Estrogen Replacement Therapy and the Prevention of Coronary Heart Disease in Women: Friend or Foe?,David Parra, Pharm.D., BCPS Clinical Pharmacy Specialist Department of Cardiology Veterans Affairs Medical Center West Palm Beach, FL,Objectives,Understand the magnitude of coronary heart disease (CHD) in postmenopausal women Explain the mechanisms behind estrogens proposed cardioprotective effect Review the observational data supporting the use of estrogen in preventing CHD Discuss the results of the recently completed Heart and Estrogen/progestin Replacement Study (HERS) and apply them to clinical practice,Cardiovascular 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 years One in 26 women will die of breast cancer if all forms of cancer were eliminated life expectancy would increase by 3 years,1998 Heart and Stroke Statistical Update, AHA.,63% of women (48% of men) die suddenly from coronary heart disease 44% 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 thousands,Leading Causes of Death for All Females,United States 1995 Mortality Data Adapted 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,22% Other,Coronary Heart Disease: Despite Advances, Still the #1 Killer,Percentage Breakdown of Deaths From Cardiovascular Diseases United States: 1995 Mortality, Final Data,16% Stroke,American Heart Association 1998 Heart and Stroke Facts: Statistical Update,Cardiovascular Disease Mortality Trends,United States 1995 Mortality Data Adapted from 1998 Heart and Stroke Statistical Update, AHA.,Premenopausal Postmenopausal,Decrease in HDL Increase in LDL, triglycerides, apolipoproteins B and A-I Increase in diastolic blood pressure,Menopause exerts a negative effect on CHD risk,Incidence of Coronary Heart Disease,Framingham Cohort,Adapted from Kannel et. al. American Heart Journal. 1987;114:413-9.,The Framingham Heart Study Annual 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, 80,3.1,3.8,5.3,7.9,11,13.6,18.2,0,5,10,15,20,25,Ages,Adapted from 1998 Heart and Stroke Statistical Update, AHA.,Estimated Prevalence of CHD in Women by Age United 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.,Premenopausal Postmenopausal,Loss of endogenous estradiol production Presumption estrogen has a role in premenopausal protection against CHD Conversely its loss has a role in postmenopausal risk,Estrogen replacement therapy (ERT) should decrease this risk by maintaining metabolic factors that affect CHD at premenopausal levels,Estrogens Cardioprotective Mechanisms,Lipids/Atheroma,Antioxidant,Hemostatic/Platelet,Carbohydrate Metabolism,Nitrous Oxide,Homocysteine,Inhibition of Constricting Agents,Calcium Channel Antagonism,Female Life Cycle and Lipids,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,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 formulation,Estrogens Mechanism of Action on Lipids,Induction of LDL receptor formation Destruction of hepatic lipase 25-50% of beneficial effect on CHD,Platelet Effects,Increased production of local prostacyclin (PGI2) enhancement of prostacyclin stabilizing factor Favorable prostacyclin/thromboxane balance increase in blood flow anti-aggregation effect,Peripheral Vascular Effects,Estrogen receptors in blood vessels Estrogen increases in blood flow decrease in arterial impedance decreased vascular tone in uterine arteries increase in cerebrovascular blood flow Decreased anginal episodes and increases in treadmill times,Peripheral Vascular Effects,Increased production of prostacyclin in endothelium Decreased thromboxane A2 synthesis by platelets Facilitate release or response to nitrous oxide Inhibit release or response to constrictor factors Calcium channel antagonist role,Direct Effect on Myocardium,Estrogen receptors present in the heart and aorta ST segment changes induced by estrogen resemble those inducible by digoxin Evidence by echocardiogram of changes in stroke volume and mean acceleration Net result of possible positive inotropic effect,Hemostatic Effects,Complex and variable decreased fibrinogen and antithrombin III increased factor VII and Protein C overall observational findings suggest a reduction in risk of thrombosis,Other Effects,Carbohydrate metabolism increased insulin release and receptor sensitivity may be opposite at doses 1.25mg Antioxidant both estrogen and progesterone Body fat gynoid fat versus android fat,Progestin Effects on the Cardiovascular System,Progestin product dependent Progesterone receptors present in blood vessels In-vitro negation of increased PGI2 Attenuation of increased uterine blood flow Decreased estrogen receptor activity Blunting of estrogens effect on lipid profile,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 control cross sectional,Adapted from Stampfer et al. Prev Med 1991;20: 47-63.,RR,Relative Risk of CHD Among All Postmenopausal Hormone Users,Adjusted for multiple risk factors Adapted from Grodstein et al. NEJM 1996;335: 453-61. Nurse Health Study 1976-1994.,Hormone Use RR Major Coronary Disease,Never used 1.0 Currently used Estrogen 0.60 (0.43-0.83) Estrogen +progesterone 0.39 (0.19-0.78),Change in RR with Estrogen Therapy with and without Progesterone,Disease ERT ERT + Progesterone,Osteoporosis 0.40 0.40 Endometrial Cancer 6.0 1.0 Breast Cancer 1.37 1.60 Ischemic Heart Disease 0.52 0.69 Stroke 0.50 0.67 Mortality Change -328 -188 (per 100,000),Adapted from Ross et al. Lancet 1981;4:858-60.,Estimated Lifetime Probability of Selected Events with ERT,Condition Not Treated (%) Assumed RR %,CHD 46.1 0.65 34.2 Stroke 19.8 0.96 20.2 Hip Fracture 15.3 0.75 12.7 Breast Cancer 10.2 1.25 13.0 Endometrial CA 2.6 8.22 19.7 Life Expectancy (y) 82.8 83.7,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.,Estimated Change in Mortality with Estrogen Replacement Therapy,Condition RR Cumulative Change,Osteoporotic Fractures 0.4 - 563 per 100,000 Gallbladder Disease 1.5 + 2 per 100,000 Endometrial Cancer 2.0 + 63 per 100,000 Breast Cancer 1.1 + 187 per 100,000 Ischemic Heart Disease 0.5 - 5,250 per 100,000 Net 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 Death Current Past Never,All Cause 0.63 (0.56-0.70) 1.03 (0.94-1.12) 1.0 CHD 0.47 (0.32-0.69) 0.99 (0.75-1.30) 1.0 Stroke 0.68 (0.39-1.16) 1.07 (0.68-1.69) 1.0 All Cancer 0.71 (0.62-0.81) 1.04 (0.92-1.17) 1.0 Breast Cancer 0.76 (0.56-1.02) 0.83 (0.63-1.09) 1.0,Hormone Use,Adjusted for multiple risk factors Adapted from Grodstein et al. NEJM 1997;336: 1769-75. Nurse Health Study 1976-1994.,Summary of Observational Evidence,Meta-analyses relative risk of coronary heart disease is 0.50-0.65 with ERT addition of progesterone does not appear to attenuate the effect of ERT ERT estimated to save 5,250 lives per 100,000 users,Confounding Factors,Effects of progesterone Study biases Limitations of meta-analyses,Confounding Factors-progesterone,Early epidemiologic studies usually in women on estrogen replacement therapy only Progesterone formulations and their effects 19-nortestosterone derivates (levonorgesterol) 17-hydroxyprogesterone derivates (medroxyprogesterone) micronized progesterone,Confounding Factors-“healthy user”,Many studies demonstrate estrogen users: higher socioeconomic status better educated younger thinner more likely to drink alcohol,Confounding Factors-compliance,Long term hormone replacement therapy (HRT) users are “compliers” More likely to take ASA, MVI, and exercise Patients who comply 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-blocker Placebo Compliance % Mortality Relative Risk % Mortality Relative Risk 75% 4.5 0.53 6.8 0.36 Crude relative risk of mortality in women participating in the trial,Confounding Factors-compliance,Clofibrate Placebo Compliance % Mortality Relative Risk % Mortality Relative Risk 80% 15.7 0.70 16.4 0.64 Adjusted 5-year mortality rate and relative risk in high-compliance group compared with low-compliance group,Coronary Drug Project,Petitte DB Ann Epidemiol 4: 115-118, 1994,Relative risk of CHD is 0.5-0.65 with ERT Relative risk of mortality in some studies is 0.36-0.64 in patients compliant with placebo Estrogen users are by definition “compliant”,Confounding Factors-compliance,Suggestive that compliance bias, in theory, could account for most of the benefit of ERT seen in CHD,Confounding Factors-surveillance,Medical care sought on a more regular basis by HRT users risk factors identified earlier more likely to have preventative health screens,Confounding Factors-“healthy survivor”,Breast Cancer Detection Demonstration Project Follow-up Study (Sturgeon et al.) current ERT users had best survival recent past users had highest all cause mortality (greater than those who never used ERT),Confounding Factors: meta-analyses,Unable to remove biases from observational studies Not predictive 35% of the time LeLorier et al. NEJM 337(8): 536-542, 1997 Example-beta carotene supporting observational and mechanistic studies lack 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: prospective randomized double-blind placebo-controlled,HERS Study,Heart and Estrogen/progestin Replacement Study 2,763 women with CHD, mean age 67 0.625mg conjugated estrogens + 2.5mg medroxyprogesterone (PremproTM) daily vs. placebo Average follow-up was 4.1 years,JAMA 1998;280:605-613,650-652,Endpoints,Primary outcome was nonfatal MI or CHD death Secondary outcomes included total mortality, cancer death, 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 effect 90% power, 2-tailed alpha of 0.05 However lower than expected event rate (3.3% versus 5%) treatment duration (4.1 years versus 4.75) compliance rate (75% and 81% at 3 years) Offset by 18% more participants than planned,Heart and Estrogen/progestin Replacement Study. JAMA 1998;280:605-613,650-652,Demographics,No differences (p0.05) between groups in Age, Education CHD risk factors (LDL 145 +/- 37 mg/dL) CHD manifestations Medication use aspirin (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 MI 42 (3%) 29 (2%) CHD Death 17 11 End of study* Combined 172 176,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 HRT year one 52% year two no difference year three 13% years 4-5 23%,Results-primary endpoint,Heart and Estrogen/progestin Replacement Study. JAMA 1998;280:605-613,650-652,* p=0.009 for trend in log relative hazard,Results-primary endpoint,As-treated analysis 80% compliant by pill count no difference between groups relative hazard 0.87 (95% CI, 0.67-1.11) Subgroup analyses no differential effects in 86 subgroups,Heart and Estrogen/progestin Replacement Study. JAMA 1998;280:605-613,650-652,Results-other endpoints,Lipids 11% reduction in LDL (125mg/dL versus 140mg/dL) 10% higher HDL (54mg/dL versus 49mg/dL) 8% higher triglycerides (181mg/d