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1、Estrogen Replacement Therapy and the Prevention of Coronary Heart Disease in Women:Friend or Foe?,David Parra,Pharm.D.,BCPSClinical Pharmacy SpecialistDepartment of CardiologyVeterans Affairs Medical CenterWest Palm Beach,FL,Objectives,Understand the magnitude of coronary heart disease(CHD)in postme
2、nopausal womenExplain the mechanisms behind estrogens proposed cardioprotective effectReview the observational data supporting the use of estrogen in preventing CHDDiscuss the results of the recently completed Heart and Estrogen/progestin Replacement Study(HERS)and apply them to clinical practice,Ca
3、rdiovascular Disease in Women,One in two women will die of cardiovascular disease(CVD)if all forms of major CVD were eliminated life expectancy would increase by 10 yearsOne in 26 women will die of breast cancerif all forms of cancer were eliminated life expectancy would increase by 3 years,1998 Hea
4、rt and Stroke Statistical Update,AHA.,63%of women(48%of men)die suddenly from coronary heart disease44%of women(27%of men)will die within one year after a heart attack,Cardiovascular Disease in Women,1998 Heart and Stroke Statistical Update,AHA.,505,440,33,130,256,844,48,961,45,136,0,Deaths in thous
5、ands,Leading Causes of Death for All Females,United States 1995 Mortality DataAdapted from 1998 Heart and Stroke Statistical Update,AHA.,50%Coronary Heart Disease,1%Congenital Heart Defects,1%Rheumatic Fever/Rheumatic Heart Disease,4%Congestive Heart Failure,2%Atherosclerosis,4%High Blood Pressure,2
6、2%Other,Coronary Heart Disease:Despite Advances,Still the#1 Killer,Percentage Breakdown of Deaths From Cardiovascular DiseasesUnited States:1995 Mortality,Final Data,16%Stroke,American Heart Association1998 Heart and Stroke Facts:Statistical Update,Cardiovascular Disease Mortality Trends,United Stat
7、es 1995 Mortality DataAdapted from 1998 Heart and Stroke Statistical Update,AHA.,Premenopausal Postmenopausal,Decrease in HDL Increase in LDL,triglycerides,apolipoproteins B and A-IIncrease in diastolic blood pressure,Menopause exerts a negative effect on CHD risk,Incidence of Coronary Heart Disease
8、,Framingham Cohort,Adapted from Kannel et.al.American Heart Journal.1987;114:413-9.,The Framingham Heart StudyAnnual Rate of Coronary Artery Disease in Women as a Function of Age,Adapted from Castelli et al.Am J Obstet Gynecol 1988;158:1553-60.,20-29,30-39,40-49,50-59,60-69,70-79,80,3.1,3.8,5.3,7.9,
9、11,13.6,18.2,0,5,10,15,20,25,Ages,Adapted from 1998 Heart and Stroke Statistical Update,AHA.,Estimated Prevalence of CHD in Women by AgeUnited States 1988-91,Percent Female Population,Early Outcome of Acute Myocardial Infarction-ISIS-3,Adapted from Malacrida R et.al.N Eng J Med.1998;338:8-14.,Premen
10、opausal Postmenopausal,Loss of endogenous estradiol productionPresumption estrogen has a role in premenopausal protection against CHDConversely its loss has a role in postmenopausal risk,Estrogen replacement therapy(ERT)should decrease this risk by maintaining metabolic factors that affect CHD at pr
11、emenopausal levels,Estrogens Cardioprotective Mechanisms,Lipids/Atheroma,Antioxidant,Hemostatic/Platelet,Carbohydrate Metabolism,Nitrous Oxide,Homocysteine,Inhibition of Constricting Agents,Calcium ChannelAntagonism,Female Life Cycle and Lipids,0,20,40,60,80,100,120,140,160,15-19,20-24,25-29,30-34,3
12、5-39,40-44,45-49,50-54,55-59,60-64,65-69,70-74,75-7,Mean values(mg/dL),HDL-C,LDL-C,Age(years),Adapted from Kannel et.al.American Heart Journal.1987;114:413-9.,Estrogen and Lipids,Decrease LDL 5-15%Increase HDL 5-15%Increase triglycerides 4-14%+/-lipoprotein(a)Effect dependent on route and formulatio
13、n,Estrogens Mechanism of Action on Lipids,Induction of LDL receptor formationDestruction of hepatic lipase25-50%of beneficial effect on CHD,Platelet Effects,Increased production of local prostacyclin(PGI2)enhancement of prostacyclin stabilizing factorFavorable prostacyclin/thromboxane balanceincreas
14、e in blood flowanti-aggregation effect,Peripheral Vascular Effects,Estrogen receptors in blood vesselsEstrogen increases in blood flowdecrease in arterial impedancedecreased vascular tone in uterine arteriesincrease in cerebrovascular blood flowDecreased anginal episodes and increases in treadmill t
15、imes,Peripheral Vascular Effects,Increased production of prostacyclin in endotheliumDecreased thromboxane A2 synthesis by plateletsFacilitate release or response to nitrous oxideInhibit release or response to constrictor factorsCalcium channel antagonist role,Direct Effect on Myocardium,Estrogen rec
16、eptors present in the heart and aortaST segment changes induced by estrogen resemble those inducible by digoxinEvidence by echocardiogram of changes in stroke volume and mean accelerationNet result of possible positive inotropic effect,Hemostatic Effects,Complex and variable decreased fibrinogen and
17、 antithrombin IIIincreased factor VII and Protein Coverall observational findings suggest a reduction in risk of thrombosis,Other Effects,Carbohydrate metabolismincreased insulin release and receptor sensitivitymay be opposite at doses 1.25mg Antioxidantboth estrogen and progesteroneBody fatgynoid f
18、at versus android fat,Progestin Effects on the Cardiovascular System,Progestin product dependentProgesterone receptors present in blood vesselsIn-vitro negation of increased PGI2Attenuation of increased uterine blood flowDecreased estrogen receptor activityBlunting of estrogens effect on lipid profi
19、le,From Mechanistic to Observational Evidence,Estrogen Use and Risk of CHD,0.5,1,1.5,2,Hospital case-control,Population case-control,Prospective internal control,Cross-sectional,Prospective external control,All studies combined,Prospective internal controlcross sectional,Adapted from Stampfer et al.
20、Prev Med 1991;20:47-63.,RR,Relative Risk of CHD Among All Postmenopausal Hormone Users,Adjusted for multiple risk factorsAdapted from Grodstein et al.NEJM 1996;335:453-61.Nurse Health Study 1976-1994.,Hormone UseRR Major Coronary Disease,Never used1.0Currently usedEstrogen 0.60(0.43-0.83)Estrogen+pr
21、ogesterone0.39(0.19-0.78),Change in RR with Estrogen Therapy with and without Progesterone,DiseaseERTERT+Progesterone,Osteoporosis0.400.40Endometrial Cancer6.01.0Breast Cancer1.371.60Ischemic Heart Disease0.520.69Stroke0.500.67Mortality Change-328-188(per 100,000),Adapted from Ross et al.Lancet 1981
22、;4:858-60.,Estimated Lifetime Probability of Selected Events with ERT,ConditionNot Treated(%)Assumed RR%,CHD46.10.6534.2Stroke19.80.9620.2Hip Fracture15.30.7512.7Breast Cancer10.21.2513.0Endometrial CA2.68.2219.7Life Expectancy(y)82.883.7,Treated,In women treated with ERT 15 years or more versus tho
23、se not treated.Adapted from Grady et al.Ann Intern Med 1992&Petitti et al.Ann Epidemiol 1994.,Estimated Change in Mortality with Estrogen Replacement Therapy,ConditionRRCumulative Change,Osteoporotic Fractures0.4-563 per 100,000Gallbladder Disease1.5+2 per 100,000Endometrial Cancer2.0+63 per 100,000
24、Breast Cancer1.1+187 per 100,000Ischemic Heart Disease0.5-5,250 per 100,000Net Change-5,561 per 100,000,Adapted from Henderson et al.Am J Obstet Gyn 1986;154:1181-6.,Relative Risk of Death Among All Postmenopausal Hormone Users,Cause of DeathCurrentPastNever,All Cause0.63(0.56-0.70)1.03(0.94-1.12)1.
25、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)1.0All Cancer0.71(0.62-0.81)1.04(0.92-1.17)1.0Breast Cancer0.76(0.56-1.02)0.83(0.63-1.09)1.0,Hormone Use,Adjusted for multiple risk factorsAdapted from Grodstein et al.NEJM 1997;336:1769-75.Nurse Health Study 1976-1994.,Summary
26、 of Observational Evidence,Meta-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 users,Confounding Factors,Effects of progesteroneStudy biasesLimitations of meta-a
27、nalyses,Confounding Factors-progesterone,Early epidemiologic studies usually in women on estrogen replacement therapy onlyProgesterone formulations and their effects19-nortestosterone derivates(levonorgesterol)17-hydroxyprogesterone derivates(medroxyprogesterone)micronized progesterone,Confounding F
28、actors-“healthy user”,Many studies demonstrate estrogen users:higher socioeconomic statusbetter educatedyoungerthinnermore likely to drink alcohol,Confounding Factors-compliance,Long term hormone replacement therapy(HRT)users are“compliers”More likely to take ASA,MVI,and exercisePatients who comply
29、with therapy(even placebo)have reduction in mortality,Confounding Factors-compliance,Beta-blocker Heart Attack Trial,Petitte DB Ann Epidemiol 4:115-118,1994,Beta-blockerPlaceboCompliance%MortalityRelative Risk%MortalityRelative Risk75%4.50.536.80.36Crude relative risk of mortality in women participa
30、ting in the trial,Confounding Factors-compliance,ClofibratePlaceboCompliance%MortalityRelative Risk%MortalityRelative Risk80%15.70.7016.40.64Adjusted 5-year mortality rate and relative risk in high-compliance group compared with low-compliance group,Coronary Drug Project,Petitte DB Ann Epidemiol 4:1
31、15-118,1994,Relative risk of CHD is 0.5-0.65 with ERTRelative risk of mortality in some studies is 0.36-0.64 in patients compliant with placeboEstrogen users are by definition“compliant”,Confounding Factors-compliance,Suggestive that compliance bias,in theory,could account for most of the benefit of
32、 ERT seen in CHD,Confounding Factors-surveillance,Medical caresought on a more regular basis by HRT usersrisk factors identified earliermore likely to have preventative health screens,Confounding Factors-“healthy survivor”,Breast Cancer Detection Demonstration Project Follow-up Study(Sturgeon et al.
33、)current ERT users had best survivalrecent past users had highest all cause mortality(greater than those who never used ERT),Confounding Factors:meta-analyses,Unable to remove biases from observational studiesNot predictive 35%of the timeLeLorier et al.NEJM 337(8):536-542,1997Example-beta carotenesu
34、pporting observational and mechanistic studieslack of benefit and potential harm in RCTs,No Benefit?,Estrogen Replacement Therapy and CHD,Benefit?,The Answer?,Need for trials to confirm these findings that are:prospectiverandomizeddouble-blindplacebo-controlled,HERS Study,Heart and Estrogen/progesti
35、n Replacement Study2,763 women with CHD,mean age 670.625mg conjugated estrogens+2.5mg medroxyprogesterone(PremproTM)daily vs.placeboAverage follow-up was 4.1 years,JAMA 1998;280:605-613,650-652,Endpoints,Primary outcome was nonfatal MI or CHD deathSecondary outcomes included total mortality,cancer d
36、eath,breast cancer,endometrial cancer,DVT,PE,fractures,gallbladder disease,Heart and Estrogen/progestin Replacement Study.JAMA 1998;280:605-613,650-652,Statistical Power,Able to detect a 24%intention-to-treat effect90%power,2-tailed alpha of 0.05However lower than expectedevent rate(3.3%versus 5%)tr
37、eatment duration(4.1 years versus 4.75)compliance rate(75%and 81%at 3 years)Offset by18%more participants than planned,Heart and Estrogen/progestin Replacement Study.JAMA 1998;280:605-613,650-652,Demographics,No differences(p0.05)between groups inAge,EducationCHD risk factors(LDL 145+/-37 mg/dL)CHD
38、manifestationsMedication useaspirin(78%)b-blockers(33%)lipid lowering medications(45-47%)calcium channel blockers(55%),Heart and Estrogen/progestin Replacement Study.JAMA 1998;280:605-613,650-652,Results-primary endpoint,HRT Placebo First Year*Nonfatal MI42(3%)29(2%)CHD Death17 11 End of study*Combi
39、ned172 176,Heart and Estrogen/progestin Replacement Study.JAMA 1998;280:605-613,650-652,*p 0.05(95%CI,0.87-1.75),Risk for CHD Death or nonfatal MI*with HRTyear one 52%year twono differenceyear three 13%years 4-5 23%,Results-primary endpoint,Heart and Estrogen/progestin Replacement Study.JAMA 1998;28
40、0:605-613,650-652,*p=0.009 for trend in log relative hazard,Results-primary endpoint,As-treated analysis80%compliant by pill countno difference between groupsrelative hazard 0.87(95%CI,0.67-1.11)Subgroup analysesno differential effects in 86 subgroups,Heart and Estrogen/progestin Replacement Study.J
41、AMA 1998;280:605-613,650-652,Results-other endpoints,Lipids11%reduction in LDL(125mg/dL versus 140mg/dL)10%higher HDL(54mg/dL versus 49mg/dL)8%higher triglycerides(181mg/dL versus 170mg/dL)Total Mortalityno differences(95%CI,0.84-1.38),Heart and Estrogen/progestin Replacement Study.JAMA 1998;280:605
42、-613,650-652,Results-other endpoints,Venous thromboembolic events with HRT34 versus 12,RH 2.89(95%CI,1.50-5.88)Gallbladder disease84 versus 62,RH 1.38(95%CI,1.00-1.92),Heart and Estrogen/progestin Replacement Study.JAMA 1998;280:605-613,650-652,Explanation?,Older population Established CHDEstrogen+p
43、rogesteroneEffects over timerandom variation?early prothrombotic,arrhythmic,ischemic effects?later change in underlying atherosclerosis?,HERS Study-Key Points,Continuous HRT in women with CHD did not reduce cardiovascular outcomes at 4.1 yearsHRT should not be started specifically for the secondary
44、prevention of CHDWomen already receiving HRT with CHD should not necessarily change therapyIncreased risk of thromboembolic events and gallbladder disease,Coumadin Aspirin Reinfarction Substudy,Incidence of post-MI cardiac events at one year in 1,853 postmenopausal womenprior/current(n=411)new(n=126
45、)never(n=1,316),Unstable Angina(RR)Death or MI(RR)Prior/current1.16(p=0.25)0.75(p=0.14)New1.96(p 0.0001)0.39(p 0.02),Alexander K.,ACC 1999 Abstracts.,Unanswered questions,Unopposed ERTMicronized or other forms of progesteroneCyclical versus continuousLag effectPrimary preventionWomens Health Initiative,
