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      Effect of Hormone Replacement Therapy on Cardiovascular Outcomes: A Meta-Analysis of Randomized Controlled Trials

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          Abstract

          Background

          Hormone replacement therapy (HRT) is widely used to controlling menopausal symptoms and prevent adverse cardiovascular events. However, the benefit and risk of HRT on cardiovascular outcomes remains controversial.

          Methodology and Principal Findings

          We systematically searched the PubMed, EmBase, and Cochrane Central Register of Controlled Trials databases for obtaining relevant literature. All eligible trials reported on the effects of HRT on cardiovascular outcomes. We did a random effects meta-analysis to obtain summary effect estimates for the clinical outcomes with use of relative risks calculated from the raw data of included trials. Of 1903 identified studies, we included 10 trials reporting data on 38908 postmenopausal women. Overall, we noted that estrogen combined with medroxyprogesterone acetate therapy as compared to placebo had no effect on coronary events (RR, 1.07; 95%CI: 0.91–1.26; P = 0.41), myocardial infarction (RR, 1.09; 95%CI: 0.85–1.41; P = 0.48), stroke (RR, 1.21; 95%CI: 1.00–1.46; P = 0.06), cardiac death (RR, 1.19; 95%CI: 0.91–1.56; P = 0.21), total death (RR, 1.06; 95%CI: 0.81–1.39; P = 0.66), and revascularization (RR, 0.95; 95%CI: 0.83–1.08; P = 0.43). In addition, estrogen therapy alone had no effect on coronary events (RR, 0.93; 95%CI: 0.80–1.08; P = 0.33), myocardial infarction (RR, 0.95; 95%CI: 0.78–1.15; P = 0.57), cardiac death (RR, 0.86; 95%CI: 0.65–1.13; P = 0.27), total mortality (RR, 1.02; 95%CI: 0.89–1.18; P = 0.73), and revascularization (RR, 0.77; 95%CI: 0.45–1.31; P = 0.34), but associated with a 27% increased risk for incident stroke (RR, 1.27; 95%CI: 1.06–1.53; P = 0.01).

          Conclusion/Significance

          Hormone replacement therapy does not effect on the incidence of coronary events, myocardial infarction, cardiac death, total mortality or revascularization. However, it might contributed an important role on the risk of incident stroke.

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          Most cited references15

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          The interpretation of random-effects meta-analysis in decision models.

          This article shows that the interpretation of the random-effects models used in meta-analysis to summarize heterogeneous treatment effects can have a marked effect on the results from decision models. Sources of variation in meta-analysis include the following: random variation in outcome definition (amounting to a form of measurement error), variation between the patient groups in different trials, variation between protocols, and variation in the way a given protocol is implemented. Each of these alternatives leads to a different model for how the heterogeneity in the effect sizes previously observed might relate to the effect size(s) in a future implementation. Furthermore, these alternative models require different computations and, when the net benefits are nonlinear in the efficacy parameters, result in different expected net benefits. The authors' analysis suggests that the mean treatment effect from a random-effects meta-analysis will only seldom be an appropriate representation of the efficacy expected in a future implementation. Instead, modelers should consider either the predictive distribution of a future treatment effect, or they should assume that the future implementation will result in a distribution of treatment effects. A worked example, in a probabilistic, Bayesian posterior framework, is used to illustrate the alternative computations and to show how parameter uncertainty can be combined with variation between individuals and heterogeneity in meta-analysis.
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            Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group.

            Observational studies have found lower rates of coronary heart disease (CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has not been confirmed in clinical trials. To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease. Randomized, blinded, placebo-controlled secondary prevention trial. Outpatient and community settings at 20 US clinical centers. A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years. Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n = 1380) or a placebo of identical appearance (n = 1383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end of 3 years. The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also considered. Overall, there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5. More women in the hormone group than in the placebo group experienced venous thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences in several other end points for which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38). During an average follow-up of 4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. The treatment did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving this treatment to continue.
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              Hormone therapy to prevent disease and prolong life in postmenopausal women.

              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. 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. 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. 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.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                8 May 2013
                : 8
                : 5
                : e62329
                Affiliations
                [1 ]Department of Cardiovascular Surgery, Shanghai First People’s Hospital affiliated to Shanghai Jiao Tong University, Shanghai, China
                [2 ]Department of Cardiology, Shanghai Chest Hospital affiliated to Shanghai Jiao Tong University, Shanghai, People’s Republic of China
                University of Valencia, Spain
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: DY XL. Performed the experiments: DY JL. Analyzed the data: DY JL. Contributed reagents/materials/analysis tools: ZY XL. Wrote the paper: DY JL.

                Article
                PONE-D-12-40607
                10.1371/journal.pone.0062329
                3648543
                23667467
                f4d2ecad-1398-46d5-b266-25007c23222b
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 19 December 2012
                : 20 March 2013
                Page count
                Pages: 9
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                Medicine
                Cardiovascular
                Cardiovascular Diseases in Women
                Coronary Artery Disease
                Myocardial Infarction
                Stroke
                Clinical Research Design
                Meta-Analyses
                Endocrinology
                Endocrine Physiology
                Hormones
                Obstetrics and Gynecology
                Menopause
                Women's Health
                Cardiovascular Diseases in Women

                Uncategorized
                Uncategorized

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