冠心病危險因素新視點(diǎn)課件

ANewLookatCoronaryRiskFactors15thGreatWallInternationalCongressofCardiologyBeijing,ChinaDavidD.Waters,MDOctober18,2004UCSFFernandoBoteroLadywithaGreenParrotLeonardo–16thCentury Botero–20thCenturyObesityinChina60,000,000obeseadultsinChina7.1%ofthepopulationthisnumberhasdoubledin10yrs

HealthMinistryreport(Oct13,2004)GuanChen,age24,191KgANewLookatCoronaryRiskFactorstheprevalenceoftype2diabetesandobesityareincreasingdramaticallyinmostoftheworldLDL-cholesterolcannowbereadilycontrolledwithstatinsnewriskfactorssuchashs-CRPandCACscorebyEBCTareenteringclinicalusetreatmentsproventoreduceriskarebeinggreatlyunderutilizedworldwide,aggressivemarketingoftobaccoandtheavailabilityofcheapatherogenicfoodswillleadtoanepidemicofcoronarydiseaseCardiovascularDiseaseHasBecometheLeadingCauseofDeathinChinacross-sectionalsurveyinanationallyrepresentativesampleof15,540Chineseadultsage35to74,conductedin2000-0124%hadborderlinehightotalcholesterol(200-240mg/dl)and9%hadhighcholesterol(>240mg/dl)17%hadLDL-Cbetween130-159mg/dl,5%hadLDL-Cbetween160-189mg/dl,and2.7%hadanLDL-C>190mg/dl19%hadlowHDL-cholesterol(<40mg/dl)only8.8%ofmenand7.5%ofwomenwereawareoftheircondition;only3.5%weretreatedHeJ,etal,Circulation2004;110:405ExplainingtheIncreaseinCoronaryHeartDiseaseMortalityinBeijingBetween1984and1999validatedmodelusingMONICAandSino-MONICAdatabetween1984and1989,CHDmortalityratesincreasedby50%inmenand27%inwomenaged35-74yearstotalcholesterolincreasedfrom166to206mg/dlsmokingprevalenceincreasedfrom49%to57%inmenanddecreasedinwomenfrom16%to9%prevalenceofdiabetesincreasedfrom3%to9%BMIincreasedfrom23.9to24.9kg/m2CritchleyJ,etal,Circulation2004;110:1236ExplainingtheIncreaseinCoronaryHeartDiseaseMortalityinBeijingBetween1984and1999changesinriskfactorstogetherproducedabestestimateof1,822moreCHDdeathsin1999comparedto1984cholesterol 77%diabetes 19%BMI 4%smoking 1%improvedtreatmentspreventedorpostponedanestimated642deathstreatmentofMI 41%treatmentofhypertension 24%secondaryprevention 11%heartfailure 10%CABGandPTCA 2%CritchleyJ,etal,Circulation2004;110:1236RelationBetweenRiskFactorsandtheIncidenceofCoronaryDiseaseinCohortStudiesLawMRandWaldNJ.BMJ

2002;324:1570-1576.DiastolicBP320.5Relative

riskRelativerisk708090100110UsualDBP(mmHg)SerumCholesterol4567mmol/LBodyMassIndexRelativeriskkg/m2

3210.52530354010.253211.50.75WhatIsNormal?PhysiologicVariablesinPrehistoricCommunitiesandinCurrentWesternSocieties

<5%

1.2

0.6%decline/yrinBMDinpostmenopausalwomen<10%2722BMI,age60<1%230mg/dL120mg/dLSerumcholesterol,age60<5%80mmHg70mmHgDiastolicBP,age60<1%145mmHg110mmHgSystolicBP,age60CurrentWesternPop<PrehistoricAverageCurrent

WesternSocieties

PrehistoricCommunities

PhysiologicVariableLawMRandWaldNJ.BMJ2002;324:1570-1576.ExtenttoWhichDiseaseIsConcentratedinthePopulationWithExtremePhysiologicValues22%HipfractureBMD23%DiabetesBMI22%CoronarydiseaseBMI21%CoronarydiseaseSerumcholesterol21%CoronarydiseaseSystolicBP28%StrokeSystolicBPCasesinSubjectsWithValues>90thPercentile

AssociatedDisorder

PhysiologicVariableImplicationsReducingtheriskfactorreducestheriskofaneventbyaconstantproportionoftheexistingrisk,irrespectiveofthestartingleveloftheriskfactororoftheriskWhetherariskfactorshouldbetreatedthusdependsonthelevelofrisk,nottheleveloftheriskfactorAllreversibleriskfactorsshouldbetreatedinapatientathighriskTermslikehypertensionandhypercholesterolemiathatfocusonthetailsofthedistributionofphysiologicvariablesaremisleadingandthusbestavoidedLawMRandWaldNJ.BMJ.2002;324:1570-1576.HeartProtectionStudy20,536patientsintheU.K.atincreasedriskofCHDdeathdueto:MIorothercoronaryheartdiseaseocclusivediseaseofnoncoronaryarteriesdiabetesmellitusortreatedhypertensionAge40-80yrTotalcholesterol>3.5mmol/L(>135mg/dL)Randomizedtosimvastatin40mg/dayorplaceboandfollowedfor5yearsVascular

EventTotalCHDTotalstrokeRevascularizationANYOFABOVE Statin Placebo

(10,269) (10,267) 914 1234 456 613 926 1185 2042 2606

(19.9%) (25.4%)RiskRatioand95%ClStatinbetterStatinworse0.40.60.81.01.21.424%SE2.6

reduction

(2p<0.00001)Simvastatin:MajorVascularEventsNo.EventsBaseline

FeatureLDL(mg/dL)<100(2.6mmol/L)≥100<130≥130(3.4mmol/L)ALLPATIENTS Statin Placebo

(10,269) (10,267) 285 360 670 881 1087 1365 2042 2606

(19.9%) (25.4%)0.40.60.81.01.21.424%SE2.6

reduction

(2p<0.00001)Simvastatin:VascularEvents

byBaselineLDL-CHet=0.82RiskRatioand95%ClStatinbetterStatinworseNo.EventsPSever(Co-chair),BDahl?f(Co-chair),NPoulter(Secretary),HWedel(Statistician),GBeevers,MCaulfield,RCollins,SEKjeldsen,AKristinsson,JMehlsen,GMcInnes,MNieminen,EO’Brien,J?stergrenOnbehalfoftheASCOTInvestigatorsASCOTStudyDesignSeverPS,etal,JHypertens.2001;19:1139-1147R9000-blocker±diuretic9000CCB±

ACEI5000TC6.5mmol/L(250mg/dL)4000TC>6.5mmol/L(>250mg/dL)4000TC>6.5mmol/L(>250mg/dL)5000TC6.5mmol/L(250mg/dL)R500openlipidlowering45002250statin2250placebo2250placebo2250statinR4500500openlipidlowering+8000openlipidlowering18,000hypertensivesR=RandomizedLipid-LoweringArm(LLA)

PrimaryObjective

Tocomparetheeffectsofatorvastatin10mgandplacebooncardiacdeath+nonfatalMIinhypertensivepatientswithtotalcholesterollevelsof6.5mmol/L(250mg/dL)SeverPS,etal,Lancet2003;361:1149PatientPopulation:LLAEligibilitycriteriaSBP160mmHgand/orDBP100mmHg(untreated)orSBP140mmHgand/or

DBP90mmHg(treated)TC6.5mmol/L(250mg/dL)andTGs<4.5mmol/L(400mg/dL)40-79yearsofage3+CVDriskfactorsNohistoryofCHDSeverPS,etal,Lancet2003;361:1149ReductionsinTotalandLDLCholesterol20015015075125100100(mg/dL)(mg/dL)Totalcholesterol(mmol/L)LDLcholesterol(mmol/L)Years50mg/dL42mg/dL46mg/dL39mg/dLSeverPSetal,Lancet2003;361:114936%reductionPrimaryEndPoint:NonfatalMI

andFatalCHDHR=0.64(0.50-0.83)Atorvastatin10mg Numberofevents 100Placebo Numberofevents 154p=0.0005SeverPS,etal,Lancet2003;361:1149SecondaryEndPoint:Fatal

andNonfatalStroke27%reductionHR=0.73(0.56-0.96)p=0.0235Atorvastatin10mg Numberofevents 89Placebo Numberofevents 121SeverPS,etal,Lancet2003;361:1149PrimaryPreventionStatinTrials:

LDL-CLevelsvsEventsPercentagewithCHDeventPrimarypreventionPravastatinLovastatinAtorvastatin105.4(210)2.3(90)2.8(110)3.4(130)3.9(150)4.4(170)4.9(190)WOSCOPS-SWOSCOPS-P05AFCAPS-SAFCAPS-P98764321ASCOT-PASCOT-SLDL-C,mmol/L(mg/dL)S=statintreated;P=placebotreated“Itisn’twhereyoucomefrom,it’swhereyou’regoingthatcounts”

EllaFitzgeraldIn1986Ellaunderwentquintuplecoronarybypasssurgery,andwasdiagnosedashavingdiabetes,whichaccountedforherfailingvision.By1991shehadrecordedover200albumsandgaveher26thandfinalconcertatCarnegieHall.Shedevelopedseverecirculatoryproblemsduetoherdiabetes,requiringbelowthekneeamputationsofbothlegs.Sheneverfullyrecovered,anddiedatage79in1996.Baseline

FeaturePreviousMIOtherCHD(notMI)NopriorCHDCVDPVD

DiabetesALLPATIENTS Statin Placebo

(10,269) (10,267) 1007 1255 452 597 182 215 332 427 279 369 2042 2606

(19.9%) (25.4%)RiskRatioand95%ClStatinbetterStatinworse0.40.60.81.01.21.424%SE2.6

reduction

(2p<0.00001)Simvastatin:VascularEvents

byPriorDiseaseNo.EventsCollaborativeAtorvastatinDiabetesStudy(CARDS)Aim:Toevaluatetheeffectivenessandsafetyofatorvastatin10mgdailyversusplacebointheprimarypreventionofcardiovasculardisease(CADandstroke)inpatientswithtype2diabeteswithoutraisedcholesterollevelsCARDSEligibilityCriteriaType2diabetes40-75yearsofageNoclinicalhistoryofcoronary,cerebrovascularorsevereperipheralvasculardiseaseLDL-C4.14mmol/L(160mg/dL)TG6.78mmol/L(600mg/dL)Oneof:HypertensiondefinedasreceivingantihypertensivetreatmentorSBP140mmHgorDBP90mmHgRetinopathyMicroalbuminuriaormacroalbuminuriaCurrentsmoking132CentresinUKandIreland4053patientsscreened2838(70%)randomizedCARDS:BaselineClinicalFeaturesPlaceboAtorvastatinAge(years)61.861.5Women32%32%Hypertension84%84%Currentsmoking23%22%BMI28.828.7Diabetesduration(years)7.87.9oraltreatmentonly65%65%insulinonly15%15%dietonly16%15%HbA1C(%)7.87.9retinopathy30%30%

LipidLevelsbyTreatment

Totalcholesterol(mmol/L)LDLcholesterol(mmol/L)023414.523414.5YearsofStudyYearsofStudy0012340246PlaceboAtorvastatinAveragedifference26%1.4mmol/L(54mg/dL)p<0.0001Averagedifference40%1.2mmol/L(46mg/dL)p<0.0001CumulativeHazardforPrimaryEndpointRelativeRiskReduction37%(95%CI:17-52)Years328305694651107410221361130613921351AtorvaPlacebo14281410Placebo127eventsAtorvastatin83eventsCumulativeHazard(%)051015012344.75P=0.001Subgroup*Placebo**Atorva**HazardRatioRiskReduction(CI)LDL-C≥3.06(120)66(9.5)44(6.1)38%(9-58)LDL-C<3.06(120)61(8.5)39(5.6)37%(6-58)p=0.96HDL-C≥1.35(54)62(8.4)36(5.2)41%(11-61)HDL-C<1.35(54)65(9.6)47(6.4)35%(5-55)p=0.71Trig.≥1.7(150)67(9.6)40(5.5)44%(18-62)Trig.<1.7(150)60(8.4)43(6.1)29%(-5-52)

p=0.40*unitsinmmol/L(mg/dL)**N(%ofrandomised)TreatmentEffectonthePrimary

EndpointbySubgroup.2.4.6.811.2FavoursAtorvastatin

FavoursPlaceboBigStatinsAreBetter

ThanLittleStatinshypertension:ASCOTversusALLHATelderly:HPSversusPROSPERsurrogateendpoints:

ASAP,ARBITER,REVERSALACS:MIRACLversusPACTandFLORIDAhead-to-head:PROVE-IT,(TNT,SEARCH,IDEAL)ComparativeStatinTrialsinHypertensionBigStatinLittleStatinNameoftrialASCOT-LLAALLHAT-LLTNumberofPatients10,305(high-risk)10,355(high-risk)DrugandDoseatorvastatin10mgpravastatin40mgComparatorplacebousualcareDuration(years)3.3(stoppedearly)4.8Primaryendpointcardiacdeath/nonfatalMI:36%(p=0.0005)all-causemortality:noeffect(RR=0.99)Otheroutcomes27%instroke(p=0.0235)9%infatalCHD+nonfatalMI(p=ns)ReferenceLancet2003;361:1149JAMA2002;288:2998ImagescourtesyofStevenE.NissenMD,

IntravascularUltrasoundLaboratory,ClevelandClinicIntracoronaryUltrasoundRevealsLesionsThatAreNotVisibleByCoronaryAngiographyDistalFiduciarySiteProximalFiduciary

SiteProximal

FiduciarySiteIVUSComputationofAtheromaVolumeDistalFiduciarySiteNissenSEetal.JAMA2004;291:1071-1080Lumen

AreaEEMAreaAtheromaAreaUltrasoundMeasurementofAtheromaAreaPreciseManualPlanimetryofEEMandLumenBordersReversalofAtherosclerosiswithLipitor(REVERSAL)Study654patientswithangiographicCAD(>20%stenosis)from34sitesrandomizedto18monthsoftreatmentwithatorvastatin80mg/dayorpravastatin40mg/dayintracoronaryultrasoundof30mmsegmentatbaselineandendofstudyprimaryendpointmeasureispercentchangeintotalplaquevolumeforallslicesofanatomicallycomparablesegmentsofthetargetcoronaryarteryNissenSEetal,JAMA2004;291:1071REVERSALPravaAtorva25%46%LDLReductionCRPReductionPravaAtorva5%36%p<0.0001p<0.0001PravaAtorvaChangeinAtheroVolume2.7%-0.4%p=0.02NissenSEetal,JAMA2004;291:1071Low-DensityLipoproteinCholesterolReductionandChangeinAtheromaVolumeMeanchangeusinglinearregressionanalysis.95%confidencelimitsformeanvalues.Nissenetal.JAMA2004;291:1071.%Changeinlow-densitylipoproteincholesterolPravastatingroup(N=249)Atorvastatingroup(N=253)52015100–5–10–15–80–70–60–50–40–30–20–1001020–80–70–60–50–40–30–20–100102052015100–5–10–15Changeinatheroma

volume,mm3PROVEIT:PRavastatin

OrAtorVastatin

EvaluationandInfectionTherapy(TIMI22)4,162ptshospitalizedwithACSwithin10daystotalcholesterol<240mg/dl(<200mg/dliftreated)randomizedtopravastatin40mg/dayoratorvastatin80mg/daymeanfollow-up24monthsprimaryendpoint=compositeofall-causemortality,MI,unstableanginarequiringhospitalization,stroke,andrevascularization(>30daysafterACSevent)studydesignedtoestablishthe“non-inferiority”ofpravacomparedtoatorvawithrespecttotimetoanendpointeventCannonCPetal,NEJM2004;350.PROVE-IT:ChangesinLDL-CholesterolNote:ChangesinLDL-Cmaydifferfrompriortrials:25%ofpatientsonstatinspriortoACSeventACSresponselowersLDL-CfromtruebaselineLDL-C(mg/dL)20406080100120Rand.30Days4Mos.8Mos.16Mos.FinalPravastatin40mgAtorvastatin80mg49%21%P<0.001MedianLDL-C(Q1,Q3)

95mg/dL(79,113)62mg/dL(50,79)<24hCannonCPetalNEJM2004;350:1495PROVE-IT:PrimaryEndpoint031821242730691215%withEventMonthsofFollow-upPravastatin40mg(26.3%)Atorvastatin80mg(22.4%)16%RRR(p=0.005)302520151050CannonCP,etalNEJM2004;350:1495PROVE-IT:MajorCardiovascularEndpoints

2YearEventRatesRRRAtorva80

Prava40 28% 2.2% 3.2% 30% 1.1% 1.4%13