Effect of estrogen plus progestin on risk for biliary tract surgery in postmenopausal women with coronary artery disease. The Heart and Estrogen/progestin Replacement Study

BACKGROUND: Animal and observational epidemiologic studies have reported that estrogens may increase the risk for gallstones. No major clinical trials have examined the effect of estrogen plus progestin therapy in postmenopausal women on the risk for biliary tract surgery. OBJECTIVE: To determine the effect of estrogen plus progestin on the risk for biliary tract surgery in postmenopausal women with known coronary artery disease. DESIGN: Randomized, double-blind placebo-controlled trial of postmenopausal hormone therapy for coronary heart disease. SETTING: 20 U.S. clinical centers. PARTICIPANTS: 2253 postmenopausal women with a gallbladder, 44 to 79 years of age at baseline, in the Heart and Estrogen/progestin Replacement Study (HERS). INTERVENTION: Conjugated equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg, daily in one tablet or identical placebo. MEASUREMENTS: Documented biliary tract surgery. RESULTS: A total of 147 women (7%) were hospitalized for biliary tract surgery in HERS. Treatment with estrogen plus progestin resulted in a marginally significant 38% increase in the relative risk for biliary tract surgery (P = 0.05). A small absolute difference in risk suggested that for every 185 women treated with estrogen plus progestin, one additional woman had biliary tract surgery per year. After adjustment for baseline and in-study statin use, the association was attenuated further (P = 0.09). After adjustment for treatment assignment and other variables, increased body mass index, fibric acid use, and a history of nonsurgical gallbladder disease were associated with an increased risk for biliary tract surgery, whereas statin use was associated with a decreased risk (for each comparison, P < 0.05). CONCLUSION: Estrogen plus progestin therapy among postmenopausal women with known coronary disease resulted in a marginally significant increase in the risk for biliary tract surgery.     

Hormone therapy to prevent disease and prolong life in postmenopausal women.

PURPOSE: To critically review the risks and benefits of hormone therapy for asymptomatic postmenopausal women who are considering long-term hormone therapy to prevent disease or to prolong life. DATA SOURCES: Review of the English-language literature since 1970 on the effect of estrogen therapy and estrogen plus progestin therapy on endometrial cancer, breast cancer, coronary heart disease, osteoporosis, and stroke. We used standard meta-analytic statistical methods to pool estimates from studies to determine summary relative risks for these diseases in hormone users and modified lifetable methods to estimate changes in lifetime probability and life expectancy due to use of hormone regimens. RESULTS: There is evidence that estrogen therapy decreases risk for coronary heart disease and for hip fracture, but long-term estrogen therapy increases risk for endometrial cancer and may be associated with a small increase in risk for breast cancer. The increase in endometrial cancer risk can probably be avoided by adding a progestin to the estrogen regimen for women who have a uterus, but the effects of combination hormones on risk for other diseases has not been adequately studied. We present estimates for changes in lifetime probabilities of disease and life expectancy due to hormone therapy in women who have had a hysterectomy; with coronary heart disease; and at increased risk for coronary heart disease, hip fracture, and breast cancer. CONCLUSIONS: Hormone therapy should probably be recommended for women who have had a hysterectomy and for those with coronary heart disease or at high risk for coronary heart disease. For other women, the best course of action is unclear.     

Who should receive hormone replacement therapy?

Coronary heart disease is the leading cause of death in women in the United States and increases dramatically in postmenopausal women. The following review summarizes the known benefits and risks of hormone replacement therapy and gives recommendations for use of hormone replacement in women. Estrogen may play a role in preventing the development of atherosclerosis in women by raising levels of HDL cholesterol, lowering levels of LDL cholesterol and lipoprotein (a), lowering levels of fibrinogen and plasminogen activator inhibitor-1, dilating coronary arteries, preventing the oxidation of LDL cholesterol, decreasing the proliferation and migration of smooth muscle cells, and decreasing the production of inflammatory cell activators. These anti-atherogenic effects of estrogen may translate into clinical benefits. A meta-analysis of 31 studies yielded a 44% reduction in the risk of coronary heart disease in women taking estrogen alone. Unopposed estrogen is associated with an increased risk of endometrial cancer; therefore, progestin is added to estrogen in women with an intact uterus. Less is known about the effect of the combination of estrogen and a progestin on the risk of coronary heart disease. Estrogen is also beneficial in the prevention of osteoporosis; however, long-term use of estrogen alone and estrogen in combination with progestin may increase the risk for breast cancer. Mathematical modeling predicted that women with no risk for cardiovascular disease, cancer, or osteoporosis may gain 0.9 years of life with the use of estrogen alone; women with risk factors for cardiovascular disease can expect to gain 1.5 years of life; and women with coronary heart disease at the age of 50 can expect to gain 2.1 years of life. The current American College of Physicians recommendations for hormone replacement are as follows: (1) All women should be considered; (2) women with a hysterectomy should receive estrogen alone; (3) women at risk for, or with, coronary heart disease are most likely to benefit from estrogen; with an intact uterus, progestin must be added; (4) risks of estrogen may outweigh benefits in women at increased risk for breast cancer. Definitive guidelines for the treatment of women must await the results of randomized clinical trials in the ongoing Women's Health Initiative. These will not be available for several years, and until then any recommendations for women will have to be judged from estimates of risk rather than of benefit from reduction of risk. The decision whether to initiate estrogen replacement in postmenopausal women is one that still needs to be made on an individual patient basis.Supported by NHLBI grant HL 02626. Dr. Welty is the 1995 recipient of the Alpha Phi Foundation Award.     

Cardiovascular disease and dyslipidemia in women

Cardiovascular disease, primarily coronary heart disease (CHD), outnumbers the next 16 causes of death in women combined. However, the long-held belief that heart disease in women has a more benign prognosis than in men has resulted in less aggressive diagnosis and management patterns. Appreciation of the differences between men and women in CHD risk factors and presentation can assist in treatment decisions. Although estrogen replacement offers substantial beneficial effects on lipid levels in postmenopausal women, the first 2 randomized trials of estrogen alone and estrogen plus progestin, the Heart and Estrogen/Progestin Replacement Study and Estrogen Replacement and Atherosclerosis Study, observed no benefit in reducing risk of CHD death and nonfatal myocardial infarction and angiographic progression of CHD, respectively, in women with CHD. Available data show that lipid-lowering therapy reduces women's CHD risk and mortality but also indicate that a considerable proportion of women remains untreated or undertreated. Randomized trials of statins for primary and secondary prevention of coronary heart disease suggest that these agents are at least as effective for lowering coronary disease risk in women as in men. Therefore, statin drugs should be the drug of first choice for women with established CHD. Hypercholesterolemic postmenopausal women who require estrogen for menopausal symptoms may derive further reductions in low-density lipoprotein cholesterol and reductions in trigyceride levels with the addition of a statin drug.     

Body mass index and body girths as predictors of mortality in black and white women.

BACKGROUND--The high prevalence of obesity in black women has been hypothesized to contribute to higher rates of coronary heart disease and total mortality. Investigators have recently refined the study of obesity by differentiating anatomic patterns of the physical location of adipose tissue on the body. We examined fat patterning as a predictor of mortality in black women. METHODS--Body mass index (BMI) and body girths were examined as predictors of all-cause and coronary heart disease mortality during 25 to 28 years of follow-up in black and white women in the Charleston Heart Study. RESULTS--The BMI was associated with all-cause and coronary heart disease mortality in white, but not black, women. After controlling for differences in BMI, the risk of all-cause mortality was greater in white women with larger chest and abdominal girths, while midarm girths were inversely associated with mortality. The hazard at the 85th percentile relative to the 15th percentile of abdomen/midarm ratio was 1.44 in models that included BMI, education, and smoking as covariates. In black women, the girths were not predictive of either all-cause or coronary heart disease mortality. CONCLUSIONS--The failure of BMI and fat patterning to predict mortality in black women challenges previously held assumptions regarding the role of overweight in the higher mortality experienced by black women.     

A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease

BACKGROUND: Most primary prevention studies have found that long-term users of postmenopausal hormone therapy are at lower risk for coronary events, but numerous questions remain. An adverse influence of hormone therapy on cardiovascular risk has been suggested during the initial year of use; however, few data are available on short-term hormone therapy. In addition, the cardiovascular effects of daily doses of oral conjugated estrogen lower than 0.625 mg are unknown, and few studies have examined estrogen plus progestin in this regard. OBJECTIVE: To investigate duration, dose, and type of postmenopausal hormone therapy and primary prevention of cardiovascular disease. DESIGN: Prospective, observational cohort study. SETTING: Nurses' Health Study, with follow-up from 1976 to 1996. PATIENTS: 70 533 postmenopausal women, in whom 1258 major coronary events (nonfatal myocardial infarction or fatal coronary disease) and 767 strokes were identified. MEASUREMENTS: Details of postmenopausal hormone use were ascertained by using biennial questionnaires. Cardiovascular disease was established by using a questionnaire and was confirmed by medical record review. Logistic regression models were used to calculate relative risks and 95% CIs, adjusted for confounders. RESULTS: When all cardiovascular risk factors were considered, the risk for major coronary events was lower among current users of hormone therapy, including short-term users, compared with never-users (relative risk, 0.61 [95% CI, 0.52 to 0.71]). Among women taking oral conjugated estrogen, the risk for coronary events was similarly reduced in those currently taking 0.625 mg daily (relative risk, 0.54 [CI, 0.44 to 0.67]) and those taking 0.3 mg daily (relative risk, 0.58 [CI, 0. 37 to 0.92]) compared with never-users. However, the risk for stroke was statistically significantly increased among women taking 0.625 mg or more of oral conjugated estrogen daily (relative risk, 1.35 [CI, 1.08 to 1.68] for 0.625 mg/d and 1.63 [CI, 1.18 to 2.26] for >/=1.25 mg/d) and those taking estrogen plus progestin (relative risk, 1.45 [CI, 1.10 to 1.92]). Overall, little relation was observed between combination hormone therapy and risk for cardiovascular disease (major coronary heart disease plus stroke) (relative risk, 0.91 [CI, 0.75 to 1.11]). CONCLUSIONS: Postmenopausal hormone use appears to decrease risk for major coronary events in women without previous heart disease. Furthermore, 0.3 mg of oral conjugated estrogen daily is associated with a reduction similar to that seen with the standard dose of 0.625 mg. However, estrogen at daily doses of 0.625 mg or greater and in combination with progestin may increase risk for stroke.     

The HERS trial results: paradigms lost? Heart and Estrogen/progestin Replacement Study.

The Heart and Estrogen/progestin Replacement Study (HERS) found no overall effect of 4.1 years of therapy with estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. However, within the overall null effect, a 50% increase in cardiovascular events was seen in the first year, followed by fewer events after 2 years of treatment in the hormone therapy group than in the placebo group. Understanding the cause of this pattern of early increase and late reduction in risk is key to interpreting the HERS results and reconciling them with the large number of observational and other studies of the cardiovascular effects of estrogen. There are two possibilities. One is that the HERS regimen of estrogen plus progestin has no effect on risk for heart disease, and the pattern of changing risk over time is simply the result of chance or confounding. The other is that the pattern of early increase and late reduction in risk is due to real but opposing effects of this regimen. Several lines of evidence support each possibility. Attrition of a susceptible cohort of women uniquely at risk for a cardiovascular complication from hormone therapy coupled with a gradually progressive beneficial effect due to lipid lowering and other factors is a promising potential explanation. The HERS results remind us of the need for clinical trials to evaluate both the benefits and risks of new therapies. They also illustrate how much more we need to know about the cardiovascular effects of hormone replacement therapy.     

Hormone replacement therapy in clinical cardiology

The relationship between coronary heart disease (CHD) and menopause remains controversial, but observational studies of hormone replacement therapy among postmenopausal women have found a lower risk of CHD among women taking postmenopausal estrogens or estrogen/progestin combination therapy. In contrast, the Heart and Estrogen/progestin Replacement Study (HERS) did not show any overall benefit of estrogen/progestin therapy over 4.1 years of follow-up in a sample of women with established CHD, despite the expected favorable changes in the participants' lipid profiles. There appeared to be an initial increase in CHD risk, but benefit with increasing duration of hormone use. More research on the relative benefits and risks of hormone replacement therapy in postmenopausal women is needed. For now, a cautionary approach to hormone replacement therapy appears warranted, at least among postmenopausal women with established coronary artery disease.     

Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The Heart and Estrogen/progestin Replacement Study

BACKGROUND: Oral contraceptive use increases risk for venous thromboembolism, but data on the effect of postmenopausal hormone therapy are limited. OBJECTIVE: To determine the effect of therapy with estrogen plus progestin on risk for venous thromboembolic events in postmenopausal women. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: 20 clinical centers in the United States. PARTICIPANTS: 2763 postmenopausal women younger than 80 years of age (mean age, 67 years) who had coronary heart disease but no previous venous thromboembolism and had not had a hysterectomy. INTERVENTION: Conjugated equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg, in one tablet (n = 1380) or placebo that was identical in appearance (n = 1383). MEASUREMENTS: Documented deep venous thrombosis or pulmonary embolism. RESULTS: During an average of 4.1 years of follow-up, 34 women in the hormone therapy group and 13 in the placebo group experienced venous thromboembolic events (relative hazard, 2.7 [95% CI, 1.4 to 5.0] [P = 0.003]; excess risk, 3.9 per 1000 woman-years [CI, 1.4 to 6.4 per 1000 woman-years]; number needed to treat for harm, 256 [CI, 157 to 692]). In multivariate analysis, the risk for venous thromboembolism was increased among women who had lower-extremity fractures (relative hazard, 18.1 [CI, 5.4 to 60.4]) or cancer (relative hazard, 3.9 [CI, 1.6 to 9.4]) and for 90 days after inpatient surgery (relative hazard, 4.9 [CI, 2.4 to 9.8]) or nonsurgical hospitalization (relative hazard, 5.7 [CI, 3.0 to 10.8]). Risk was decreased with aspirin (relative hazard, 0.5 [CI, 0.2 to 0.8]) or statin use (relative hazard, 0.5 [CI, 0.2 to 0.9]). CONCLUSIONS: Postmenopausal therapy with estrogen plus progestin increases risk for venous thromboembolism in women with coronary heart disease. This risk should be considered when the risks and benefits of therapy are being weighed.     

Hormone Replacement Therapy in Postmenopausal Women: Does It Lessen Coronary Heart Disease Risk?

Coronary heart disease is the leading cause of death in adult women in the U.S. Since clinical manifestations of coronary disease predominate in postmenopausal women, the need to evaluate coronary disease-gonadal hormone relationships is compelling. Further, estrogen exerts biologically plausible benefits: improved lipid profile, lower fibrinogen levels, favorable changes in vascular reactivity, possible antioxidant effects, among others. Although observational studies of estrogen use suggest substantial lessening of coronary risk, selection biases favoring a healthy cohort of women mandate randomized clinical trial data, with such trials currently in progress. Information is lacking regarding benefit: risk ratios of transdermal estrogen and estrogen/progestin combinations as coronary preventive therapies.     

Hormone replacement therapy for prevention of coronary heart disease: current evidence

Postmenopausal estrogen replacement, with or without progestin therapy, has a generally favorable impact on lipids, improves endothelial function, and has anti-inflammatory and antioxidant effects. These properties should favorably impact coronary risk; indeed, epidemiologic studies have consistently associated hormone replacement therapy with reduced coronary risk. Nonetheless, the Heart & Estrogen/progestin Replacement Study (HERS), a randomized, placebo-controlled, secondary prevention trial of conjugated estrogen with progestin, found no overall reduction in coronary events among women assigned to active hormone treatment. This review explores the role of estrogen replacement among interventions intended to prevent coronary heart disease in the post-HERS era.     

Estrogen is associated with improved survival in aging women with congestive heart failure: analysis of the vesnarinone studies

OBJECTIVES: This study sought to evaluate the effects of postmenopausal estrogen use on mortality in aging women with congestive heart failure (CHF). BACKGROUND: The age-related increase in CHF mortality in women may be related to a menopause-associated increased incidence of coronary artery disease. In addition to inhibiting coronary atherosclerosis, estrogen may also have protective effects on cardiac myocytes independent of the coronary vasculature. We hypothesized that estrogen use is associated with improved survival in elderly women with CHF. METHODS: Associations between survival, estrogen use and patient characteristics were assessed in 1,134 women who were at least 50 years of age, had CHF and left ventricular ejection fraction (EF) < or =30% and were enrolled in one of three clinical trials of vesnarinone. RESULTS: All-cause 12-month mortality was 15.0% among the 237 estrogen users versus 27.1% among the 897 estrogen nonusers (p = 0.004 for unadjusted comparison of survival). Similar results were observed for cardiac mortality. Regression analysis demonstrated that estrogen use was independently associated with improved survival (relative risk of mortality = 0.68, 95% confidence interval 0.48 to 0.96, p = 0.03). Advanced age, low EF, New York Heart Association class IV CHF, Caucasian race and abnormal serum creatinine, sodium, potassium and transaminase were independently associated with increased mortality. CONCLUSIONS: Estrogen use among older women with CHF is associated with decreased overall and cardiac mortality.     

Impact of heart failure and left ventricular function on long-term survival--report of a community-based cohort study in Taiwan

BACKGROUND: There is little community-based information on heart failure (HF) prognosis in ethnic Chinese populations, in whom there is a low prevalence of coronary heart disease. AIMS: To study the impact of HF and left ventricular function on long-term all-cause mortality. METHODS AND RESULTS: This community-based prospective cohort study included 2660 subjects (1215 men, 1445 women, mean age 54.4+/-11.9 years) over a 10 year follow-up period. The prevalence of HF was 5.5%. Hypertension was the most common factor related to HF. The five and ten year all-cause mortality was higher in the HF/preserved LVEF group (14.1% and 24.4%) and the HF/impaired LVEF group (29.2% and 48.2%) than in the HF-free group (6.0% and 14.6%, p<0.0001 for both). In multivariable Cox analyses, controlling for sex, LV mass, atrial fibrillation, hypertension, coronary heart disease, HF/preserved LVEF and HF/impaired LVEF were important predictors of all-cause mortality (p=0.007). CONCLUSIONS: Hypertension is a major heart failure related disease. HF and LV systolic dysfunction are associated with a significant increase in all-cause mortality in an ethnic Chinese population.     

Postmenopausal hormone use for cardioprotection: what we know and what we must learn.

Coronary heart disease is a highly prevalent and lethal illness for women, particularly in their menopausal years, a fact that fostered interest in hormone use for cardioprotection. Despite the compelling evidence of cardiovascular benefit of estrogen therapy and estrogen and progestin therapy in observational studies of postmenopausal women, and multiple biologically plausible mechanisms for estrogen benefit, precise clinical outcome information from prospective randomized controlled trials is lacking. The only such trial reported, the Heart and Estrogen/Progestin Replacement Study, not only failed to demonstrate cardioprotection, but showed an early adverse outcome in women with documented coronary heart disease who received daily conjugated equine estrogen and medroxy-progesterone acetate. Several large randomized clinical trials of hormone and selective estrogen receptor moderator therapy for primary and secondary prevention are currently underway.     

Should progestins be blamed for the failure of hormone replacement therapy to reduce cardiovascular events in randomized controlled trials?

Many observational studies and experimental and animal studies have demonstrated that estrogen replacement therapy (ERT) or hormone replacement therapy (HRT) (estrogen plus progestin) significantly reduces the risk of coronary heart disease. Nonetheless, recent randomized controlled trials demonstrated some trends toward an increased risk of cardiovascular events rather than a reduction of risk. Recently, both the HRT and ERT arms of the Women's Health Initiative (WHI) study were terminated early because of an increased/no incidence of invasive breast cancer, increased incidence of stroke, and increased trend/no protective effects of cardiovascular disease. We discuss the controversial effects of HRT and ERT on cardiovascular system and provide a hypothesis that the failure of HRT and ERT in reducing the risk of cardiovascular events in postmenopausal women might be because of the stage of their atherosclerosis at the time of initiation of HRT or ERT.     

Neoplasia of the female reproductive tract: effects of hormone therapy

This review presents the data on the relationship between estrogen and estrogen plus progestin therapy in postmenopausal women and the occurrence of neoplasia in the endometrium, ovary, and uterine cervix. Estrogen only in women with an intact uterus consistently is shown to increase the incidence of endometrial cancer. Estrogen plus a cyclic or sequential progestin reduces the incidence of endometrial cancer to that found in never users. The duration of the progestin administration appears to be important with less than 10 d of progestin having an increased incidence of cancer after 5 yr of therapy. Continuous estrogen plus progestin does not increase the incidence of endometrial cancer. Estrogen and estrogen plus progestin effects on the occurrence of ovarian cancer are inconsistent. The data suggest a possible increase in ovarian epithelial tumors with >10 years use of estrogen only. There is no evidence of a change in the incidence of uterine cervical neoplasia with either estrogen or progestin.     

Postmenopausal hormone use and secondary prevention of coronary events in the nurses' health study. a prospective, observational study.

BACKGROUND: The Heart and Estrogen/progestin Replacement Study (HERS) was the first randomized clinical trial of combined hormone therapy and secondary prevention of coronary events. The trial had overall null results but reported an unexpected increased risk for recurrent events in the initial year, followed by a decrease during the final years. OBJECTIVE: To provide additional data on a time trend in risk for recurrent heart disease. DESIGN: A prospective, observational cohort study of secondary prevention of coronary heart disease. SETTING: Nurses' Health Study. PATIENTS: 2489 postmenopausal women with previous myocardial infarction or documented atherosclerosis; 213 cases of recurrent nonfatal myocardial infarction or coronary death were identified from 1976 through 1996. MEASUREMENTS: Information on hormone status and on recurrent disease was collected by using biennial questionnaires. Multivariable-adjusted relative risks and 95% CIs were calculated from logistic regression models. RESULTS: A trend of decreasing risk for recurrent major coronary heart disease events with increasing duration of hormone use was observed (P for trend = 0.002). For short-term current users, the multivariate-adjusted relative risk for major coronary heart disease was 1.25 (95% CI, 0.78 to 2.00) compared with never-users. However, after longer-term hormone use, the rate of second events was lower in current users than in never-users (relative risk, 0.38 [CI, 0.22 to 0.66]). No clear differences emerged between users of estrogen alone and users of estrogen combined with progestin. Overall, with up to 20 years of follow-up, the relative risk for a second event among current users of hormone therapy was 0.65 (CI, 0.45 to 0.95) compared with never-users. CONCLUSIONS: The risk for recurrent major coronary events seems to increase among short-term hormone users with previous coronary disease but to decrease with longer-term use.     

Aortic plaque size and endometrial response in cholesterol-fed rabbits treated with estrogen plus continuous or sequential progestin.

ERT is associated with a reduced incidence of coronary risk and cardiac events in postmenopausal women, but increases the risk of endometrial hyperplasia and carcinoma. Combined estrogen and progestin therapy protects the endometrium; however, its effects on heart disease risk factors are not completely known. In our study, 56 ovariectomized New Zealand White rabbits in 7 groups received a 0.5% cholesterol diet for 12 weeks. Controls were not treated with hormones. All other animals received (per kilogram body weight per week) intramuscular injections of either 0.3 mg estrogen (estradiol valerate) alone, 8.3 mg progestin (hydroxyprogesterone caproate) alone, estrogen and progestin continuously in 3 different dosages (0.3 and 8.3 mg; 1 and 8.3 mg; or 1 and 2.8 mg; estrogen and progestin, respectively), or 1 mg estrogen with 25 mg progestin sequentially in 2-week cycles. Eight non-ovariectomized animals served as further controls for endometrial analysis. Morphometric analysis of plaque size in the aortic arch showed that estrogen monotherapy, and the 3 combined therapies with 1 mg estrogen, significantly reduced intimal thickening (P<0.05). The application of progestin alone had no effect on plaque size. The endometrium was enlarged by 3-fold after estrogen treatment, and was decreased by half after progestin treatment, compared with control uteri (P<0.05). In all groups with combined hormone regimens, endometrial size was not significantly different from control uteri. However, these uteri showed more inflammatory reactions, especially when higher doses of hormones were given. In this animal model, doses of progestin that are able to successfully reduce the proliferative effect of estrogen on endometrium do not diminish the desirable antiatherosclerotic properties of estrogen.     

Individual and combined effects of estrogen/progestin therapy and lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with coronary artery disease

OBJECTIVES

We sought to examine the individual and combined effects of estrogen/progestin therapy versus lovastatin on lipids and flow-mediated vasodilation in postmenopausal women with heart disease.

BACKGROUND

Little information is available regarding the relative benefits of estrogen replacement therapy versus reductase inhibitors and the potential utility of their combination as lipid-lowering therapy for postmenopausal women.

METHODS

We conducted a randomized, double-blind, crossover trial in 24 postmenopausal women, each of whom received the following drug regimens during three consecutive six-week treatment periods: 1) hormone replacement (oral dose of 0.625 mg/day conjugated equine estrogens and 2.5 mg/day medroxyprogesterone acetate); 2) 20 mg lovastatin/day and 3) hormone replacement plus lovastatin.

RESULTS

Total and low density lipoprotein (LDL) cholesterol were significantly lowered and high density lipoprotein (HDL) cholesterol was significantly increased by all three regimens compared with baseline (p < 0.05). Lovastatin was more effective than estrogen/progestin in reducing LDL (p < 0.001), but estrogen/progestin was slightly more effective in increasing HDL. The hormone replacement and lovastatin regimen blocked the estrogen-associated increase in triglycerides. Hormone replacement (alone and with lovastatin) resulted in increases in brachial artery flow-mediated vasodilator capacity (p = 0.01 for both regimens) and the area under the curve (p = 0.016 and p = 0.005, respectively) compared with baseline. Percent dilation was greatest after the hormone replacement regimen, whereas the area under the curve was greatest after hormone replacement plus lovastatin (69% improvement vs. baseline).

CONCLUSIONS

In postmenopausal women with coronary disease and hyperlipidemia, conjugated equine estrogen produced significant improvements in lipids and vasodilator responses despite the concurrent administration of low dose medroxyprogesterone acetate. Low dose lovastatin produced greater reductions in LDL, but less dramatic improvements in vasodilator responses. Estrogen/progestin plus lovastatin may provide additional benefits via a greater reduction in the LDL/HDL ratio and attenuation of estrogen-associated hypertriglyceridemia. More information is needed about the safety and efficacy of such combinations of hormone replacement and reductase inhibitor therapy.     

The association between the length of the QT interval and mortality in the Cardiovascular Health Study

PURPOSE: A long QT interval is a risk factor for arrhythmic events and sudden death. Whether moderate QT prolongation is associated with clinical events in community-dwelling elderly patients is uncertain. METHODS: We measured the QT interval in a population-based sample of 5888 men and women at least 65 years of age who were participants in the Cardiovascular Health Study. The association between Bazett's rate-corrected QT (QTc, in ms) and mortality during the subsequent 10 years was evaluated. We stratified participants by the presence or absence of coronary heart disease status at baseline, and adjusted for coronary heart disease risk factors. RESULTS: The rates of all-cause and coronary heart disease mortality were greater in participants with longer QTc intervals. Among participants without known coronary heart disease, those whose QTc interval was >450 ms were at increased risk of all-cause mortality (relative risk [RR] = 1.34; 95% confidence interval [CI]: 1.07 to 1.67) and coronary heart disease mortality (RR = 1.6; 95% CI: 1.0 to 2.5) when compared with participants whose QTc interval was <410 ms. The associations were stronger among those with known coronary heart disease (RR for all-cause mortality = 2.3; 95% CI: 1.6 to 3.3; and RR for coronary heart disease mortality = 2.0; 95% CI: 1.1 to 3.7). CONCLUSIONS: The QT interval from the standard electrocardiograms is of value for identification of elderly persons at increased risk of coronary heart disease and total mortality. A QTc interval >450 ms should prompt clinical evaluation and possible interventions to reduce the risk of coronary events.