HORMONE REPLACEMENT THERAPY AND CARDIOVASCULAR DISEASE

, Chapter 4 HORMONE REPLACEMENT THERAPY AND CARDIOVASCULAR DISEASE BACKGROUND Considerable available data demonstrate that postmenopausal hormone replacement therapy (HR T) is cardioprotective. The benefits, for an overall reduction in mortality, are greatest for those women at highest risk for coronary heart disease (CHD). EPIDEMIOLOGICAL STUDIES OF EFFECTS OF HRT ON CHD RISK Coronary heart disease (CHD) is the leading cause of death amongst post-menopausal women. A 50-year-old Caucasian woman has a tenfold greater likelihood of dying from CHD than from breast cancer} The majority of cohort and case-control studies which have evaluated the relationship between post-menopausal HRT and CHD have found a decrease in CHD risk which is between 40 and 50 percent. I Cessation of therapy is associated with a reduced rate of cardiovascular protection, suggesting that much of the beneficial effect of HRT on CHD risk is due to a direct vascular action. 1 3 Angiographic studies have also demonstrated benefit: Four human studies, including the Nurses' Health Studyl have suggested similar benefit for women taking estrogen therapy alone or estrogen with progestin. Further data on the effects of estrogen and progestin on CHD and non-chd outcomes are expected by 2005, when results become available from the Women's Health Initiative (WHI). EFFECTS OF ESTROGEN AND PROGESTINS ON LIPOPROTEIN METABOLISM In women, plasma HDL-cholesterol (HDL-C) and triglyceride levels are recognized to be independent predictors of cardiovascular death. 6 Part of the beneficial effect of' HR T on CHD risk can be attributed to effects on plasma lipoproteins (Table 1). Oral estrogen results in an eight to fifteen percent decrease in plasma levels ofldl-cholesterof-8 and a 14 to 18 percent decrease in plasma levels of lipoprotein(a).9 The majority of these studies used conjugated equine estrogens (CEE). Postmenopausal women have lower levels of HDL-cholesterol than do premenopausal women,1o and HDL-C levels increase by seven to fifteen percent with oral estrogen replacement therapy. Transdermal estrogen decreases LDL-C by five to eight percent, has little effect on HDL-C and lowers Lp(a) by 19 to 24 percent. non Medroxyprogesterone acetate, but not micronized progesterone, attenuates the effect of estrogen on HDL-C. ll The effect ofhrt on plasma lipoproteins appears to be important in predicting cardiovascular benefit. Oral (but not transdermal) estrogen therapy increases serum triglyceride levels. Clinically, this effect is likely to be important only in women with underlying hypertriglyceridaemia, but a full lipid profile should be carried out before starting HR T. TABLE 1 EFFECTS OF ESTROGEN AND SERMs34 ON PLASMA LlPOPROTEINS Oral Transdermal SERMs Estrogen Estrogen Triglyceride 15-35% i 6-18%.1 minimal change LDL-C 8-15%.1 5-8%.1 12%.1 HDL-C 7-15%i minimal change 'Hoi. 2 -c 15-1 i%t HDL-C minimal change Lp(a) 14-18%.1 19-24%.1 7-8%.1. - - JOURNALSOGC 1259 NOVEMBER1998

ENDOTHELIAL EFFECTS OF ESTROGEN It is estimated that only 25 to 30 percent of the observed reduction in CHD incidence is attributable to changes in the lipid profile, 1 based on recent studies which have focused on the beneficial effects of estrogen on vasomotor function, haemostasis and insulin resistance. Circulating estrogen may promote endothelial vasodilatation by a number of mechanisms. Premenopausal women have lower levels of plasma endothelin than men. Recently, transdermal HRT has been shown to induce rapid and sustained release of nitric oxide (NO) from endothelial cells, resulting in vasodilatation. 14 Exposure of arterial endothelium to estrogens appears to induce an estrogen receptor-mediated, antioxidant effect, which enhances the biological activity of NO. The effects of HRT on exercise tolerance, anginal symptoms, acetylcholine (ACh) responses in epicardial coronary arteries, and flow-mediated vasodilatation in the brachial arteries have been studied. Estrogen replacement therapy improves anginal symptoms, decreases coronary artery resistance and increases basal coronary blood flowy-ls These effects were demonstrable in women but not in men,19 indicating that the immediate effects of estrogen are receptor-mediated. In postmenopausal women, estrogen receptor concentrations are decreased in smooth muscle cells of coronary arteries and in atherosclerotic segments of coronary arteries. Estrogen administration results in upregulation of estrogen receptors, suggesting that chronic exposure may enhance the vascular effects of estrogen. CARDIOVASCULAR EFFECTS OF SELECTIVE ESTROGEN RECEPTOR MODULATORS Estrogens exert their protective effect on the cardiovascular system by diverse mechanisms. Information regarding the cardiovascular effects of selective estrogen receptor modulators (SERMs) is much less complete. In healthy post-menopausal women, raloxifene (Table 1) and tamoxifen reduce plasma LDL-cholesterollevels.21 22 Raloxifene does not, however, increase total HDL-cholesterollevelsY Long-term tamoxifen administration appears to be associated with a sustained decrease in circulating fibrinogen. 21 Tamoxifen and, more clearly, 4- hydroxytamoxifen, has been shown to protect isolated human LDL-cholesterol against oxidative modification,zl similar to the reported effects of estrogen. Thus, SERMs appear to have some, but not all of the protective effects of estradiol on the cardiovascular system. Long-term studies are underway to determine whether SERMs have beneficial effects on cardiovascular outcomes. SUMMARY The available epidemiological and clinical data indicate benefical effects of HR T on CHD risk. Women with multiple risk factors for CHD, are likely to demonstrate the greatest overall benefit (Tables 2 and 3 ).24 Further studies are required to define optimal HR T regimens for cardioprotection. QUESTIONS AND ANSWERS 1. Can I use HRT in patients with a history of deep vein thrombosis (DVT)? Yes, after appropriate counselling and investigation. There are differences in plasma levels of procoagulant and fibrinolytic factors in premenopausal and postmenopausal women, and these are altered by HR T. TABLE 2 WOMEN WITH ABOVE-AVERAGE RISK FOR CORONARY HEART DISEASE Women with the following risk factors are at above average risk for CHD, and may have the strongest indications for HRT: - coronary or peripheral vascular disease - serum LDL-C > 3_S mmol/l - serum HDL C < 1_0 mmol/l - diabetes mellitus - a family history of CHD in a first degree relative (male < 55y; female < 6Sy) - cigarette smoking - hypertension (systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg or on antihypertensive drugs) TABLE 3 RISK FACTORS FOR HEART DISEASE Modifiable Non modifiable 1_ smoking 1. Geneticfactors 2. hypertension 2. Increasing age 3_ hyperlipidaemia 4. abdominal obesity 5_ physical inactivity 6_ diabetes mellitus 7. estrogen.deficient post menopausal status -.- JOURNAL SOGe 1260 NOVEMBER 1998

Numbers of controlled studies have shown increased fibrinolytic activity25 in women receiving HRT compared to estrogen-deficient controls. At the same time, oral estrogen has procoagulant activity, as demonstrated by an increase in anti-thrombin-iil activity and prothrombin activation peptide (F 1 + 2). 26 Two case-control studies of venous thrombo-embolism (VTE) and one prospective study of pulmonary emboli each showed a similar three-fold to four-fold increase in risk with postmenopausal oral HR T use. 17-29 Although the data are less extensive, studies have reported a three- to five-fold increase in risk for VTE with use of tamoxifen and a three-fold increase in risk for raloxifene.'o While biochemical data suggest a theoretical advantage of transdermal HRT in women with a history of VTE, clinical data are not yet available. Hormone replacement therapy is not contra-indicated for women with thrombophilia who are appropriately anticoagulated. Recommended investigations for a patient with a history of VTE contemplating use of an estrogen-containing preparation are listed in Table 4. 2. Can I use HRT in a woman who has had a stroke? Yes, after appropriate investigations and counselling. The HRT does not appear to alter the overall risk of stroke. There is no contra-indication to HRT in a patient who has had a haemorrhagic stroke or in a patient who is appropriately anticoagulated following an embolic event. Hormone replacement therapy can also be used in a patient with a prior history of thrombotic stroke treated with prophylactic doses of acetylsalycylic acid (ASA). Patients with carotid vessel atherosclerosis and a history of an ischaemic cerebral vascular event may benefit from concomitant HRT and lipid-lowering therapy. 3. What about the use of aspirin in women? Data from the Nurses' Health Study indicate that, in women, the regular use of low-dose ASA (one to six TABLE 4 INVESTIGATIONS FOR THE PATIENT WITH A HISTO RY OF DVT Platelet count INR. PTT Protein S Protein C Antithrombin III Activated protein C resistance (Factor V Leiden) Lupus anticoagulant tablets per week) may provide protection against initial myocardial infarction. Prophylactic ASA may be of particular importance in high-risk women (smokers, women with hypercholesterolaemia, diabetics). Higher ASA doses do not confer additional protection. 31 4. What are the cardiovascular effects of adding progestin or androgen to estrogen replacement? Synthetic progestins (but not micronized progesterone) attenuate the beneficial effects of estrogen on serum HDL-cholesterol concentrations. 11 However, in prospective studies, the degree of cardioprotection conferred by estrogen-progestin replacement appears to be similar to that of estrogen alone. 6 There are no data on the risk of cardiovascular disease if androgen is added to HRT, but androgens tend to have more profound effects than progestins in lowering HDL-cholesterol levels. 5. What do I need to know about HRT and hyperlipidaemia? Women should undergo a full lipid screen (serum total cholesterol, triglycerides, LDL- and HDL-cholesterol) starting at the time of the menopause and repeated every five years until the age of 75, if normal. 32 The lipid screen should be repeated three to six months after beginning HRT if the initial serum triglyceride level was 2.5 mmol/l or greater. Optimal lipid levels in women with or without coronary heart disease or peripheral vascular disease (PVD) are shown in Table 5. 6. Can I use HRT in patients with hypertension? Large controlled trials, for example, the PEPI Trial, II have found no significant changes in blood pressure with oral administration of HRT. A study comparing percutaneous and oral HR T found no change in blood pressure in treated women over two years, whereas the placebo group showed an increase." The presence of hypertension is not a contra-indication to HRT use. It may, in fact, have a favourable effect on blood pressure due to beneficial changes in thromboxane and pros tacyclin activity. TABLES OPTIMAL LIPID LEVELS LDL-cholesterol Ratio of total to T riglycerides (mmoi/l) HDL-cholesterol (mmoill) No history of CHD < 3.5 < 5 < 2.0 CHD or PVD < 2.5 < 4 < 2.0 JOURNAL SOGC 1261 NOVEMBER 1998

ADDENDUM There arc extensive data from observational studies ugge'ting that oral HRT i as ociated with a ub tantial decrea e in CHD ri k. In contra t, the recently published Heart and Estrogen/Proge tin Replacement tudy (HERS) did not indicate any overall benefit of continuou combined therapy with Premarin and Provera.1 There was a statistically non- ignificant increa e in non-fatal MI and CHD death in the fir t year among women randomized to HRT, and a trend toward decrea ed mortality in the HRT-treated group from the second to fourth years of the study. Interpretation of the e re ult wa confounded by the fact that concomitant medical treatment was not in accord with current practice guidelines e.g. only 78 percent of women were taking aspirin, 32 percent were taking ~ - b l o and c k only e r 10 percent achieved the LDL-chole terol target for patient with CHD «2.6 mmol/l).2 In addition, significantly more women in the placebo group were given lipid lowering treatment (mainly tatin) which ha it elf been hown to reduce CHD event in women. It is possible that longer term follow-up might have demonstrated on overall benefit of HRT in women with CHD. The author were careful to tre that their findings could only be appli d to thi particular combination of medication in this particular group of patients. While the data did not upport de novo treatment with continuou Premarin and Provera for the purpo e of secondary prevention of CHD, the author did not recommend alteration or discontinuation of e tablished HRT regimens in women with CHD. There is a need for further clinical and laboratory tudies on the effect of HRT on a variety of CHD ri k factor. Information on the long-term benefit of various HRT regimens on CHD and non-chd outcome for women without a previous history of CHD i being collected in the Women' Health Initiative Randomized Trial. Result are expected after 2005. 1 REFERENCES 1. Hulley S, Grady D, Bush T, Furberg K, Herrington D, Riggs B, Vittinghoff E for the Heart and Estrogen/Progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:60S-13. 2. Second Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel). JAMA 1993;269:3015-23. REFERENCES 1. Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Emster VL, Cummings SR. 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