Estrogen and Coronary Heart Disease

1. Estrogen and Coronary Heart Disease by Brad Jones

2. Case Presentation • 56 y/o WF PMH significant for TAH on Premarin for 10 years. • Cardiovascular risk factors include history of early MI in father. • No documented coronary disease. • Should this patient be continued on estrogen for primary prevention of coronary heart disease (CHD)?

3. Goals of this presentation: • Discuss history of estrogen in CHD and review cardioprotective effects and observational studies • Review course of HRT not being recommended for secondary prevention of CHD ie HERS,ERA • Discuss the results from WHI • Review data that suggests that estrogen could be beneficial in preventing atherosclerosis formation • Attempt to go a step further and understand what is happening from a basic science standpoint • Finally, present some evidence to Dr. Dubose for the fishing in North Carolina.

4. Introduction Coronary heart disease is the leading cause of death in women, and mortality rates from this disease substantially increase after menopause. Bilateral oophorectomy before natural menopause increases the risk for CHD. This pattern along with over 40 observational studies have suggested that HRT reduces the cardiovascular risk in postmenapausal women. Furthermore, estrogen has been demonstrated to have seemingly beneficial effects on the cardiovascular system.

5. Beneficial effects on blood vessels Effects on Lipids Effects on coagulation cascade, both thrombosis and the fibrinolytic cascade. Decreases renin,ACE,endothelin-1,vascular expression of angiotensin receptor type 1,with the net effect of promoting vasodilation This increase in vasodilatation has been demonstrated by echo to decrease LV mass Antioxidant effects Effects of estrogen on the cardiovascular system

6. Many observational studies showing decreased mortality and cardiovascular events with estrogen The most comprehensive observational study is the Nurses’ Health Study. The NHS was first published in 1985 and updated in 1991,1996 and most recently updated in Annals of Internal Medicine(Grodstein et. al.) It began in 1976 when 121,700 female nurses age 30 to 55 years of age completed a mailed questionnaire about hormone use and CVD. In the latest report, with 70,533 post-menopausal women followed for up to 20 years, current HRT was associated with a relative risk reduction of 39% and .625mg and .3mg of conjugated estrogen with a relative risk reduction of 46% and 42% respectively.

7. Tanya and Chief (before Chief’s amazing growth spurt)

8. So when did we first realize that Estrogen was not beneficial in prevention of coronary heart disease?

9. The Coronary Drug Project • This study was published in JAMA in 1970 and among other interventions, looked at the effect of estrogen on CHD. • This study consisted of men age 30 to 64 with documented previous myocardial infarction. • After 18 months it was noticed that the estrogen group had significantly more events of nonfatal myocardial infarction than placebo. • Therefore the study arm receiving 5mg of daily estrogen was discontinued.

10. Excessive beverage intake

11. Excessive pork intake

12. Randomized Trial of Estrogen Plus Progestin for Secondary Prevention of Coronary Heart Disease in Postmenopausal Women • The HERS trial was the first randomized, double-blind, placebo-controlled trial of daily use of conjugated equine estrogens plus medroxyprogesterone acetate on the combined rate of nonfatal MI and CHD among postmenopausal women with coronary disease. • Briefly the study population was 2,763 postmenopausal women age 44 to 79 years old(mean age 66.7 years) with established coronary disease.(defined as history of MI, revascularization or angiographic evidence fof CAD) • Follow-up visits were every 4 months during the study period of 4.1 years. • Rsults: Primary events(nonfatal MI or CHD death) occurred in 172 women in the hormone group and in 176 in the placebo group; 33.1/1000 and 33.6/1000 respectively.

13. Results did not reach statistical significance; however it was noted that during the first year there was a trend towards increased events in the hormone group(relative hazard=1.52) followed by decreased events later in the trial.(see graph below) Figure 3. Kaplan-Meier estimates of the cumulative incidence of primary coronary heart disease (CHD) events (left) and to its constituents: nonfatal myocardial infarction (MI) (center) and CHD death (right). The number of women observed at each year of follow-up and still free of an event are provided in parentheses, and the curves become fainter when this number drops below half of the cohort. Log rank P values are .91 for primary CHD events, .46 for nonfatal MI, and .23 for CHD death.

14. Effects of Estrogen Replacement on the Progression of Coronary-Artery Atherosclerosis • In this study published by Herrington et. al. in The New England Journal of Medicine, 309 women age 41 to 80(mean 65.8)with angiographically verified coronary disease (>= to 1 stenoses of >= to 30% luminal diameter on angiography)were randomly assigned to receive .625mg of conjugated estrogen, .625 of estrogen plus 2.5mg of medroxyprogesterone, or placebo. • Patients underwent follow-up angiograms at 3.2 years. • Results: Repeat angiogram showed the mean minimal coronary-artery diameters at follow-up to be 1.87+/-.02mm,1.84+/-.02mm and 1.87+/-mm in the estrogen, estrogen and progesterone and placebo groups respectively. • Conclusions: Neither estrogen alone nor estrogen plus medroxyprogesterone affected the progression of coronary atherosclerosis in women with established diseased.

15. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal WomenPrincipal Results From the Women’s Health Initiative Randomized Controlled Trial The Women’s Health Initiative(WHI) is a randomized double blind placebo trial that enrolled 161,809 post menopausal women in the age range from 50 to 79 years. The trial was stopped early based on health risks that exceeded health benefits over an average follow-up of 5.2 years. A parallel trial of estrogen alone in women who have had a hysterectomy is being continued, and the planned end of this trial is March 2005, by which time the average follow-up will be about 8.5 years. Results Estimated hazard ratios (HRs) were as follows: CHD, 1.29; breast cancer 1.26; stroke, 1.41; PE, 2.13; colorectal CA, .63; endometrial cancer, .83; hip fracture, .66 and death due to other causes .92. Absolute excess risks per 10,000 person-years attributable to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while absolute risk reductions per 10,000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10,000 person-years.

16. Coronary Heart Disease in WHI Study • CHD was defined as acute MI requiring overnight hospitalization, silent MI determined from serial electrocardiograms(ECGs), or CHD death. • Overall the rate of women experiencing CHD events was increased by 29% for women taking estrogen plus progestin relative to placebo(37 vs 30 per 10,000 person-years). Of note the excess was in nonfatal MI with no significant differences in CHD deaths or revascularization procedures. • A small group was eligible for HERS

17. Figure 3. Kaplan-Meier Estimates of Cumulative Hazards for Selected Clinical Outcomes

18. How could it be with the beneficial effects of estrogen on the CVS, along with multiple observational trials that these trials have shown estrogen to have no benefit and even mild increase in CHD events? In interpreting the data one has to realize that HERS and ERA are secondary prevention trials. Also WHI, which is thought of as a primary prevention trial, the mean age of beginning HRT was much later than most clinicians institute HRT for perimenapausal symptoms. Also some of the women in the WHI had documented coronary disease.

19. Chief meets Bailey

20. Do we have any RCTs for estrogen decreasing progression of atherosclerosis Hodis et. al. published an article in Ann In Med 2001 titled The Estrogen in the Prevention of Atherosclerosis Trial(EPAT). This was a randomized, double-blind, placebo-controlled, carotid artery ultrasound trial designed to test whether unopposed estrogen vs placebo reduces progression of subclinical atherosclerosis in healthy postmenopausal women without preexisting CVD. Methods:222 subjects with a mean age of 61.1 years and average time from menopause to randomization of 13 years. Carotid ultrasound was performed at baseline and every 6 months during the trial. The primary endpoint was the was the rate of change in the distal common carotid artery IMT(intima-medial wall thickness) Note: Thickening of the intima-media of the arterial wall is the earliest detectable anantomic change in the development and progression of atherosclerosis and carotid intima-media thickness is a marker of generalized atherosclerosis and is predictive of clinical cardiovascular events.

21. Results After 2 years, there was a significant reduction in the progression of carotid IMT in women randomized to unopposed estrogen replacement therapy versus those randomized to placebo. The authors concluded that unopposed 17b-estradiol reduced the progression of subclinical atherosclerosis to the same degree as lipid-lowering therapy and lipid-lowering therapy appeared not to add any additional benefit to unopposed estrogen in reducing the progression of subclinical atherosclerosis.

22. Data for atherosclerosis prevention in cynonmologus monkeys • Dr. TB Clarkson published a review in Cardiovascular Research in which they describe the life cycle into 3 stages: • Stage 1, or immediately after ovariectomy, monkeys given CEE had average inhibition of coronary artery atherosclerosis of 70% • Stage 2, monkeys were allowed to develop a moderate amount of atherosclerosis before surgical menopause. The degree of inhibition of CAD by CEE was reduced to 50%. • Stage 3, CEE was held 2 years after surgical menopause, and no inhibition of in the extensiveness of CAD was observed.

24. Therefore, it seems that the effects of estrogen on the CVS could be beneficial if started prior to development of significant coronary disease; whereas after coronary lesion development it could actually precipitate plaque rupture.

25. It is possible that the disappointing results from the previously described trials could be from the effects of estrogen on the coagulation cascade or polymorphisms that alter gene expression of proteins that regulate coagulation or fibrinolysis. While recognizing this as a likely reason, I would like to introduce another possibility.

26. To understand what could be causing increased early events with estrogen therapy, it is helpful to understand the microstrucure of the atheromatous plaque within coronary arteries.

27. Beach trip 2001

28. Estrogen Effects on the Natural History of Atherosclerosis • Estrogen Effects in Atherogenesis • LDL oxidation  LDL atherogenicity • LDL binding/accum  lesion prog • Cell adhesion mol.  monocyte adhesion/  macrophage accum • SMC proliferation  lesion progression • Endothelial function  vasodilation Estrogen Effects in Established Plaques Inflammation  PQ instability lesion progression MMP expression  PQ instability/rupture Neovascularization  PQ hemorrhage Loss of Estrogen Benefits Methylation of estrogen receptors Vascular responsivity Benefits of estrogen on atherosclerosis Potentially adverse effects of estrogen on athero/CHD

32. So what causes erosion or more frequently rupture of the fibrous cap surrounding the prothrombotic contents in the lipid core? It is thought that enzymes that reside in the shoulder region of atheromatous plaques may digest the collagen matrix and cause plaque rupture with resulting thrombus formation. These enzymes are intricately tied to the coagulation cascade as well as platelet aggregation.

33. Matrix Metalloproteinases or MMPs MMPs are members of a family of Zn-dependent endopeptidases capable of cleaving components of extracellular matrix. They are secreted as inactive proenzymes or zymogens and subsequently are activated and are capable of collectively degrading all components of the fibrous cap. Of interest to the topic at hand MMPs have been identified to reside in the shoulder region of atheromatous plaques. Furthermore estrogen has been implicated in their activation as well increased levels of MMP-9.

35. Beach trip 2002

36. Metalloproteinase and Gelatinolytic Activity of Human Coronary Artery Atherosclerotic Plaques From Galis et al, J Clin Invest, 1994

37. Divergent effects of hormone therapy on serum markers of inflammation in postmenopausal women with coronary artery disease on appropriate medical management In this study 10 women with CAD were randomly assigned to .625mg of equine estrogen(progestin 2.5mg added to women with uterus in tact) Results: By zymography proteolysis by MMP-9 was greater in serum samples from patients on HRT relative to placebo. Also MMP-9 levels measured by ELISA was greater as well in the serum of the HRT users.

38. Conclusion Physiologic rationale or an observational study usually accurately predicts the results of RCTs. However, this is not always the case. The problem is, one never knows in advance if the particular instance is one in which the preliminary data reflect the truth, or whether they are misleading. Confident clinical action must generally await the results of RCTs.

39. Finally I wanted to present some evidence to Dr. Dubose for the fishing in North Carolina.

40. More evidence for the fishing in North Carolina…

41. So what do I tell my patients and similar patients in clinical practice? I feel that it is obvious from the data that patients should not be started on HRT for secondary prevention of coronary disease. Also the results from the WHI show that women without known coronary disease should not be started on combined estrogen + progesterone for primary prevention. It is much less clear about the patient at hand, however we do not have RCTs to support continuing estrogen. What I plan to do is what we should do with all patients, which is to educate them to help to collectively make the best decision about their health. The risks of HRT are small and it is not known if there is benefit in the patient at hands case. Of course, in all circumstances the effects of estrogen on other preventions as well as benefit from postmenapausal symptoms must be considered. But with respect to CHD we still await completion of the estrogen arm of the WHI and studies of HRT being started in a younger group of women. Until then we have treatment proven for prevention of atherosclerosis (i.e. statins) and should use these in the interim.

42. Chief on the last day of vacation at the beach.

43. Special thanks to: • Dr. Herrington • Dr. Clarkson • Dr. Hadley • My, wife Tanya