《雌激素代治疗》PPT课件.ppt

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1、Estrogen Replacement Therapy and the Prevention of Coronary Heart Disease in Women:Friend or Foe?David Parra,Pharm.D.,BCPSDavid Parra,Pharm.D.,BCPSClinical Pharmacy SpecialistClinical Pharmacy SpecialistDepartment of CardiologyDepartment of CardiologyVeterans Affairs Medical CenterVeterans Affairs M

2、edical CenterWest Palm Beach,FLWest Palm Beach,FLObjectivesUnderstand the magnitude of coronary heart disease(CHD)in postmenopausal womenExplain the mechanisms behind estrogens proposed cardioprotective effectReview the observational data supporting the use of estrogen in preventing CHDDiscuss the r

3、esults of the recently completed Heart and Estrogen/progestin Replacement Study(HERS)and apply them to clinical practiceCardiovascular Disease in WomenuOne in two women will die of cardiovascular disease(CVD)if all forms of major CVD were eliminated life if all forms of major CVD were eliminated lif

4、e expectancy would increase by 10 yearsexpectancy would increase by 10 yearsuOne in 26 women will die of breast cancerif all forms of cancer were eliminated life if all forms of cancer were eliminated life expectancy would increase by 3 yearsexpectancy would increase by 3 years1998 Heart and Stroke

5、Statistical Update,AHA.1998 Heart and Stroke Statistical Update,AHA.u63%of women(48%of men)die suddenly from coronary heart diseaseu44%of women(27%of men)will die within one year after a heart attackCardiovascular Disease in Women1998 Heart and Stroke Statistical Update,AHA.1998 Heart and Stroke Sta

6、tistical Update,AHA.505,440505,44033,13033,130256,844256,84448,96148,96145,13645,1360 0100100200200300300400400500500600600Total CVTotal CVCancerCancerCOPDCOPDPneumoniaPneumoniaFluFluDiabetesDiabetesDeaths in thousandsDeaths in thousandsLeading Causes of Death for All FemalesUnited States 1995 Morta

7、lity DataUnited States 1995 Mortality DataAdapted from 1998 Heart and Stroke Statistical Update,AHA.Adapted from 1998 Heart and Stroke Statistical Update,AHA.50%Coronary Heart Disease50%Coronary Heart Disease1%Congenital Heart Defects1%Congenital Heart Defects1%Rheumatic Fever/1%Rheumatic Fever/Rheu

8、matic Heart DiseaseRheumatic Heart Disease4%Congestive Heart Failure4%Congestive Heart Failure2%Atherosclerosis2%Atherosclerosis4%High Blood Pressure4%High Blood Pressure22%Other22%OtherCoronary Heart Disease:Despite Advances,Still the#1 KillerPercentage Breakdown of Deaths From Cardiovascular Disea

9、sesPercentage Breakdown of Deaths From Cardiovascular DiseasesUnited States:1995 Mortality,Final DataUnited States:1995 Mortality,Final Data16%Stroke16%StrokeAmerican Heart AssociationAmerican Heart Association1998 Heart and Stroke Facts:Statistical Update1998 Heart and Stroke Facts:Statistical Upda

10、te4204204404404604604804805005005205207979808081818282838384848585868788888989909091919292939394949595YearsYearsDeaths in ThousandsDeaths in Thousands MalesMalesFemalesFemalesCardiovascular Disease Mortality TrendsUnited States 1995 Mortality DataUnited States 1995 Mortality DataAdapted from 1998 He

11、art and Stroke Statistical Update,AHA.Adapted from 1998 Heart and Stroke Statistical Update,AHA.Premenopausal PostmenopausaluDecrease in HDL uIncrease in LDL,triglycerides,apolipoproteins B and A-IuIncrease in diastolic blood pressure Menopause exerts a negative effect on CHD riskIncidence of Corona

12、ry Heart Disease0 02 24 46 68 81010121214141616Annual rate perAnnual rate per1000 subjects1000 subjectsM.I.M.I.Clinical CoronaryClinical CoronaryArtery DiseaseArtery DiseaseWomen age 35-64Women age 35-64Women age 65-94Women age 65-94Framingham Cohort Adapted from Kannel et.al.Adapted from Kannel et.

13、al.American Heart JournalAmerican Heart Journal.1987;114:413-9.1987;114:413-9.The Framingham Heart StudyAnnual Rate of Coronary Artery Disease in Women as a Function of AgeAnnual Rate of Coronary Artery Disease in Women as a Function of AgeNumber cases/1000 Number cases/1000 0 05 5101015152020252530

14、30353540404545patients per yearpatients per year35-4435-4445-5445-5455-6455-6465-7465-7475-8475-8485-9485-94Age(years)Adapted from Castelli et al.Am J Obstet Gynecol 1988;158:1553-60.Adapted from Castelli et al.Am J Obstet Gynecol 1988;158:1553-60.20-2920-2930-3930-39 40-4940-4950-5950-5960-6960-697

15、0-7970-79 80 803.13.13.83.85.35.37.97.9111113.613.618.218.20 05 51010151520202525AgesAgesAdapted from 1998 Heart and Stroke Statistical Update,AHA.Adapted from 1998 Heart and Stroke Statistical Update,AHA.Estimated Prevalence of CHD in Women by AgeUnited States 1988-91United States 1988-91Percent Fe

16、male PopulationPercent Female PopulationEarly Outcome of Acute Myocardial Infarction-ISIS-30 05 51010151520202525%Patients607070Any ageAny ageAge(years)35-Day MortalityWomenWomenMenMenAdapted from Malacrida R et.al.N Eng J Med.1998;338:8-14.Adapted from Malacrida R et.al.N Eng J Med.1998;338:8-14.Pr

17、emenopausal PostmenopausaluLoss of endogenous estradiol productionuPresumption estrogen has a role in premenopausal protection against CHDuConversely its loss has a role in postmenopausal risk Estrogen replacement therapy(ERT)should decrease this risk by maintaining metabolic factors that affect CHD

18、 at premenopausal levelsEstrogens Cardioprotective MechanismsLipids/AtheromaLipids/Atheroma AntioxidantAntioxidantHemostatic/PlateletHemostatic/PlateletCarbohydrate MetabolismCarbohydrate Metabolism Nitrous OxideNitrous OxideHomocysteineHomocysteineInhibition of Inhibition of Constricting AgentsCons

19、tricting AgentsCalcium ChannelCalcium ChannelAntagonismAntagonismFemale Life Cycle and Lipids0 0202040406060808010010012012014014016016015-1915-1920-2420-2425-2925-2930-3430-3435-3935-3940-4440-4445-4945-4950-5450-5455-5955-5960-6460-6465-6965-6970-7470-7475-775-7Mean values(mg/dL)Mean values(mg/dL)

20、HDL-CHDL-CLDL-CLDL-CAge(years)Age(years)Adapted from Kannel et.al.Adapted from Kannel et.al.American Heart JournalAmerican Heart Journal.1987;114:413-9.1987;114:413-9.Estrogen and LipidsuDecrease LDL 5-15%uIncrease HDL 5-15%uIncrease triglycerides 4-14%u+/-lipoprotein(a)uEffect dependent on route an

21、d formulationEstrogens Mechanism of Action on LipidsuInduction of LDL receptor formationuDestruction of hepatic lipaseu25-50%of beneficial effect on CHDPlatelet EffectsuIncreased production of local prostacyclin(PGI2)enhancement of prostacyclin stabilizing factorenhancement of prostacyclin stabilizi

22、ng factoruFavorable prostacyclin/thromboxane balanceincrease in blood flowincrease in blood flowanti-aggregation effectanti-aggregation effectPeripheral Vascular EffectsuEstrogen receptors in blood vesselsuEstrogen increases in blood flowdecrease in arterial impedancedecreased vascular tone in uteri

23、ne arteriesincrease in cerebrovascular blood flowuDecreased anginal episodes and increases in treadmill timesPeripheral Vascular EffectsuIncreased production of prostacyclin in endotheliumuDecreased thromboxane A2 synthesis by plateletsuFacilitate release or response to nitrous oxideuInhibit release

24、 or response to constrictor factorsuCalcium channel antagonist roleDirect Effect on MyocardiumuEstrogen receptors present in the heart and aortauST segment changes induced by estrogen resemble those inducible by digoxinuEvidence by echocardiogram of changes in stroke volume and mean accelerationuNet

25、 result of possible positive inotropic effectHemostatic EffectsuComplex and variable decreased fibrinogen and antithrombin IIIincreased factor VII and Protein Coverall observational findings suggest a reduction in risk of thrombosisOther EffectsuCarbohydrate metabolismincreased insulin release and r

26、eceptor sensitivityincreased insulin release and receptor sensitivitymay be opposite at doses 1.25mg may be opposite at doses 1.25mg uAntioxidantboth estrogen and progesteroneboth estrogen and progesteroneuBody fatgynoid fat versus android fatgynoid fat versus android fatProgestin Effects on the Car

27、diovascular SystemuProgestin product dependentuProgesterone receptors present in blood vesselsuIn-vitro negation of increased PGI2uAttenuation of increased uterine blood flowuDecreased estrogen receptor activityuBlunting of estrogens effect on lipid profileFrom Mechanistic to Observational EvidenceE

28、strogen Use and Risk of CHD0.50.51 11.51.52 2Hospital case-controlHospital case-controlPopulation case-controlPopulation case-controlProspective internal controlProspective internal controlCross-sectionalCross-sectionalProspective external controlProspective external controlAll studies combinedAll s

29、tudies combinedProspective internal controlProspective internal controlcross sectionalcross sectionalAdapted from Stampfer et al.Prev Med 1991;20:47-63.Adapted from Stampfer et al.Prev Med 1991;20:47-63.RRRRRelative Risk of CHD Among All Postmenopausal Hormone UsersAdjusted for multiple risk factors

30、Adjusted for multiple risk factorsAdapted from Grodstein et al.NEJM 1996;335:453-61.Nurse Health Study 1976-1994.Adapted from Grodstein et al.NEJM 1996;335:453-61.Nurse Health Study 1976-1994.Hormone UseRR Major Coronary DiseaseNever usedNever used1.01.0Currently usedCurrently usedEstrogen Estrogen

31、0.60(0.43-0.83)0.60(0.43-0.83)Estrogen+progesteroneEstrogen+progesterone0.39(0.19-0.78)0.39(0.19-0.78)Change in RR with Estrogen Therapy with and without ProgesteroneDiseaseERTERT+ProgesteroneOsteoporosisOsteoporosis0.400.400.400.40Endometrial CancerEndometrial Cancer6.06.01.01.0Breast CancerBreast

32、Cancer1.371.371.601.60Ischemic Heart DiseaseIschemic Heart Disease0.520.520.690.69StrokeStroke0.500.500.670.67Mortality ChangeMortality Change-328-328-188-188(per 100,000)(per 100,000)Adapted from Ross et al.Lancet 1981;4:858-60.Adapted from Ross et al.Lancet 1981;4:858-60.Estimated Lifetime Probabi

33、lity of Selected Events with ERTConditionConditionNot Treated(%)Not Treated(%)Assumed RRAssumed RR%CHDCHD46.146.10.650.6534.234.2StrokeStroke19.819.80.960.9620.220.2Hip FractureHip Fracture15.315.30.750.7512.712.7Breast CancerBreast Cancer10.210.21.251.2513.013.0Endometrial CAEndometrial CA2.62.68.2

34、28.2219.719.7Life Expectancy(y)Life Expectancy(y)82.882.883.783.7TreatedTreatedIn women treated with ERT 15 years or more versus those not treated.In women treated with ERT 15 years or more versus those not treated.Adapted from Grady et al.Ann Intern Med 1992&Petitti et al.Ann Epidemiol 1994.Adapted

35、 from Grady et al.Ann Intern Med 1992&Petitti et al.Ann Epidemiol 1994.Estimated Change in Mortality with Estrogen Replacement TherapyConditionRRCumulative ChangeOsteoporotic FracturesOsteoporotic Fractures0.40.4-563 per 100,000-563 per 100,000Gallbladder DiseaseGallbladder Disease1.51.5+2 per 100,0

36、00+2 per 100,000Endometrial CancerEndometrial Cancer2.02.0+63 per 100,000+63 per 100,000Breast CancerBreast Cancer1.11.1+187 per 100,000+187 per 100,000Ischemic Heart DiseaseIschemic Heart Disease0.50.5-5,250 per 100,000-5,250 per 100,000Net ChangeNet Change-5,561 per 100,000-5,561 per 100,000Adapte

37、d from Henderson et al.Am J Obstet Gyn 1986;154:1181-6.Adapted from Henderson et al.Am J Obstet Gyn 1986;154:1181-6.Relative Risk of Death Among All Postmenopausal Hormone UsersCause of DeathCause of DeathCurrentCurrentPastPastNeverNeverAll CauseAll Cause0.63(0.56-0.70)0.63(0.56-0.70)1.03(0.94-1.12)

38、1.03(0.94-1.12)1.01.0CHDCHD0.47(0.32-0.69)0.47(0.32-0.69)0.99(0.75-1.30)0.99(0.75-1.30)1.01.0StrokeStroke0.68(0.39-1.16)0.68(0.39-1.16)1.07(0.68-1.69)1.07(0.68-1.69)1.01.0All CancerAll Cancer0.71(0.62-0.81)0.71(0.62-0.81)1.04(0.92-1.17)1.04(0.92-1.17)1.01.0Breast CancerBreast Cancer0.76(0.56-1.02)0.

39、76(0.56-1.02)0.83(0.63-1.09)0.83(0.63-1.09)1.01.0Hormone UseHormone UseAdjusted for multiple risk factorsAdjusted for multiple risk factorsAdapted from Grodstein et al.NEJM 1997;336:1769-75.Nurse Health Study 1976-1994.Adapted from Grodstein et al.NEJM 1997;336:1769-75.Nurse Health Study 1976-1994.S

40、ummary of Observational EvidenceuMeta-analysesrelative risk of coronary heart disease is 0.50-0.65 with ERTaddition of progesterone does not appear to attenuate the effect of ERTERT estimated to save 5,250 lives per 100,000 usersConfounding FactorsuEffects of progesteroneuStudy biasesuLimitations of

41、 meta-analysesConfounding Factors-progesteroneuEarly epidemiologic studies usually in women on estrogen replacement therapy onlyuProgesterone formulations and their effects19-nortestosterone derivates(levonorgesterol)19-nortestosterone derivates(levonorgesterol)17-hydroxyprogesterone derivates 17-hy

42、droxyprogesterone derivates(medroxyprogesterone)(medroxyprogesterone)micronized progesteronemicronized progesteroneConfounding Factors-“healthy user”uMany studies demonstrate estrogen users:higher socioeconomic statusbetter educatedyoungerthinnermore likely to drink alcoholConfounding Factors-compli

43、anceuLong term hormone replacement therapy(HRT)users are“compliers”uMore likely to take ASA,MVI,and exerciseuPatients who comply with therapy(even placebo)have reduction in mortalityConfounding Factors-complianceuBeta-blocker Heart Attack TrialPetitte DB Ann Epidemiol 4:115-118,1994Petitte DB Ann Ep

44、idemiol 4:115-118,1994Beta-blockerBeta-blockerPlaceboPlaceboComplianceCompliance%Mortality%MortalityRelative RiskRelative Risk%Mortality%MortalityRelative RiskRelative Risk75%75%75%4.54.50.530.536.86.80.360.36Crude relative risk of mortality in women participating in the trialCrude relative risk of

45、mortality in women participating in the trialConfounding Factors-complianceConfounding Factors-complianceClofibrateClofibratePlaceboPlaceboComplianceCompliance%Mortality%MortalityRelative RiskRelative Risk%Mortality%MortalityRelative RiskRelative Risk80%80%80%15.715.70.700.7016.416.40.640.64Adjusted

46、 5-year mortality rate and relative risk in high-compliance group Adjusted 5-year mortality rate and relative risk in high-compliance group compared with low-compliance groupcompared with low-compliance groupuCoronary Drug ProjectPetitte DB Ann Epidemiol 4:115-118,1994Petitte DB Ann Epidemiol 4:115-

47、118,1994uRelative risk of CHD is 0.5-0.65 with ERTuRelative risk of mortality in some studies is 0.36-0.64 in patients compliant with placebouEstrogen users are by definition“compliant”Confounding Factors-complianceConfounding Factors-complianceSuggestive that compliance bias,in theory,could account

48、 for most of the benefit of ERT seen in CHDConfounding Factors-surveillanceuMedical caresought on a more regular basis by HRT usersrisk factors identified earliermore likely to have preventative health screensConfounding Factors-“healthy survivor”uBreast Cancer Detection Demonstration Project Follow

49、-up Study(Sturgeon et al.)current ERT users had best survivalcurrent ERT users had best survivalrecent past users had highest all cause mortality recent past users had highest all cause mortality(greater than those who never used ERT)(greater than those who never used ERT)Confounding Factors:meta-an

50、alysesuUnable to remove biases from observational studiesuNot predictive 35%of the timeLeLorier et al.NEJM 337(8):536-542,1997LeLorier et al.NEJM 337(8):536-542,1997uExample-beta carotenesupporting observational and mechanistic studiessupporting observational and mechanistic studieslack of benefit a