IntegratingAggressiveCVRiskManagementinPrimaryCareHighprevalenceofmultipleCVriskfactors

inUSadultsCDC.MMWR.2005;54:113-40.BehavioralRiskFactorSurveillanceSystem,2003≥2ofhypertension,hypercholesterolemia,diabetes,smoking,physicalinactivity,obesity40.0%–46.2%36.0%–39.9%33.0%–35.9%27.0%–32.9%INTERHEART:ExponentialriseinCVdiseasewithaddedriskfactorsOdds

ratiofor

1stMI*

(99%CI)6451216122561283284Smk

(1)DM

(2)HTN

(3)ApoB/

A1ratio

(4)1+2+3All4All4

+ObesAll4

+PsAll9risk

factors3.313.042.368.5182.9333.7YusufSetal.Lancet.2004;364:937-52.Smk=smoking;DM=diabetes;HTN=hypertension;

Obes=obesity;Ps=psychosocialfactors*Plottedonadoublingscale3-fold26-foldINTERHEART:AnysmokingincreasesCVriskTeoKKetal.Lancet.2006;368:647-58.*vsneversmokedN=27,098from52countries1–23–45–67–89–1011–1213–1415–1617–1819–20OddsratioforfirstMI*Cigarettessmoked(n/day)Never≥21-0.751248LifetimeCVDriskestimateandrisk

factorburden70605040302010050607080906950463656050403020100Men

(n=3564)Women(n=4362)AdjustedcumulativeincidenceofCVD

(%)5060708090≥2MajorRFs1MajorRF≥1ElevatedRF≥1NotoptimalRFAlloptimalRFs705039278Attainedage(years)Lloyd-JonesDMetal.Circulation.2006;113:791-8.2-foldinhigheragegroupAdditiveriskofagewithhypertension+hypercholesterolemiaWongNDetal.AmJCardiol.2006;98:204-8.

NHANES2001-2002;N=286426.552.743.121.4ClinicalmanifestationsofobesityInsulin

resistanceGlucotoxicityLipotoxicityAdiponectinLeptinAtherosclerosisCourtesyofSelwynAP,WeissmanPN.2006.Type2diabetesand

glycemicdisordersFFAsDyslipidemiaLowHDLSmall,denseLDLHypertriglyceridemiaHypertensionEndothelialdysfunction/

inflammation(hsCRP)Impairedthrombolysis

PAI-1MetabolicconsequencesofvisceralobesityVisceral/abdominalobesityCorrelatesmorestronglywithinsulinresistancethanlowerbodyobesityIsassociatedwithplasmalevelsoffattyacidsandaccompanyingTG Insulinresistance Alteredhepaticfataccumulationandmetabolism Dyslipidemia Proinflammatoryadipokines(insulinresistance,riskforCVdisease)VisceralfatcorrelatesmorestronglywithinsulinresistancethansubcutaneousfatGrundySMetal.Circulation.2005;112:2735-52.DesprésJ-Petal.BMJ.2001;322:716-20.VisceralobesityinCVriskCTscansfrommenmatchedforBMIandtotalbodyfatWhite=visceralfatarea(VFA);black=subcutaneousfatDesprésJ-P.EurHeartJSuppl.2006;8(supplB):B4-12.SubcutaneousobesityFatmass:19.8kgVFA:96cm2Visceralobesity

Fatmass:19.8kgVFA:155cm2Visceralobesity

drivesCVriskprogressionindependentofBMIMeasurementofwaistcircumferencemayofferamoreuseful

surrogatemarkerofvisceraladipositythanwaist-hipratioOptimalmarker(s)forvisceraladiposityDesprésJPetal.BMJ.2001;322:716-720.MeasuringwaistcircumferenceIliaccrestCDCProjections––2005to2050:DiabetesfocusNarayanKMVetal.DiabetesCare.2006;29:2114-6.*Revisedprojection““appearsmorealarmingthanpreviouslyestimated”32.1millionnewdiabetespatientsby2050*174%220%470%423%606%inblacks≥≥75yr20502005Individualswithdiabetes(millions)Diabetes

2005-2050(%)Multipleriskfactors:UndertreatedandpoorlycontrolledWongNDetal.AmJCardiol.2006;98:204-8.NHANES2001-2002;n=638withhypertensionandhypercholesterolemiaSuddencardiacdeath:Toooftenthefirstsign

ofCVdiseaseFoxCSetal.Circulation.2004;110:522-7.50%ofsuddencardiacdeathsoccurinpersonswithnoCVdiseasehistoryCalltoactionIdentifyall

riskfactorsBasetreatmentonglobalriskassessmentTreatmultipleriskfactorsaggressivelyCVeventsABCsofmultipleriskfactormanagementAAspirin

ACEinhibition

A1CcontrolBBPcontrol

-blockadeCCholesterolmanagementControlweightDDietDon’tsmokeEExercisePlateletactivationandaggregationHypertensionHyperglycemia/InsulinresistanceDyslipidemiaAdaptedfromCohenJD.Lancet.2001;357:972-3.BeckmanJAetal.JAMA.2002;287:2570-81.AHAdietandlifestylerecommendationsHealthydietFruits,vegetables,legumes,wholegrains,non-fat/low-fatdairy,fish,poultry,limitedalcoholintakePhysicalactivity≥30minonmostdaysNosmokingAvoiduseofandexposure

totobaccoproductsLichtensteinAHetal.Circulation.2006;114:82-96.CVriskWeightlossimprovesCVriskfactorsSj?str?mLetal.NEnglJMed.2004;351:2683-93.Conventionaltreatment(n=1660)Gastricsurgery(n=1845)*At2yearsN=4047withobesity3-Weekdiet+exerciseregimenyieldsfavorablemetabolicchanges*P<0.01?P<0.05RobertsCK.etal.JApplPhysiol.2006;100:1657-65.μU/mLN=31overweight/obesemen;weight8.4lbsBaselineFollow-upPhysicalactivityreducesCVandall-causemortalityFangJetal.AmJHypertens.2005;18:751-8.N=9791;moderatephysicalactivityvslittleornophysicalactivity0.75(0.53–1.05)0.76(0.39–1.49)0.79(0.65–0.97)All-causedeathCVdeathAll-causedeathPrehypertensionCVdeathHypertensionHazardratio1.51.00.5NormalBP02.0All-causedeathCVdeath0.79(0.58–1.09)0.88(0.80–0.98)0.84(0.73–0.97)AdjustedHR(95%CI)Favors

exerciseFavors

noexerciseNHANES1EpidemiologicalFollow-upSurvey(1971–1992)DietaryprogramscanbeeffectiveyetdifficulttomaintainDansingerMLetal.JAMA.2005;293:43-53.N=160overweightorobesewith≥≥1CVriskfactorEmergingstrategiesinweightcontrolLifestyleinterventionsmustincludebothdietandexerciseEvenmoderateweightloss(5%–10%)can:DecreasecardiometabolicriskfactorsEncouragecontinuedhealth-promotingbehaviorsandadherencetomedicaltherapyNovelapproachestodecreasingcardiometabolicriskfactorsareneededEckelRHetal.Circulation.2006;113:2943-6.GelfandEV,CannonCP.JAmCollCardiol.2006;47:1919-26.GoalsforoptimalhealthAACE.EndocrPract.2002;8(suppl1):40-82.LifestyleinterventionDietPhysicalactivitySmokingcessationWeightcontrolAggressivemanagement

ofcomorbidconditions*LipidmodifyingBPloweringASAforprevention

ofvascularevents*Dyslipidemia,hypertension,earlyrenaldiseaseIntensiveglycemiccontrolA1C≤6.5%Glucose(mg/dL)Preprandial≤110Postprandial≤140Steno-2:RationaleforTarget-DrivenBehaviorModificationandPolypharmacySteno-2:GoalsofintensivepharmacologicstrategyTherapyGoalACEinhibitorsAllpatients(ARBs,ifcontraindicated)AspirinAllpatients(150mg/d)BPcontrol<130/80mmHgLipidcontrolTotal-C<175mg/dLTriglycerides<150mg/dLGlucosecontrolA1C<6.5%G?dePetal.NEnglJMed.2003;348:383-93.Steno-2results:BettercontrolwithintensivetherapyG?dePetal.NEnglJMed.2003;348:383-93.Conventionaltherapy(n=80)Intensivetherapy(n=80)Follow-up(years)Follow-up(years)0123456785015025035000123456781101301501700SBP(mmHg)P<0.001Total-C(mg/dL)P<0.001012345678501502503500AlC(%)P<0.001TG(mg/dL)P=0.015012345678579110Steno-2:MultifactorialinterventionimprovesmacrovascularoutcomesG?dePetal.NEnglJMed.2003;348:383-93.*CVdeath,MI,stroke,revascularization,amputation,PADsurgery;?UnadjustedPrimarycompositeoutcome*(%)Follow-up(months)6050403020100ConventionalIntensive01224364860728496NNT=5

Absoluteriskreduction=20%53%RRR?

P=0.01N=160withtype2diabetesandmicroalbuminuriaSteno-2:IntensiveinterventionimprovesvascularandneuropathicoutcomesG?dePetal.NEnglJMed.2003;348:383-93.0.01.02.0NephropathyRetinopathyAutonomic

neuropathyPeripheral

neuropathyVariableRRPIntensivebetterConventionalbetter0.390.420.371.090.0030.020.0020.66Riskofmicrovascularcomplicationsafter4yearswasmaintainedat8yearsRelativerisk3.0IntegratingAntihypertensiveAgentsinCVRiskReductionRelationofBPtoCVdiseaseiscontinuousMeta-analysisof61observationalstudies;N=958,074ProspectiveStudiesCollaboration.Lancet.2002;360:1903-13.120140160180UsualSBP(mmHg)UsualDBP(mmHg)709010011080SystolicBPDiastolicBPAgeatrisk(y):80–8970–7960–6950–5940–49Ageatrisk(y):80–8970–7960–6950–5940–492561286432168421025612864321684210IHDmortality

(floatingabsoluterisk)**PlottedonadoublingscaleBPLTTC:Comparisonofmore-vsless-intensiveBPloweringEvents/participantsby

BP-loweringstrategyMoreintensiveLessintensiveStroke140/7494261/13,394CHD274/7494348/13,394Major

CVevents482/8034719/13,948BloodPressureLoweringTreatmentTrialists’Collaboration.Lancet.2003;362:1527-35.Meta-analysisof4trials;1998-2002;N=162,3410.61.01.4RelativeriskFavorsmoreintensiveFavorslessintensiveASCOT-BPLA:RationalePremiseMultipleriskfactorsmarkedlyincreaseCVdiseaseseverityStandardBP-loweringtherapies(diureticsandβ-blockers)havenotbeenproventopreventCHDeventsASCOT-BPLAcomparednewervsolderantihypertensiveregimensinpatientswith≥≥3riskfactorsHypothesisNewer,aggressivecombinationBP-loweringagentswillpreventmoreCVeventsBPLTTC.ArchInternMed.2005;165:1410-9.

Dahl??fBetal.Lancet.2005;366:895-906.Anglo-ScandinavianCardiacOutcomesTrial-BloodPressureLoweringArmASCOT-BPLA:Comparisonofoldervsnewertherapy*PlusKsupplementifneededBP≥≥160/100mmHg(untreated)orBP≥≥140/90mmHg(treated)+≥3otherriskfactorsN=19,257Amlodipine5––10mg±perindopril4––8mgAtenolol50–100mg±bendroflumethiazide1.25–2.5mg*Primaryoutcome:NonfatalMIandfatalCHDFollow-up:5.5yearsRandomized

Double-blindDahl?fBetal.Lancet.2005;366:895-906.ASCOTpatientprofileSeverPSetal.JHypertens.2001;19:1139-47.SeverPSetal.Lancet.2003;361:1149-58.Patientswithriskfactor(%)0102030405060708090100HypertensionAged≥55yearsMaleMicroalbuminuria/proteinuriaSmokerFamilyhistoryofCHDPlasmaTC:HDL-C≥6Type2diabetesECGabnormalitiesLVHPriorcerebrovasculareventsPeripheralvasculardiseaseASCOT-BPLA:BPreductionsovertimeBloodpressure(mmHg)Atenolol50–100mg±±bendroflumethiazide1.25–2.5mg/potassiumAmlodipine5––10mg±±perindopril4–8mgDahl?fBetal.Lancet.2005;366:895-906.Time(years)1.02.03.04.05.00BPMeandifference=1.9,P<0.000160100080120140160180Meandifference=2.7,P<0.0001DiastolicBP137.7136.179.277.4SystolicBPASCOT-BPLA:ReductioninprimaryoutcomeProportion

ofevents(%)62401234810560Time(years)10%RRRHR0.90(0.79–1.02)P=0.1052Atenolol50–100mg±±bendroflumethiazide1.25––2.5mg/potassiumAmlodipine5––10mg±±perindopril4–8mgDahl?fBetal.Lancet.2005;366:895-906.NonfatalMIandfatalCHDASCOT-BPLA:Additionalreductionswithamlodipine-basedregimenDahl?fBetal.Lancet.2005;366:895-906.SecondaryendpointsNonfatalMI(excludingsilent)7.48.5+fatalCHDTotalcoronaryendpoint14.616.8TotalCVeventsandprocedures27.432.8All-causemortality13.915.5CVmortality 4.96.5Fatal/nonfatalstroke 6.2 8.1Fatal/nonfatalHF 2.53.0TertiaryendpointsDevelopmentofdiabetes11.015.9Developmentofrenalimpairment 7.7 9.1Rate/1000patient-yearsAmlodipine-based

(n=9639)Atenolol-based(n=9618)Amlodipine-

basedbetterAtenolol-basedbetter0.500.701.001.452.00UnadjustedhazardratioP<0.05<0.01<0.0001<0.050.001<0.001NS<0.0001<0.05CAFE:LowercentralaorticBPwithnewervsolderantihypertensiveregimenAtenolol±bendroflumethiazideAmlodipine±±perindopril140135130125120000.51.01.52.02.53.03.54.04.55.05.56.0Time(years)mmHgBrachialSBPCentralaorticSBPCAFEInvestigators.Circulation.2006;113:1213-25.SimilareffectsonbrachialBPCAFE:SummarySubstantialandconsistentdifferencesincentralaorticBPandhemodynamicswithamlodipine±perindoprilvsatenolol±bendroflumethiazide,despitesimilarbrachialsystolicBPeffectsCentralaorticsystolicBPandpulsepressuredifferencesmayexplainASCOT-BPLAoutcomesCentralaorticpulsepressuremaybeadeterminantofCVoutcomesCAFEInvestigators.Circulation.2006;113:1213-25.BeyondBPReduction:IntegratingRAASModulationinVascularProtectionHOPEStudyInvestigators.NEnglJMed.2000.EUROPAInvestigators.Lancet.2003.PEACETrialInvestigators.NEnglJMed.2004.Vascularprotection:FocusonACEinhibitionStudyACEinhibitorKeyinclusioncriteriaPrimaryoutcomeHOPE N=9297 (4.5years)Ramipril10mgVasculardisease*

(80%hadCAD)LVEF≥40%NoheartfailureAge≥55yearsCVdeath,

MI,strokeEUROPA N=12,218

(4.2years)Perindopril8mgCHDNoheartfailureAge≥18yearsCVdeath,MI,cardiacarrestPEACE N=8290 (4.8years)

Trandolapril4mgCADLVEF>40%Age≥50yearsCVdeath,MI,coronaryrevascularization*ordiabetes+≥≥1CVriskfactorLVEF=leftventricularejectionfractionHOPEStudyInvestigators.NEnglJMed.2000.EUROPAInvestigators.Lancet.2003.PEACETrialInvestigators.NEnglJMed.2004.HOPE,EUROPA,PEACE:ConcomitantCVtherapiesatbaselineHOPEEUROPAPEACEAntiplateletagents(%)769291-blockers(%)406260Lipid-loweringagents(%)295870Calciumchannelblockers(%)473136Diuretics(%)15913HOPEStudyInvestigators.NEnglJMed.2000.EUROPAInvestigators.Lancet.2003.PEACETrialInvestigators.NEnglJMed.2004.HOPE,EUROPA,PEACE:PrimaryoutcomesHOPEPatients(%)Placebo22%RRP<0.001155100200Ramipril10mg2413Time(years)PEACEPlaceboTrandolapril4mg3020101551234525064%RRP=0.43EUROPA124100134140PlaceboPerindopril

8mg8625220%RRP=0.0003RR=riskreductionHOPE,EUROPA,PEACE:Reductioninall-causemortalityEvents(%)ACEIPlaceboHOPE10.412.2EUROPA6.16.9PEACE7.28.1Total7.88.9FavorsACEIFavorsplaceboOddsratio(95%CI)DagenaisGRetal.Lancet.2006;368:581-1.4HOPE,EUROPA:BenefitconsistentacrossancillarytherapyAdaptedfromDagenaisGRetal.Lancet.2006;368:581-0.50.9Oddsratio(95%CI)Antiplatelets

NoantiplateletsLipid-loweringagents

Nolipid-loweringagents-blockersNo-blockersRevascularization

NorevascularizationSubgroupPatients(n)4-year

ratesin

placebogroups0.0030.6510.1390.078PInteraction18,331

3184948912,02611,323

10,19210,394

11,12313.217.910.616.413.414.311.516.0ACEIbetterACEIworseCVdeath,nonfatalMI,orstrokeHOPE,EUROPA,PEACE:BenefitofACEIsacrossbroadspectrumofriskDagenaisGRetal.Lancet.2006;368:581-8.TrialPatients

(n)Annualratesin

placebogroupsOR

(95%CI)P-520405301535Oddsreduction(%)25100PEACE82902.137(-8to19)0.328HOPEtotal92973.9525(16to32)0.0001HOPElowerrisk30832.1718(-4to35)HOPEmedrisk31003.5820(3to33)HOPEhighrisk31145.9824(12to34)EUROPAtotal12,2182.6019(8to28)0.0007EUROPAlowerrisk39761.4019(-5to38)EUROPAmedrisk39752.4128(11to41)EUROPAhighrisk39754.0010(-4to22)AIRE198622.624(7to38)0.0068TRACE174917.025(9to33)0.0028SOLVD-P42287.415(2to27)0.0252SOLVD-T256913.123(10to33)0.0009SAVE22319.820(4to33)0.0168CVdeath,*nonfatalMIorstrokeACEIworseACEIbetter*OrtotalmortalityinAIRE,TRACE,SOLVD,SAVEtrialsACEIsvsARBs:Comparativeeffectonstroke,HF,andCHDTurnbullF.15thEuropeanMeetingonHypertension.2005.AdaptedbyStraussMH,HallAS.Circulation.2006;114:838-54.CHD=MIandCVdeathBloodPressureLoweringTreatmentTrialists’Collaborationmeta-analysis

N=137,356;21randomizedclinicaltrialsACEIARBStroke-1%(9%to-10%)HF10%(10%to0%)CHD9%(14%to3%)Stroke2%(33%to-3%)HF16%(36%to-5%)CHD-7%(7%to-24%)30%030%DecreaseIncreaseStroke

P=0.6HFP=0.4CHDP=0.001RiskRRRACEIsinvasculardisease:ConclusionsACEIsreducemortality,MI,HF,andstrokeinpatientswithvasculardiseasewith/withoutLVSDorHFBenefitinadditiontoantiplateletagents,β-blockers,andlipid-loweringagentsCombiningACEIswiththeseagentsprovidesgreatestbenefitBenefitinpatientsacrossabroadrangeofriskforCVeventsAnnualrateinplacebogroupsof1.4%––22.6%DagenaisGRetal.Lancet.2006;368:581-8.FoxKetal.EurHeartJ.2006;27:2154-7.ConsiderACEIsinallpatientswithvasculardiseaseAssessrisk/benefitsandtolerabilityUsedosesproveninclinicaltrialsIntegratingStatinsinCVRiskReductionStatinsreduceall-causedeathCTTCollaborators.Lancet.2005;366:1267-78.CholesterolTreatmentTrialists’’Collaboration;N=90,056Causeofdeath3.40.810.910.950.93Vascularcauses:StrokeOthervascularAnyvascularAnynon-CHDvascularNonvascularcauses:CancerRespiratory0.831.010.820.890.870.950.88TraumaOther/unknownAnynonvascularAnydeathEvents(%)TreatmentbetterControlbetter1.51.00.5CHDRelativeriskTreatment(n=45,054)Control(n=45,002)Meta-analysisof14trialsHPS:Assessingstatinbenefitinhigh-riskpatientsHPSCollaborativeGroup.Lancet.2002;360:7-22.HeartProtectionStudyTotal-C135mg/dLanddiabetes,CAD,stroke,PAD,ortreatedhypertension(ifmale,aged≥≥65years)N=20,536Simvastatin40mgFollow-up:5yearsPrimaryoutcomes:Mortality(overallanalysis)Fatal/nonfatalvascularevents(subcategoryanalysis)PlaceboRandomized

Open-label

BlindedoutcomeHPS:StatinsconferbenefitindependentofbaselineLDL-C358(21.0%)282(16.4%)<100871(24.7%)668(18.9%)100to<1302585(25.2%)2033(19.8%)Allpatients1356(26.9%)1083(21.6%)≥130Placebon(%)Statinn(%)BaselineLDL-C(mg/dL)StatinbetterPlacebobetter1.01.21.424%reduction2P<0.00001Rateratio(95%CI)PatientswithmultipleriskfactorsmaydevelopCVdiseaseatLDL-Clevels<100mg/dLN=20,536;Fatal/nonfatalvasculareventsASCOT-LLA:RationalePremiseHighprevalenceofdyslipidemiainhypertensivepatientsMostCVdiseaseeventsoccurinpatientswithBPandlipidconcentrationsdeemednormalHypothesisLipidloweringwillbenefithypertensivepatientsnotconventionallydeemeddyslipidemicSeverPSetal.Lancet.2003;361:1149-58.Anglo-ScandinavianCardiacOutcomesTrial-LipidLoweringArmASCOT-LLA:DesignDahl??fBetal.Lancet.2005;366:895-906.

SeverPSetal.Lancet.2003;361:1149-58.*PlusKsupplementifneededBP≥160/100mmHg(untreated)orBP≥≥140/90mmHg(treated)+≥3otherriskfactorsN=19,257Amlodipine5––10mg±perindopril4–8mgAtenolol50–100mg±bendroflumethiazide1.25–2.5mg*Total-C≤≤250mg/dL

n=10,305Atorvastatin10mgPlaceboRandomized

Double-blindASCOT-LLA:StatinreducesprimaryoutcomeinhypertensionSeverPSetal.Lancet.2003;361:1149-58.MeanbaselineLDL-C133mg/dLNonfatalMIandfatalCHDPatients(%)Placebo001234Atorvastatin1.01.53.03.52.02.50.5Follow-up(years)36%RRRHR0.64(0.50–0.83)P=0.0005n=10,305*Per1000patient-yearsCensoringtimeHazardratioRRR(%)Eventrate*AtorvastatinPlacebo30days90days180days1year2yearsEndofstudy83 2.4 14.267 5.5 16.648 7.5 14.345 6.6 12.038 5.9 9.536 6.0 9.400.51.01.52.0AtorvastatinbetterPlacebobetterSeverPSetal.AmJCardiol.2005;96(suppl):39F-44F.ASCOT-LLAposthocanalysis:Timetobenefitn=10,305ASCOT:IntegrationofantihypertensiveregimenswithstatinCumulative

incidence(%)4.03.002.01.001.02.03.03.54.03.002.01.001.02.03.03.5PlaceboAtorvastatinPrimaryendpoint:NonfatalMIandfatalCHDYearsHR0.47(0.32–0.69)P=0.00153%16%HR0.84(0.60–1.17)P=0.30Amlodipine5––10mg±±perindopril4–8mgAtenolol50–100mg

±bendroflumethiazide1.25–2.5mg/KASCOT:TotalCVeventsandprocedures12.010.008.04.001.02.03.03.501.02.03.03.52.06.012.010.008.04.02.06.0HR0.73(0.60–0.88)P=0.00127%15%HR0.85(0.71–1.02)P=0.08Cumulative

incidence(%)PlaceboAtorvastatinYearsAmlodipine5––10mg±±perindopril4–8mgAtenolol50–100mg±±bendroflumethiazide1.25––2.5mg/KHPS,ASCOT:SummaryandimplicationsStatinsreducedCVeventsinmoderate-tohigh-riskpatientswith““normal”LDL-CGlobalCVrisk,notabsoluteLDL-Clevel,determinesneedforstatintherapyOcclusivevasculardiseaseHypertensionplus≥≥3otherriskfactorsHPSCollaborativeGroup.Lancet.2003.

SeverPSetal.Circulation.2005.

SeverPSetal.AHAScientificSessions.Nov2005.Extendingthescopeofaggressivelipid-lowering:TNTandIDEALStudyTreatmentsPatientsPrimaryoutcomeTNT

N=10,001

(4.9years)Atorvastatin10mgAtorvastatin80mgStableCHDandLDL-C152mg/LCVdeath,MI,resuscitatedcardiacarrest,fatal/nonfatalstrokeIDEAL

N=8888

(4.8years)Simvastatin20mgAtorvastatin80mgPost-MIand

LDL-C122mg/dLCVdeath,nonfatalMI,resuscitatedcardiacarrestLaRosaJCetal.NEnglJMed.2005;352:1425-35.

PedersenTRetal.JAMA.2005;294:2437-45.TNT:TreatingtoNewTargetsIDEAL:IncrementalDecreaseinEndPointsThroughAggressiveLipidLoweringOn-treatmentLDL-C(mg/dL)High-dosestatinStandard-dosestatinPTNT77101<0.001IDEAL811040.07BenefitsofaggressiveLDL-CloweringinstableCADLaRosaJCetal.NEnglJMed.2005;352:1425-35.

PedersenTRetal.JAMA.2005;294:2437-45.Reductioninprimaryendpoint0.6511.35HazardratioFavorshighdoseFavorsstandarddose003.300.130.040.40.360.840.060.040070.05000.161.37RhabdomyolysisCK>10×ULNASTand/orALT

>3×ULNTrialStandarddose(%)Highdose(%)Standarddose(%)Highdose(%)Standarddose(%)Highdose(%)PROVEIT-TIMI22(n=4,162)AtoZ(n=4,497)TNT(n=10,001)IDEAL(n=8,888)Lowincidenceofsevereadverseeventswithhigh-dosestatinCannonCPetal.JAmCollCardiol.2006;48:438-45.IntegratingAggressiveMedicalTherapyinDiabetesAggressivemedicaltherapyindiabetesAdaptedfromBeckmanJAetal.JAMA.2002;287:2570-81.AtherosclerosisMetforminTZDsSulfonylureas

NonsulfonylureasecretagoguesIncretinsInsulinStatins

FibricacidderivativesACEinhibitorsARBsβ-blockers

CCBsDiureticsASAClopidogrelTiclopidineHyperglycemia/InsulinresistanceDyslipidemiaHypertensionPlateletactivation

andaggregationHOPEStudyInvestigators.Lancet.2000;355:253-9.DalyCAetal.EurHeartJ.2005;26:1369-78.012345Follow-up(years)(N=1502)CVdeath/MI/cardiacarrest(N=3577)CVdeath/MI/strokeMICRO-HOPE,PERSUADE:ACEIsreduceprimaryoutcome012345MICRO-HOPEPERSUADEPlaceboRamipril10mg2520151050%25%RRR

P=0.0004201612840PlaceboPerindopril8mg19%RRR

P=0.131PrimaryoutcomeTotalmortalityCVmortalityAllMIStroke0.81.01.8FavorsACEIFavorsplaceboRelativerisk(95%CI)MICRO-HOPE(N=3577)PERSUADE(N=1502)MICRO-HOPE,PERSUADE:RelativeriskreductionsindiabetesHOPEStudyInvestigators.Lancet.2000;355:253-9.DalyCAetal.EurHeartJ.2005;26:1369-78.HOPEStudyInvestigators.Lancet.2000;355:253-9.3.02.01.0001234.5PlaceboRamipril10mgMeanalbumin/creatinineratioYears0-10-20-30-40Overtnephro-pathyCVdeathStrokeMIRelativeriskreduction(%)P=0.027P=0.0001P=0.007P=0.01N=3577(32%withmicroalbuminuria)MICRO-HOPE:ACEIimprovesrenalandCVoutcomesindiabetesPvalues:ACEIvsplaceboP=0.02P=0.001at1yrAggressiveLDL-C––loweringbenefitsindiabetesShepherdJetal.DiabetesCare.2006;SeverPSetal.DiabetesCare.2005;HPSCollaborativeGroup.Lancet.2003;ColhounHMetal.Lancet.2004.DifferenceinLDL-C(mg/dL)Aggressivelipid-loweringbetterAggressivelipid-loweringworse0.0260.0360.001<0.00010.0003Primaryeventrate(%)17.911.99.012.613.5Control9.49.3Treatment0.630.670.78PTNTDiabetes,CHDASCOT-LLADiabetes,HTNCARDSDiabetes,noCVDHPSAlldiabetesDiabetes,noCVD*Atorvastatin10vs80mg/day?StatinvsplaceboRelativerisk0.70.9722*35?46?39?35?0.75Eventrate(%)HPS:StatinbenefitsirrespectiveofbaselinelipidlevelanddiabetesstatusPlacebon=10,2670.41.01.2Simvastatinn=10,269Eventrateratio(95%CI)StatinbetterPlacebobetterLDL-C<116mg/dLWithdiabetesNodiabetes15.718.820.922.9LDL-C≥≥116mg/dLWithdiabetesNodiabetes23.320.027.926.224%reductionP<0.000125.219.8AllpatientsHPSCollaborativeGroup.Lancet.2003;361:2005-16.CARDS:AssessmentoflipidloweringinpatientswithdiabetesCollaborativeAtoRvastatinDiabetesStudyColhounHMetal.Lancet.2004;364:685-96.Type2diabetesand≥≥1ofhypertension,retinopathy,

micro-ormacroalbuminuria,currentsmoker

N=2838Atorvastatin10mg

n=1428Follow-up:4yearsPrimaryoutcome:Fatal/nonfatalMI,unstableangina,acuteCHDdeath,resuscitatedcardiacarrest,coronaryrevascularization,strokePlacebon=1410RandomizedDouble-blindColhounHMetal.Lancet.2004;364:685-96.151050Follow-up(years)01234Cumulativehazard

(%)4.75Placebo

127eventsAtorvastatin10mg83eventsCARDS:Statinreducesprimaryoutcome

indiabetesFatal/nonfatalMI,unstableangina,acuteCHDdeath,resuscitatedcardiacarrest,coronaryrevascularization,strokeMeanbaselineLDL-C117mg/dL37%RRR(17%–52%)P=0.001CARDS:SafetyconsiderationsColhounHMetal.Lancet.2004;364:685-96.Atorvastatin(%)

(n=1428)Placebo(%)

(n=1410)ALT≥3xULN1.01.0AST≥3xULN0.40.3CK≥10xULN0.10.7Myopathy0.070.07Myalgia4.35.1Rhabdomyolysis00IntegratingPreventiveTreatmentsinDiabetesDiabetesPreventionProgram:DesignDPPResearchGroup.NEnglJMed.

2002;346:393-403.*≥7%weightloss/maintenance+≥≥150minutesmoderatephysicalactivityweekly?PlusstandardlifestylerecommendationsIFGorIGT,withoutdiabetesN=3234Randomized,double-blind“Intensive””

lifestylemodification*Metformin850mgbid?Placebo?Follow-up:2.8yearsPrimaryoutcome:New-onsetdiabetesDPP:Benefitofdiet+exerciseormetforminondiabetespreventioninat-riskpatientsDPPResearchGroup.NEnglJMed.2002;346:393-403.YearsN=3234withIFGandIGTwithoutdiabetes00102030401.02.03.04.0PlaceboMetforminLifestyleCumulativeincidenceofdiabetes(%)31%58%P*<0.001<0.001*vsplaceboDPP:Benefitofdiet+exerciseormetforminondiabetesbyraceandethnicityDPPResearchGroup.NEnglJMed.2002;346:393-403.Reductioninnew-onsetdiabetes

(%)White(n=1768)AfricanAmerican(n=645)Hispanic(n=508)AmericanIndian(n=171)Asian(n=142)N=3234withIFGandIGTwithoutdiabetesLifestylevsplaceboMetforminvsplaceboLifestylevsmetformin0-20-40-60-80HOPE,EUROPA,PEACE:Reductioninnew-onsetdiabetes(placebo-controlledtrials)DagenaisGRetal.Lancet.2006;368:581-8.n=23,340freefromdiabetes*atbaselineRamipril10mgPerindopril

8mgTrandolapril

4mgOverall

14%RRRRR0.86(0.78–0.95)P=0.0023(alltrials)*NotaprespecifiedendpointPrimaryoutcome:

DiabetesordeathfromanycauseDREAMTrialInvestigators.Diabetologia.2004;47:1519-27.DREAM:StudydesignSecondaryoutcomesI:

CVeventsCombinedMI,stroke,CVdeath,revascularization,HF,angina,ventriculararrhythmiaSecondaryoutcomesII:Renale