《雌激素代治疗》PPT课件.ppt

EstrogenReplacementTherapyandthePreventionofCoronaryHeartDiseaseinWomen:FriendorFoe?,DavidParra,Pharm.D.,BCPSClinicalPharmacySpecialistDepartmentofCardiologyVeteransAffairsMedicalCenterWestPalmBeach,FL,Objectives,Understandthemagnitudeofcoronaryheartdisease(CHD)inpostmenopausalwomenExplainthemechanismsbehindestrogensproposedcardioprotectiveeffectReviewtheobservationaldatasupportingtheuseofestrogeninpreventingCHDDiscusstheresultsoftherecentlycompletedHeartandEstrogen/progestinReplacementStudy(HERS)andapplythemtoclinicalpractice,CardiovascularDiseaseinWomen,Oneintwowomenwilldieofcardiovasculardisease(CVD)ifallformsofmajorCVDwereeliminatedlifeexpectancywouldincreaseby10yearsOnein26womenwilldieofbreastcancerifallformsofcancerwereeliminatedlifeexpectancywouldincreaseby3years,1998HeartandStrokeStatisticalUpdate,AHA.,63%ofwomen(48%ofmen)diesuddenlyfromcoronaryheartdisease44%ofwomen(27%ofmen)willdiewithinoneyearafteraheartattack,CardiovascularDiseaseinWomen,1998HeartandStrokeStatisticalUpdate,AHA.,505,440,33,130,256,844,48,961,45,136,0,Deathsinthousands,LeadingCausesofDeathforAllFemales,UnitedStates1995MortalityDataAdaptedfrom1998HeartandStrokeStatisticalUpdate,AHA.,50%CoronaryHeartDisease,1%CongenitalHeartDefects,1%RheumaticFever/RheumaticHeartDisease,4%CongestiveHeartFailure,2%Atherosclerosis,4%HighBloodPressure,22%Other,CoronaryHeartDisease:DespiteAdvances,Stillthe#1Killer,PercentageBreakdownofDeathsFromCardiovascularDiseasesUnitedStates:1995Mortality,FinalData,16%Stroke,AmericanHeartAssociation1998HeartandStrokeFacts:StatisticalUpdate,CardiovascularDiseaseMortalityTrends,UnitedStates1995MortalityDataAdaptedfrom1998HeartandStrokeStatisticalUpdate,AHA.,PremenopausalPostmenopausal,DecreaseinHDLIncreaseinLDL,triglycerides,apolipoproteinsBandA-IIncreaseindiastolicbloodpressure,MenopauseexertsanegativeeffectonCHDrisk,IncidenceofCoronaryHeartDisease,FraminghamCohort,AdaptedfromKannelet.al.AmericanHeartJournal.1987;114:413-9.,TheFraminghamHeartStudyAnnualRateofCoronaryArteryDiseaseinWomenasaFunctionofAge,AdaptedfromCastellietal.AmJObstetGynecol1988;158:1553-60.,20-29,30-39,40-49,50-59,60-69,70-79,80,3.1,3.8,5.3,7.9,11,13.6,18.2,0,5,10,15,20,25,Ages,Adaptedfrom1998HeartandStrokeStatisticalUpdate,AHA.,EstimatedPrevalenceofCHDinWomenbyAgeUnitedStates1988-91,PercentFemalePopulation,EarlyOutcomeofAcuteMyocardialInfarction-ISIS-3,AdaptedfromMalacridaRet.al.NEngJMed.1998;338:8-14.,PremenopausalPostmenopausal,LossofendogenousestradiolproductionPresumptionestrogenhasaroleinpremenopausalprotectionagainstCHDConverselyitslosshasaroleinpostmenopausalrisk,Estrogenreplacementtherapy(ERT)shoulddecreasethisriskbymaintainingmetabolicfactorsthataffectCHDatpremenopausallevels,EstrogensCardioprotectiveMechanisms,Lipids/Atheroma,Antioxidant,Hemostatic/Platelet,CarbohydrateMetabolism,NitrousOxide,Homocysteine,InhibitionofConstrictingAgents,CalciumChannelAntagonism,FemaleLifeCycleandLipids,0,20,40,60,80,100,120,140,160,15-19,20-24,25-29,30-34,35-39,40-44,45-49,50-54,55-59,60-64,65-69,70-74,75-7,Meanvalues(mg/dL),HDL-C,LDL-C,Age(years),AdaptedfromKannelet.al.AmericanHeartJournal.1987;114:413-9.,EstrogenandLipids,DecreaseLDL5-15%IncreaseHDL5-15%Increasetriglycerides4-14%+/-lipoprotein(a)Effectdependentonrouteandformulation,EstrogensMechanismofActiononLipids,InductionofLDLreceptorformationDestructionofhepaticlipase25-50%ofbeneficialeffectonCHD,PlateletEffects,Increasedproductionoflocalprostacyclin(PGI2)enhancementofprostacyclinstabilizingfactorFavorableprostacyclin/thromboxanebalanceincreaseinbloodflowanti-aggregationeffect,PeripheralVascularEffects,EstrogenreceptorsinbloodvesselsEstrogenincreasesinbloodflowdecreaseinarterialimpedancedecreasedvasculartoneinuterinearteriesincreaseincerebrovascularbloodflowDecreasedanginalepisodesandincreasesintreadmilltimes,PeripheralVascularEffects,IncreasedproductionofprostacyclininendotheliumDecreasedthromboxaneA2synthesisbyplateletsFacilitatereleaseorresponsetonitrousoxideInhibitreleaseorresponsetoconstrictorfactorsCalciumchannelantagonistrole,DirectEffectonMyocardium,EstrogenreceptorspresentintheheartandaortaSTsegmentchangesinducedbyestrogenresemblethoseinduciblebydigoxinEvidencebyechocardiogramofchangesinstrokevolumeandmeanaccelerationNetresultofpossiblepositiveinotropiceffect,HemostaticEffects,ComplexandvariabledecreasedfibrinogenandantithrombinIIIincreasedfactorVIIandProteinCoverallobservationalfindingssuggestareductioninriskofthrombosis,OtherEffects,Carbohydratemetabolismincreasedinsulinreleaseandreceptorsensitivitymaybeoppositeatdoses1.25mgAntioxidantbothestrogenandprogesteroneBodyfatgynoidfatversusandroidfat,ProgestinEffectsontheCardiovascularSystem,ProgestinproductdependentProgesteronereceptorspresentinbloodvesselsIn-vitronegationofincreasedPGI2AttenuationofincreaseduterinebloodflowDecreasedestrogenreceptoractivityBluntingofestrogenseffectonlipidprofile,FromMechanistictoObservationalEvidence,EstrogenUseandRiskofCHD,0.5,1,1.5,2,Hospitalcase-control,Populationcase-control,Prospectiveinternalcontrol,Cross-sectional,Prospectiveexternalcontrol,Allstudiescombined,Prospectiveinternalcontrolcrosssectional,AdaptedfromStampferetal.PrevMed1991;20:47-63.,RR,RelativeRiskofCHDAmongAllPostmenopausalHormoneUsers,AdjustedformultipleriskfactorsAdaptedfromGrodsteinetal.NEJM1996;335:453-61.NurseHealthStudy1976-1994.,HormoneUseRRMajorCoronaryDisease,Neverused1.0CurrentlyusedEstrogen0.60(0.43-0.83)Estrogen+progesterone0.39(0.19-0.78),ChangeinRRwithEstrogenTherapywithandwithoutProgesterone,DiseaseERTERT+Progesterone,Osteoporosis0.400.40EndometrialCancer6.01.0BreastCancer1.371.60IschemicHeartDisease0.520.69Stroke0.500.67MortalityChange-328-188(per100,000),AdaptedfromRossetal.Lancet1981;4:858-60.,EstimatedLifetimeProbabilityofSelectedEventswithERT,ConditionNotTreated(%)AssumedRR%,CHD46.10.6534.2Stroke19.80.9620.2HipFracture15.30.7512.7BreastCancer10.21.2513.0EndometrialCA2.68.2219.7LifeExpectancy(y)82.883.7,Treated,InwomentreatedwithERT15yearsormoreversusthosenottreated.AdaptedfromGradyetal.AnnInternMed1992154:1181-6.,RelativeRiskofDeathAmongAllPostmenopausalHormoneUsers,CauseofDeathCurrentPastNever,AllCause0.63(0.56-0.70)1.03(0.94-1.12)1.0CHD0.47(0.32-0.69)0.99(0.75-1.30)1.0Stroke0.68(0.39-1.16)1.07(0.68-1.69)1.0AllCancer0.71(0.62-0.81)1.04(0.92-1.17)1.0BreastCancer0.76(0.56-1.02)0.83(0.63-1.09)1.0,HormoneUse,AdjustedformultipleriskfactorsAdaptedfromGrodsteinetal.NEJM1997;336:1769-75.NurseHealthStudy1976-1994.,SummaryofObservationalEvidence,Meta-analysesrelativeriskofcoronaryheartdiseaseis0.50-0.65withERTadditionofprogesteronedoesnotappeartoattenuatetheeffectofERTERTestimatedtosave5,250livesper100,000users,ConfoundingFactors,EffectsofprogesteroneStudybiasesLimitationsofmeta-analyses,ConfoundingFactors-progesterone,EarlyepidemiologicstudiesusuallyinwomenonestrogenreplacementtherapyonlyProgesteroneformulationsandtheireffects19-nortestosteronederivates(levonorgesterol)17-hydroxyprogesteronederivates(medroxyprogesterone)micronizedprogesterone,ConfoundingFactors-“healthyuser”,Manystudiesdemonstrateestrogenusers:highersocioeconomicstatusbettereducatedyoungerthinnermorelikelytodrinkalcohol,ConfoundingFactors-compliance,Longtermhormonereplacementtherapy(HRT)usersare“compliers”MorelikelytotakeASA,MVI,andexercisePatientswhocomplywiththerapy(evenplacebo)havereductioninmortality,ConfoundingFactors-compliance,Beta-blockerHeartAttackTrial,PetitteDBAnnEpidemiol4:115-118,1994,Beta-blockerPlaceboCompliance%MortalityRelativeRisk%MortalityRelativeRisk75%4.50.536.80.36Cruderelativeriskofmortalityinwomenparticipatinginthetrial,ConfoundingFactors-compliance,ClofibratePlaceboCompliance%MortalityRelativeRisk%MortalityRelativeRisk80%15.70.7016.40.64Adjusted5-yearmortalityrateandrelativeriskinhigh-compliancegroupcomparedwithlow-compliancegroup,CoronaryDrugProject,PetitteDBAnnEpidemiol4:115-118,1994,RelativeriskofCHDis0.5-0.65withERTRelativeriskofmortalityinsomestudiesis0.36-0.64inpatientscompliantwithplaceboEstrogenusersarebydefinition“compliant”,ConfoundingFactors-compliance,Suggestivethatcompliancebias,intheory,couldaccountformostofthebenefitofERTseeninCHD,ConfoundingFactors-surveillance,MedicalcaresoughtonamoreregularbasisbyHRTusersriskfactorsidentifiedearliermorelikelytohavepreventativehealthscreens,ConfoundingFactors-“healthysurvivor”,BreastCancerDetectionDemonstrationProjectFollow-upStudy(Sturgeonetal.)currentERTusershadbestsurvivalrecentpastusershadhighestallcausemortality(greaterthanthosewhoneverusedERT),ConfoundingFactors:meta-analyses,UnabletoremovebiasesfromobservationalstudiesNotpredictive35%ofthetimeLeLorieretal.NEJM337(8):536-542,1997Example-betacarotenesupportingobservationalandmechanisticstudieslackofbenefitandpotentialharminRCTs,NoBenefit?,EstrogenReplacementTherapyandCHD,Benefit?,TheAnswer?,Needfortrialstoconfirmthesefindingsthatare:prospectiverandomizeddouble-blindplacebo-controlled,HERSStudy,HeartandEstrogen/progestinReplacementStudy2,763womenwithCHD,meanage670.625mgconjugatedestrogens+2.5mgmedroxyprogesterone(PremproTM)dailyvs.placeboAveragefollow-upwas4.1years,JAMA1998;280:605-613,650-652,Endpoints,PrimaryoutcomewasnonfatalMIorCHDdeathSecondaryoutcomesincludedtotalmortality,cancerdeath,breastcancer,endometrialcancer,DVT,PE,fractures,gallbladderdisease,HeartandEstrogen/progestinReplacementStudy.JAMA1998;280:605-613,650-652,StatisticalPower,Abletodetecta24%intention-to-treateffect90%power,2-tailedalphaof0.05Howeverlowerthanexpectedeventrate(3.3%versus5%)treatmentduration(4.1yearsversus4.75)compliancerate(75%and81%at3years)Offsetby18%moreparticipantsthanplanned,HeartandEstrogen/progestinReplacementStudy.JAMA1998;280:605-613,650-652,Demographics,Nodifferences(p0.05)betweengroupsinAge,EducationCHDriskfactors(LDL145+/-37mg/dL)CHDmanifestationsMedicationuseaspirin(78%)b-blockers(33%)lipidloweringmedications(45-47%)calciumchannelblockers(55%),HeartandEstrogen/progestinReplacementStudy.JAMA1998;280:605-613,650-652,Results-primaryendpoint,HRTPlaceboFirstYear*NonfatalMI42(3%)29(2%)CHDDeath1711Endofstudy*Combined172176,HeartandEstrogen/progestinReplacementStudy.JAMA1998;280:605-613,650-652,*p0.05(95%CI,0.87-1.75),RiskforCHDDeathornonfatalMI*withHRTyearone52%yeartwonodifferenceyearthree13%years4-523%,Results-primaryendpoint,HeartandEstrogen/progestinReplacementStudy.JAMA1998;280:605-613,650-652,*p=0.009fortrendinlogrelativehazard,Results-primaryendpoint,As-treatedanalysis80%compliantbypillcountnodifferencebetweengroupsrelativehazard0.87(95%CI,0.67-1.11)Subgroupanalysesnodifferentialeffectsin86subgroups,HeartandEstrogen/progestinReplacementStudy.JAMA1998;280:605-613,650-652,Results-otherendpoints,Lipids11%reductioninLDL(125mg/dLversus140mg/dL)10%higherHDL(54mg/dLversus49mg/dL)8%highertriglycerides(181mg/dLversus170mg/dL)TotalMortali