atorvastatin10mg(n=5006)MonthsScreeningFinal6048362430406012Atorvastatin80mg(n=4995)TreatingtoNewTargetsN=10,001第55頁/共126頁TNT:TreatmenteffectsonprimaryoutcomeLaRosaJCetal.NEnglJMed.2005;352:1425-35.MajorCVevents

(%)CHDdeath,MI,resuscitationafter

cardiacarrest,fatal/nonfatalstrokeFollow-up(years)654213Atorvastatin10mg(n=5006)Atorvastatin80mg(n=4995)00.000.050.100.1522%Riskreduction

HR=0.78(0.69–0.89)P<0.001TreatingtoNewTargetsN=10,001第56頁/共126頁TNT:Incidenceofelevatedliver

ormuscleenzymesAtorvastatin

80mg(%)

(n=4995)Atorvastatin

10mg(%)

(n=5006)ALTand/orAST>3xULNCK>10xULNMyalgiaRhabdomyolysis0.21.2*0060.04LaRosaJCetal.NEnglJMed.2005;352:1425-35.*P<0.001vsatorvastatin10mgALT=alanineaminotransferase

AST=aspartateaminotransferase

ULN=upperlimitofnormalTreatingtoNewTargetsN=10,001第57頁/共126頁TNT:ClinicalimplicationsInpatientswithstableCHD,aggressivelipidloweringwasassociatedwithgreaterclinicalbenefitvslessintensivelipidlowering:22%RRRinCHDdeath,MI,resuscitationaftercardiacarrest,

andfatal/nonfatalstrokeLaRosaJCetal.NEnglJMed.2005;352:25-35.TNTsupportslowerLDL-CgoalinpatientswithstableCHDTreatingtoNewTargets第58頁/共126頁P(yáng)otentialfactorscontributingtoearlystatinbenefitHighbaselineriskIntensiveLDL-CloweringRapidanti-inflammatory

effectPepineCJandSelwynAP.

VascBiolClinPract.CMEMonograph.UFCollegeofMedicine.2004;6(2).High

riskRapidIntensive第59頁/共126頁HPSandCARDS:

BenefitsofloweringLDL-CindiabetesHPSCollaborativeGroup.Lancet.2003;361:2005-16.

ColhounHMetal.Lancet.2004;364:685-96.LDL-C

(mg/dL)*34.846.4StatinbetterPlacebobetterAlldiabetesHPSCARDSRelativerisk1<0.00010.00030.001Eventrate(%)12.613.59.0PlaceboStatin0.630.670.73PDiabetes,noCVD1.7*Statinvsplacebo34.8HeartProtectionStudyandCollaborativeAtoRvastatinDiabetesStudy第60頁/共126頁CARDS:Adverseevents1(0.1)1(0.1)Myopathy17(1)14(1)ALT≥3ULN6(0.4)4(0.3)AST≥3ULN00Rhabdomyolysis122(9)145(10)DiscontinuedforAE19(1.1)20(1.1)Seriousadverseevent(AE)*No.ofevents

(%ofpatientswithevent)Atorvastatin10mg

(n=1428)

TypeofEventPlacebo

(n=1410)

ColhounHMetal.Lancet.2004;364:685-96.*Judgedbyattendingcliniciantobepossibly

associatedwithstudydrugALT=alaninetransaminaseAST=aspartatetransaminaseULN=upperlimitofnormal第61頁/共126頁P(yáng)=0.03NS-50-40-30-20-1001020LDL-CNonfatalMICHDdeathStrokeCoronaryeventsCerebrovascevents

4DTrial:Neutraleffectofstatinin

hemodialysispatientswithdiabetesN=1255randomizedtoatorvastatin20mgorplacebofor4yearsWannerCetal.NEnglJMed.2005;353:238-48.%

ChangeFatalstroke103%*

P=0.04Baseline

LDL-C

121mg/dLNS*Relativeriskreduction8%*18%*12%*第62頁/共126頁Statinsreduceall-causedeath:

Meta-analysisof14trials

Causeofdeath3.40.810.910.950.93Vascularcauses:StrokeOthervascularAnyvascularAnynon-CHDvascularNonvascularcauses:CancerRespiratory0.831.010.820.890.870.950.88TraumaOther/unknownAnynonvascularAnydeathEvents(%)Treatment

(n=45,054)Control

(n=45,002)Treatment

betterControl

better1.51.00.5CHDCTTCollaborators.Lancet.2005;366:1267-78.RelativeriskCholesterolTreatmentTrialis