Estrogen-Progestin Replacement Study Research Articles

Racial Differences in Atrial Fibrillation Prevalence and Left Atrial Size

Background Previous studies relying on clinical care data have suggested that atrial fibrillation is less common in African Americans than Caucasians, but the mechanism remains unknown. Clinical care may itself vary by race, potentially affecting the accuracy of atrial fibrillation ascertainment in studies relying on clinical data. We sought to examine racial differences in atrial fibrillation prevalence determined by protocol-driven electrocardiograms (ECGs) obtained in prospective cohort studies and to study racial differences in echocardiographic characteristics. Methods We pooled primary data from 3 cohort studies with atrial fibrillation adjudicated from study protocol ECGs and documentation of potentially important confounders: the Heart and Soul Study (n = 1014), the Heart and Estrogen-Progestin Replacement Study (n = 2673), and The Osteoporotic Fractures in Men Sleep Study (n = 2911). Left atrial anatomic dimensions were compared among races from sinus rhythm echocardiograms in the Heart and Soul Study. Results Of the 6611 participants, 268 (4%) had atrial fibrillation: Caucasians had the highest prevalence (5%), and African Americans had the lowest (1%; P <.001 for each compared with all other races). After adjustment for potential confounders, Caucasians had a 3.8-fold greater odds of having atrial fibrillation than African Americans (95% confidence interval, 1.6-8.8, P = .002). Although ventricular and atrial volumes and function were similar in Caucasians and African Americans, Caucasians had a 2 mm larger anterior-posterior left atrial diameter after adjusting for potential confounders (95% confidence interval, 1-3 mm, P <.001). Conclusion ECG confirmed atrial fibrillation is more common in Caucasians than in African Americans, which might be related to the larger left atrial diameter observed in Caucasians.

Hormone Replacement Therapy and Stroke

Stroke is the third most common cause of death in women and a major cause of disability. Stroke occurs in older age in women compared with men. High premenopausal estrogen concentrations in women are thought to be protective against stroke and cardiovascular disease. Estrogens are essential for normal reproductive function and they exert complex and diverse non reproductive actions on multiple tissues such as neuroprotective effects, vasodilatation, improved vascular reactivity, antithrombotic effects and lipid lowering effects. After menopause estrogen concentrations are depleted and in the past estrogen replacement therapy was considered as a potential protective agent against both cardiovascular disease and stroke. Although the use of hormone therapy was originally associated with a reduction in the risk of heart disease by about 50% in observational studies, the results regarding stroke have been less clear. In order to investigate the effect of hormone therapy on stroke risk, randomized controlled trials of cardio-and/or cerebrovascular-disease prevention in women with established heart disease have been designed. The Heart Estrogen-Progestin Replacement Study included stroke as secondary outcome. This study did not show any differences in myocardial infarction (MI) or coronary death (HR 0.99; 95%CI 0.80-1.22) and in stroke rate. In another study, the Women Estrogen Stroke Trial, 17 beta estradiol 1 mg/placebo was administered to women with previous ischemic stroke or transient ischaemic attack (TIA) having a mean age 71. No differences in stroke rate (RR 1.1; 95% CI 0.8-1.4) and in mortality rate (RR 1.2; 95% CI 0.8-1.8) were found, while a trend showing an increased rate of fatal strokes (RR 2.9; 95% CI 0.9-9.0) and for more severe non-fatal strokes (% patients with final National Institutes of Health Stroke Scale (NIHSS) 0-1: 19 % vs. 33%; p = 0.12) was observed. The Women's Health Initiative, a primary prevention study, where conjugated equine estrogen (CEE) plus medroxyprogesterone acetate/placebo was utilized, was stopped because of an excess in breast cancer and increased stroke rates (RR 1.4; 95% CI 1.1-1.8). Recently, a meta-analysis including 39,769 women participating in 28 trials has been published. Twelve studies were of secondary prevention and the overall stroke rate was 2%. In the hormone replacement therapy (HRT) arm there was a 29% increased rate of ischemic stroke (Number Needed to Harm, NNH:147). Furthermore, a 56% increased rate of death or dependency after stroke and a tendency of more fatal stroke were observed. Additionally, a higher stroke risk was reported in the first year of treatment. There seems to be no indication for hormone replacement therapy in the prevention of stroke in women. Further studies are needed to discover why estrogens have different effects on the heart and brain. Conventional risk-factors which could increase the risk of estrogen therapy need to be identified and as well as more restrictive inclusion and exclusion criteria such as coagulation parameters and intimal thickness should be adopted before new randomized trials are started.

In Defense of Pharmacoepidemiology — Embracing the Yin and Yang of Drug Research

The past decade has not been kind to observational studies of medications. The damage began in 1998 with the publication of the Heart and Estrogen–Progestin Replacement Study, a randomized controlled trial showing that hormone replacement increased the risk of cardiac events among postmenopausal women with heart disease. Like many physicians, I had been teaching the gospel that estrogen use prevented heart disease — an idea based on observational studies1 showing that postmenopausal women who regularly took estrogen were less likely to have heart disease than apparently similar women who did not take hormones. It now appeared that this had been . . .

Hormone replacement therapy and colorectal cancer: an update

Observational studies and randomized clinical trials that have looked at the effect of hormone replacement therapy (HRT) on the risk of colorectal cancer are reviewed. Nine cohort studies in this area have included a total of over 2700 cases of colorectal cancer. Most of these studies found a relative risk (RR) of around or below unity. Of 15 case-control studies, with a total of over 7300 cases, six reported a 20-40% risk reduction among women who had ever used HRT. With reference to randomized clinical trials, in the Women's Health Initiative (WHI) study, after seven years of follow-up, 45 cases of colorectal cancer were observed in the combined HRT group versus 67 in the placebo group, corresponding to a RR of 0.63. A combined reanalysis of data from both the WHI and the Heart and Estrogen Progestin Replacement Study (HERS) included 56 cases in the combined HRT group and 83 cases in the placebo group (pooled RR = 0.64). However, in the WHI study cancers diagnosed in the HRT group were more advanced and there were more positive lymph nodes. Furthermore, among women in the WHI who had had a hysterectomy, there was no difference at the eight-year follow-up in the incidence of colorectal cancer between those in the estrogen-only arm of the trial (n = 61) and those in the control group (n = 68).

The Relation of Postmenopausal Hormone Therapy to Serum Uric Acid and the Risk of Coronary Heart Disease Events: The Heart and Estrogen–Progestin Replacement Study (HERS)

To determine whether baseline serum uric acid (UA) levels and estrogen-progestin (E+P)-associated change in serum UA in postmenopausal women with coronary disease are associated with recurrent coronary heart disease (CHD) events. 2763 postmenopausal women enrolled in the Heart and Estrogen-Progestin Replacement Study (HERS) were randomly assigned to take conjugated E+P or placebo in a secondary CHD prevention study. The primary outcome for these analyses was nonfatal myocardial infarction or CHD death during a mean follow up of 4.1 years. The baseline serum UA for the cohort was 5.4 mg/dl and, compared with placebo, E+P on average lowered serum UA levels slightly (0.2 mg/dl) at one year of follow up (p<0.0001). Baseline serum UA levels were associated in simple proportional hazards models with CHD events; each standard deviation increase (1.3 mg/dl) was associated with a 22% increased risk of primary CHD events (p=.0001). This association, however, was no longer statistically significant after multivariable adjustment (p=0.36). There was no association between on-study change in serum UA level and any CHD outcome. Treatment with E+P lowered serum UA levels slightly, but neither baseline UA nor change in UA affected CHD risk.

Effect of hormone therapy on mortality rates among women with heart failure and coronary artery disease

Randomized, controlled trial data from the Heart and Estrogen-progestin Replacement Study were used to evaluate the effect of estrogen plus progestin use on all-cause mortality in women with heart failure and coronary disease. Over the 4.1-year follow-up, estrogen plus progestin use had no effect on all-cause mortality (hazard ratio 1.0, 95% confidence interval 0.7 to 1.4, p = 0.8) in women with heart failure and coronary disease.

Matters of Sex

Despite the popular concept that heart disease preferentially affects the male population, in every year for the past 16 years, cardiovascular disease has killed more women than men.1 Unfortunately, a disparity still exists between men and women in the diagnosis and aggressive treatment of heart disease. The perception that women are relatively protected is reflected by the fact that women are much more fearful of dying from some form of cancer than from cardiovascular disease.1 Understanding any risk factors that predispose or protect the female population from cardiovascular and coronary disease is therefore a compelling goal for the research community. See p 1419 Left ventricular hypertrophy is a compensatory response of the heart to a variety of stresses, and it is a strong predictor of morbidity and mortality in individuals whether or not they have been diagnosed with cardiovascular disease. Sex differences in the development of this disease over time have been suggested by clinical studies dealing with patients who suffer from aortic stenosis or hypertension.2,3 For example, older female patients with aortic stenosis tend to have increased hypertrophy accompanied by greater concentric remodeling and preserved left ventricular function when compared with male patients. Premenopausal women, in fact, exhibit a thinner posterior wall, smaller left ventricular mass, and better load-dependent and load-independent cardiac function than age-matched men under conditions of mild essential hypertension.4 Population studies have shown an age-dependent increase in left ventricular mass in healthy normotensive women that is not seen in men, as determined by echocardiography.5 These and many other studies in both humans and animals suggest that estrogens can affect the remodeling of the heart. Estrogens are potent vasodilators; they act in this capacity by increasing nitric oxide production. However, recent findings indicate that estrogens have direct actions on the myocardium as …

Postmenopausal Hormone Therapy and Risk of Stroke: The Heart and Estrogen-Progestin Replacement Study (HERS)

Background—Observational studies have shown that postmenopausal hormone therapy may increase, decrease, or have no effect on the risk of stroke. To date, no clinical trial has examined this question. To investigate the relation between estrogen plus progestin therapy and risk of stroke among postmenopausal women, we analyzed data collected from the Heart & Estrogen-progestin Replacement Study (HERS), a secondary coronary heart disease prevention trial. Methods and Results—Postmenopausal women (n=2763) were randomly assigned to take conjugated estrogen plus progestin or placebo. Primary outcomes for these analyses were stroke incidence and stroke death during a mean follow-up of 4.1 years. The number of women with strokes was compared with the number of women without strokes. A total of 149 women (5%) had 1 or more strokes, 85% of which were ischemic, resulting in 26 deaths. Hormone therapy was not significantly associated with risk of nonfatal stroke (relative hazard [RH] 1.18; 95% CI 0.83 to 1.66), fatal...

Postmenopausal hormone therapy and risk of stroke. The Heart and Estrogen-Progestin Replacement Study (HERS)

Postmenopausal hormone therapy and risk of stroke. The Heart and Estrogen-Progestin Replacement Study (HERS)

Cardiovascular effects of estrogen

There is a strong link between menopause and increased cardiovascular disease incidence in women, and observational studies suggest that postmenopausal hormone replacement therapy (HRT) reduces cardiovascular disease risk. However, the only published prospective controlled trial of the effects of HRT on cardiovascular outcomes (Heart and Estrogen-Progestin Replacement Study, HERS) showed no net benefit of conventional HRT in women with established coronary disease. An angiograpic study of HRT in a similar patient population showed no regression of established coronary lesions in the active treatment group. Fundamental mechanistic studies of the cellular and molecular events by which hormones protect (or fail to protect) blood vessels are needed to define the role of postmenopausal HRT in cardiovascular disease. Herein, we review studies from our laboratory using the rat carotid injury model showing that estrogen inhibits neointima formation through an estrogen receptor (ER)-dependent mechanism operative in the early period after vascular injury. We have demonstrated that activation of vascular smooth muscle cells and subsequent release of soluble factors including osteopontin stimulate the migration of adventitial fibroblasts in a luminal direction to eventually take up residence in the neointima, and furthermore, that production, release, or posttranslational processing of these factors are inhibited by estrogen through an ER-dependent mechanism. The relevant observational and prospective data on HRT in cardiovascular disease prevention are reviewed, and the cardiovascular effects of estrogen are discussed.

Women's heart problems are poorly understood.

Why and when women develop heart disease is both poorly understood and studied, said experts at the 21st Congress of the European Society of Cardiology, held in Barcelona. “Men and women are similar with regard to risk factors,” said John Martin, MD, of the University of London Cardiology Group. These similar heart disease risk factors include high blood pressure, high cholesterol, smoking, and age, said Dr Martin. Yet, he said, women with diabetes often have a higher risk of heart disease than men with diabetes. Women are also more likely to die of a first heart attack than men. As with men, death rates from heart disease in women vary from country to country. Heart disease death rates for women are lowest in Spain and highest in Scotland, he said. Again, as with men, this variation in rates is not well-understood. Even more puzzling are the variations in death rates, particularly in the acute phase just after a heart attack, when the patient is hospitalized. In a recent study in the New England Journal of …

Arthur C. Corcoran Memorial Lecture. Hormones and vasoprotection.

There is a strong link between menopause and increased cardiovascular disease incidence in women, and observational studies suggest that postmenopausal hormone replacement therapy reduces cardiovascular disease risk by about half. Observational studies suffer from important limitations, however, and the only published prospective controlled trial of the effects of hormone replacement therapy on cardiovascular outcomes, the Heart Estrogen-Progestin Replacement Study (HERS), showed no net benefit of continuous estrogen plus synthetic progestin treatment in women with established coronary disease. Fundamental mechanistic studies of the cellular and molecular events by which hormones protect (or fail to protect) blood vessels from damage are needed to define the role of postmenopausal hormone replacement therapy in cardiovascular disease prevention. Most studies suggest that estrogen inhibits the neointimal response to acute injury in normal blood vessels, but this vasoprotective effect was not seen in vessels with preexisting atherosclerosis. Studies from our laboratory in the rat carotid injury model have shown that estrogen inhibits neointima formation via effects on all 3 layers of the vascular wall, including inhibition of medial smooth muscle cell migration and proliferation, stimulation of regrowth of endothelium, and inhibition of adventitial cell migration into neointima. Our laboratory is currently using transduced (lacZ) syngeneic fibroblasts as 'reporter' cells to delineate the factors that stimulate migration of adventitial cells into neointima after vascular injury and their modulation by estrogen and the other sex hormones. These fundamental studies will establish more rational strategies for therapeutic intervention in vascular diseases, including the basis for future gene therapy.

Ascorbic Acid Supplement Use and the Prevalence of Gallbladder Disease

To investigate the relation of ascorbic acid supplement use to gallbladder disease and cholecystectomy, we conducted a cross-sectional analysis of baseline from 2744 postmenopausal women, aged 44–79 years, enrolled in the Heart & Estrogen-progestin Replacement Study (HERS), a secondary coronary heart disease prevention trial. A total of 629 HERS participants (23%) reported a history of gallbladder disease. Of these, 508 (19%) also reported a history of cholecystectomy. In bivariate models, ascorbic acid supplement use was associated with a decreased prevalence of gallbladder disease (odds ratio [OR] = 0.74; 95% confidence interval [CI], 0.57, 0.96) and a trend toward a decreased prevalence of cholecystectomy (OR = 0.77; 95% CI, 0.58, 1.02). Because we detected significant interactions between ascorbic acid supplement use and alcohol consumption, multivariate analyses were performed stratified by drinking status. After adjustment for potential confounding variables, use of ascorbic acid supplements among drinkers was associated with a decreased prevalence of gallbladder disease (adjusted OR = 0.50; 95% CI, 0.31, 0.81) and cholecystectomy (adjusted OR = 0.38; 95% CI, 0.21, 0.67). Use of ascorbic acid supplements among non-drinkers was not significantly associated with either prevalence of gallbladder disease or cholecystectomy. Further study is necessary to confirm our findings and, specifically, to examine the combined effects of ascorbic acid and alcohol on cholesterol metabolism.

Megatrials of hormonal replacement therapy.

Despite the fact that estrogen replacement therapy has been demonstrated to be of great value to postmenopausal women, many patients are still reluctant to use it. This is primarily because of fears that sex hormone therapy increases the risk of developing uterine and breast cancer. Because retrospective epidemiological studies have failed to clarify the issue for breast cancer, ambitious prospective trials have been initiated to determine the role of hormones in the development of breast cancer and cardiovascular disease. The main studies have been the Women's Health Initiative, the Postmenopausal Estrogen/Progestin Intervention (PEPI) Trial, the Heart and Estrogen-Progestin Replacement Study (HERS), the Women's International Study of long Duration Oestrogen after Menopause (WISDOM) and the Million Women Study. Only the PEPI Trial has been completed. It showed a substantial benefit for women using hormone replacement therapy, but was insufficiently powerful to determine whether such therapy affected the incidence of breast cancer. Despite the immense costs involved and the considerable time that must elapse before results are published, it is imperative that these major prospective studies are completed, analysed and published. Only then can physicians advise their patients in an appropriate manner.

Venous Thromboembolic Events Associated With Hormone Replacement Therapy

To the Editor. —The Heart and Estrogen-Progestin Replacement Study (HERS) is a randomized, double-blind, placebocontrolled trial designed to test the effect of hormone replacement therapy on the rate of new coronary heart disease (CHD) events in 2763 postmenopausal women younger than 80 years who had preexisting CHD and an intact uterus at enrollment. Participants were randomly assigned to take 1 tablet daily, either a placebo or the combination of 0.625 mg of conjugated equine estrogens and 2.5 mg of medroxyprogesterone acetate. Recruitment for HERS was completed in September 1994, and the trial is scheduled to continue until mid 1998. In addition to the primary end point of CHD events, a number of secondary end points were specified in the HERS protocol for evaluation in planned interim monitoring; these include the occurrence of venous thromboembolic events (VTE), ie, deep vein thrombosis, pulmonary embolism, or both. Recently, 4 observational studies 1-4 and

Effects of estrogens on lipoprotein metabolism and cardiovascular disease in women

Estrogen use is associated with protection from cardiovascular disease in postmenopausal women. This benefit appears to be magnified among women with pre-existing heart disease. The possible bias of intrinsically better health in women using estrogen has not been ruled out in observational studies. Therefore, two double-blind randomized clinical trials are underway in postmenopausal women. One in women with coronary disease is known as HERS (Heart Estrogen-progestin Replacement Study) and another in predominantly healthy women is the WH1 (Women's Health Initiative). Several mechanisms of estrogen mediated protection from cardiovascular disease have been identified including increased HDL, lower LDL, lower VLDL-cholesterol/triglyceride ratio, increased clearance of intermediate density lipoprotein (IDL) and LDL via an upregulated LDL receptor, diminished penetration and degradation of LDL in the arterial wall, an inhibition of LDL oxidation by various estrogens and a reversal of inappropriate acetylcholine (EDRF)-mediated vasoconstriction in arteriosclerotic vessels. The predominating mechanism is not known, but estrogen replacement therapy is both likely to be beneficial to female health, pending randomized trials, as well as a tool to understand mechanisms of prevention of coronary artery disease.