Abstract
Background
There is apparently compelling evidence, from observational studies, that hormone replacement therapy (HRT) may have benefits in reducing cardiovascular events in post-menopausal women. However, these observational data are subject to biases and confounding and require support from formally designed randomised controlled trials of the effects of HRT on cardiovascular disease risk.
Objectives
To assess the effects of HRT for the primary and secondary prevention of cardiovascular diseases in post-menopausal women.
Search methods
We searched MEDLINE (1998 to December 2002)), EMBASE (1998 to December 2002), the Cochrane Controlled Trials Register (CCTR) (Issue 4 2002), the National Research Register (1998 to present), ClinicalTrials.gov (1998 to present), and the database of Spanish Clinical Trials (1998 to present) and reference lists of articles.
Selection criteria
Randomised controlled trials comparing HRT with controls (placebo or no treatment) with a minimum follow up of 6 months for treating or preventing cardiovascular disease in postmenopausal women with or without cardiovascular disease.
Data collection and analysis
Three independent reviewers extracted information from the articles, solving discrepancies by consensus. All outcomes studied were dichotomous. Risk ratios and 95% confidence intervals (CI) were calculated for each study and plotted. Random effects meta-analysis was used in efficacy outcomes (cardiovascular events) and fixed-effects meta-analysis in variables regarding side effects (deep venous thrombosis).
Main results
No protective effect of HRT was seen for any of the cardiovascular outcomes assessed: all cause mortality, cardiovascular death, non-fatal MI, venous thromboemboli or stroke. Higher risks of venous thromboembolic events (Relative risk (RR) 2.15, 95% CI 1.61 to 2.86), pulmonary embolus (RR 2.15, 95% CI 1.41 to 3.28), and stroke (RR 1.44, 95% CI 1.10 to 1.89) was found in those randomised to HRT compared with placebo. No substantial heterogeneity (p <0.1) was detected in any of the outcomes studied.
Authors’ conclusions
At present, a recommendation for initiating HRT for the reason of preventing cardiovascular events in post-menopausal women (with or without cardiovascular disease) should not be made. Women with other risk factors for venous thromboembolic events should be discouraged from using HRT if the sole goal is to prevent cardiovascular events.
Medical Subject Headings (MeSH): *Estrogen Replacement Therapy, Cardiovascular Diseases [*prevention & control], Hormone Replacement Therapy, Postmenopause
MeSH check words: Female, Humans
BACKGROUND
Post-menopausal women are at higher risk of cardiovascular disease (CVD) than their younger counterparts. Age at menopause, a measure of the exposure to endogenous oestrogen, is a fair predictor of cardiovascular disease mortality (de Klejin 2002), and it is biologically plausible that exogenous oestrogens might be cardio-protective (Wenger 2000). There have been many observational studies on the use of Hormone Replacement Therapy (HRT) in post-menopausal women in recent years. The potential benefits claimed for HRT include a wide variety of diseases in women, from osteoporosis to dementia, and a special interest exists in the prevention of coronary heart disease. Observational studies have consistently found that use of HRT is protective against CHD, with a meta-analysis of observational studies yielding a summary relative risk for ever use of HRT of 0.56 (95% confidence interval (CI) 0.50 to 0.61) (Stampfer 1991). Although the bulk of evidence from observational studies suggests that the use of exogenous oestrogens is cardio-protective for post-menopausal women (Grodstein 1996), the efficacy and effectiveness of HRT in the prevention of cardiovascular diseases in unselected women is not yet clear. Evidence from observational studies is difficult to interpret due to variation in the hormones used, the dose and mode of administration. But above all women willing to take hormones after menopause may differ substantially from those who do not, resulting in seriously confounded estimates of effects of HRT (Lawlor 2004), as well as adding to a general healthy cohort effect (Petitti 1994).
There are some data on intermediate cardiovascular outcomes from clinical trials, the most important of which is the PEPI trial. In this randomised controlled trial 875 healthy post-menopausal women were randomised to receive either placebo or oestrogens, either alone or combined with progestatins. All hormone regimens improved the coronary risk profile at three years, with some adverse effects, mainly endometrial hyperplasia in women with intact uterus. However, an important question remained: was the improvement in cardiovascular risk factors translated into a lower cardiovascular mortality? Although this was widely accepted, it remained to be examined in clinical trials.
In parallel with the PEPI trial (PEPI), the first randomised controlled trial (RCT) to primarily assess the cardio-protective effect of HRT in women with diagnosed cardiovascular disease showed no benefit (HERS). In response to the results from the HERS trial (HERS), many investigators claimed that women included in the trial were not healthy, all had a diagnosis of coronary heart disease (despite this being a design feature of the HERS trial intended to maximise event rates, thereby making detection of any beneficial effect easier) and would not have been put on HRT by any thoughtful clinician as the relevance of using data gathered from observational studies of HRT to predict a reduction in cardiovascular risk is questionable without other supporting evidence. Attention has been drawn to the difficulties women and their doctors face in attempting to deal with contradictory findings (Anon 2004). Although systematic reviews of this topic have been published, they have either pre-dated publication of the large, recent RCTs (Hemminki 1997), or have not been systematic in their conduct (Beral 2002). A systematic review focused on the effects of HRT on cardiovascular outcomes therefore seemed to be a reasonable approach to clarify the growing data on this topic. Material from this systematic review has contributed to an overview of the effects of HRT on a wide range of clinical outcomes (HRT Study Group 2005), which may be of interest to readers of this systematic review.
OBJECTIVES
To determine the effects of HRT in post-menopausal women with and without pre-existing cardiovascular disease for the prevention of cardiovascular diseases.
METHODS
Criteria for considering studies for this review
Types of studies
Randomised controlled trials comparing HRT with controls (placebo or no treatment) in post-menopausal women with a duration of follow up of 6 months or longer, with primary or secondary outcomes of cardiovascular events.
In the original protocol, prospective longitudinal observational studies (with at least 1000 post-menopausal women at baseline with a minimum of 1 year follow-up), were to be included but with the extent of randomised trial evidence, this aspect of the work was abandoned.
Types of participants
Post-menopausal women (spontaneous or induced cessation of menstrual bleeding for a continuous period of 6 or more months) with or without evidence of cardiovascular disease.
Types of interventions
Hormone Replacement Therapy (HRT), either with oestrogens alone or in different combinations with progestogens;
Placebo (control);
No treatment (open control.
Types of outcome measures
Primary outcomes
Deaths from any cause;
Cardiovascular deaths;
Non-fatal acute myocardial infarction;
Stroke;
Combined cardiovascular events outcomes: angina, acute myocardial infarction, venous thromboembolism, stroke and revascularizations (coronary by-pass, angioplasty, coronary stent).
Secondary outcomes
Pulmonary emboli;
Venous thromboemboli (pulmonary emboli plus deep venous thromboses).
In terms of possible harms, data on gynaecological cancers were abstracted from the trials included in addition to the secondary outcomes listed above.
The following outcomes appeared in the protocol but were not considered finally in the analysis:
side effects and tolerability of treatment;
intermediate cardiovascular outcomes (blood pressure, blood cholesterol, and coagulation factors);
quality of life measures.
Search methods for identification of studies
The latest issue (Issue 4 2002) of the Cochrane Controlled Trials Register (CCTR) on The Cochrane Library was searched using the strategy outlined below. This was adapted appropriately for searching MEDLINE (1998 to present), EMBASE (1998-present), and the database of Spanish Clinical Trials. In addition, a standard RCT filter was used for MEDLINE (Dickersin 1994) and EMBASE (Lefebvre 1996). The reference lists of relevant papers were checked. The National Research Register and ClinicalTrials.gov were searched for any ongoing trial on CV diseases.
#1 CARDIOVASCULAR-DISEASES*:ME
#2 CEREBROVASCULAR-DISORDERS*:ME
#3 CHOLESTEROL*:ME
#4 BLOOD-COAGULATION-FACTORS*:ME
#5 CARDIOVASCULAR
#6 CORONARY
#7 ANGINA*
#8 MYOCARDIAL
#9 STROKE
#10 HYPERTENSION
#11 CHOLESTEROL
#12 EMBOLI*
#13 THROMBO*
#14 CEREBROVASCULAR
#15 ATHEROSCLERO*
#16 ARTERIOSCLERO*
#17 LIPIDS*:ME
#18 LIPID*
#19 HYPERLIPIDEMIA*:ME
#20 (HYPERLIPIDEMIA or HYPERLIPIDAEMIA)
#21 FIBRIN*
#22 ((((((((#1 or #2) or #3) or #4) or #5) or #6) or #7) or #8) or #9)
#23 ((((((((((#11 or #12) or #13) or #14) or #15) or #16) or #17) or #18) or #19) or #20) or #21)
#24 (#22 or #23)
#25 ESTROGEN-REPLACEMENT-THERAPY*:ME
#26 HRT
#27 (HORMONE near REPLAC*)
#28 (OESTROGEN near REPLAC*)
#29 (ESTROGEN near REPLAC*)
#30 ((MENOPAUS* or POSTMENOPAUS*) or POSTMENOPAUS*)
#31 OESTROGEN
#32 ESTROGEN
#33 (#31 or #32)
#34 (#30 and #33)
#35 ((((#25 or #26) or #27) or #28) or #29)
#36 (#34 or #35)
#37 (#24 and #36)
Data collection and analysis
References for all articles identified from the search strategy were stored and managed within a bibliographic database (Reference Manager 8.5). All titles were screened by two of the reviewers (LCO, LMSG) independently in order to discard those clearly unrelated to the aim of the study.
Inclusion of articles
Inclusion Criteria
Only those articles meeting the following criteria were considered for closer assessment:
Clinical trials according to the Cochrane Collaboration criteria, i.e. studies using random allocation methods (explicit or implicit) of individuals in 2 or more groups of treatment (including the control group or placebo group);
Hormonal replacement treatments administered alone or in combination;
Inclusion of CV outcomes of relevance for post-menopausal women.
Exclusion Criteria
According to the inclusion criteria mentioned above, trials with only surrogate end-points (i.e. electrocardiographic changes, symptoms, blood pressure, or biochemical changes), reviews, open trials, and animal studies were excluded from further examination.
Data Extraction
A specific questionnaire for data extraction was designed to record data from the studies selected for inclusion. Three independent reviewers (MRF, LCO and LMSG) extracted the information from the articles. Discrepancies in the results were solved by consensus.
Statistical Analysis
All outcomes studied were dichotomous. Risk ratios and 95% confidence intervals (CI) were calculated for each study. The results of each RCT were plotted as point estimates with corresponding 95% confidence intervals. For each outcome, a test of heterogeneity was carried out. Random effects meta-analyses were performed for situations where heterogeneity of effects was apparent. Sensitivity analyses were carried out to explore heterogeneity.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.
Of a total of 1497 abstracts of articles and studies retrieved by the different search strategies. 1450 references were discarded. The discarded studies were non-human studies, reviews, editorials, not controlled-trials, laboratory studies, only men included, assessing other drugs different from HRT, language different from English, French, or Spanish. Forty seven (47) articles were assessed in detail. Of these 29 studies (comprising 33 articles) were excluded. Many studies were discarded as the main outcome variables appearing in the abstract were markers, or risk factors, rather than events with no indication that events had been measured. Details for exclusion are given in the excluded studies tables. Ten studies comprising 16 articles were included. Details of included studies are given in the included studies tables.
There was a certain redundancy of publications from the same study, and only the latest versions or that including the newest versions with the outcomes of interest were included.
The ten included studies were randomised placebo controlled trials with a minimum follow-up of one year (EPAT; ERA; EVTET; HALL; HERS; HERS II; SPRIT 2002; WAWE; WEST;WHI-2002). All studies included postmenopausal women with a mean age between 50 and 79. Eight studies were focused on secondary prevention of cardiovascular events (ERA; EVTET; HALL; HERS; HERS II; SPRIT 2002; WAWE; WEST), and two on primary prevention (EPAT; WHI-2002) in persons with one cardiovascular risk factor (hypercholesterolemia)(EPAT). The EPAT study (EPAT) was focused in an intermediate outcome of CV disease, carotid artery intima-media thickness, but also included CV events as secondary outcomes, and the follow-up period was extensive. The EVTET study (EVTET) was focused on venous thromboembolism for women with previous venous thromboembolism.
We also found four ongoing studies at the time of our search which will be included in an update of this review.(PHASE; NHLBI; WHISP; WISDOM). Of these, WHISP has now been completed and publications are expected. WISDOM has been stopped early due to scientific and practical concerns (White 2002). PHASE has now reported, demonstrating an increased event rate in those allocated to transdermal HRT; the relative risk was 1.29 (95% confidence interval 0.84 to 1.95, P = 0.24) (Clarke 2002). Finally, the NHLBI trial of short term HRT in acute unstable angina has reported 6 month clinical outcomes demonstrating no difference in outcomes between those randomised to either HRT regimen or placebo (Schulman 2002).
Risk of bias in included studies
All RCTs included yielded a score of five in the Jadad’s scale, except for the ERA and Hall’s study, with a score of four (Jadad 1996). The extension of follow-up was adequate, and, despite losses of patient, there were efforts to measure the outcomes by secondary approaches other than by visits (clinical records, emergency rooms and intensive care units records, mortality registries).
Effects of interventions
Overall, information on 12,353 women randomised to HRT were compared with 11930 women randomised to placebo, with an average duration of follow up of 5 years. The plots show the combined effect of HRT on cardiovascular events and side effects. No substantial heterogeneity (p <0.1) was detected in any of the outcomes studied.
When considering all the trials (primary and secondary prevention) together
No protective effect of HRT was seen regarding any of the CV outcomes assessed: death from all causes (Relative risk (RR) = 1.06; 95% CI 0.94 to 1.19); death from CV causes only (RR = 1.04; 95% CI 0.85 to 1.26); non-fatal MI (RR = 1.11; 95% CI 0.95 to 1.28) or combined CV events (RR = 1.04; 95% CI 0.96 to 1.14). In contrast, a higher risk of venous thromboembolic events (including pulmonary embolus) was observed in the whole population, with a RR=2.13 (95% CI 1.68 to 2.70) or pulmonary embolus only with a RR=2.14 (95% CI 1.49 to 3.07) and stroke with a RR =1.25 (95% CI 1.07 to 1.45) related to HRT. Over 60% of the weight was contributed by only two trials, HERS and HERS II.
When considering only the primary prevention trials
No protective effect of HRT was seen regarding any of the CV outcomes assessed: death from all causes (RR = 1.00; 95% CI 0.984 to 1.21); death from CV causes only (RR = 1.16; 95% CI 0.70 to 1.92). In contrast, a higher risk of venous thromboembolic events (including pulmonary embolus) was observed in the whole population, with a RR=2.15 (95% CI 1.61 to 2.86) or pulmonary embolus only with a RR=2.15 (95% CI 1.41 to 3.28) or combined CV events with a RR = 1.20 (95% CI 1.05 to 1.36) or non-fatal MI with a RR = 1.32 (95% CI 1.02 to 1.71) and stroke with a RR =1.44 (95% CI 1.10 to 1.89) related to HRT. As only 1 event was observed in EPAT, these findings are essentially those for WHI-2002, and this applies to all subsequent primary prevention findings.
When considering only the secondary prevention trials
No protective effect of HRT was seen regarding any of the CV outcomes assessed: death from all causes (RR = 1.08; 95% CI 0.94 to 1.25); death from CV causes only (RR = 1.00; 95% CI 0.82 to 1.23); non-fatal MI (RR = 1.01; 95% CI 0.85 to 1.20); stroke (RR =1.15; 95% CI 0.97 to 1.36) or combined CV events (RR = 0.96; 95% CI 0.89 to 1.04) .
In contrast, a higher risk of venous thromboembolic events (including pulmonary embolus) was observed in the whole population, with a RR=2.03 (95% CI 1.36 to 3.04) or pulmonary embolus only with a RR=2.07 (95% CI 1.04 to 4.10) related to HRT.
When considering only the oestrogen alone trials (in primary or secondary prevention)
No protective effect of HRT was seen regarding any of the CV outcomes assessed: death from all causes (RR = 0.96; 95% CI 0.69 to 1.33); death from CV causes only (RR = 0.70 95% CI 0.44 to 1.12); non-fatal MI (RR = 1.26; 95% CI 0.84 to 1.90); stroke (RR =1.21; 95% CI 0.84 to 1.74); combined CV events (RR = 0.74; 95% CI 0.53 to 1.02); venous thromboembolic events including pulmonary embolus (RR=0.97; 95% CI 0.28 to 3.38) or pulmonary embolus only (RR=0.98; 95% CI 0.28 to 3.39).
When considering only the combined HRT (oestrogen + progestogen) trials
No protective effect of HRT was seen regarding any of the CV outcomes assessed: death from all causes (RR = 1.07; 95% CI 0.94 to 1.22); death from CV causes only (RR = 1.13; 95% CI 0.91 to 1.41); non-fatal MI (RR = 1.08; 95% CI 0.92 to 1.27) or combined CV events (RR = 1.07; 95% CI 0.98 to 1.17). In contrast, a higher risk of venous thromboembolic events (including pulmonary embolus) was observed in the whole population, with a RR=2.19 (95% CI 1.72 to 2.79) or pulmonary embolus only with a RR=2.29 (95% CI 1.57 to 3.35) and stroke with a RR = 1.26 (95% CI 1.06 to 1.49) related to HRT.
A sensitivity analysis was conducted in order to differentiate the effect on primary and secondary prevention of CV diseases, by taking out of the analysis the two studies aimed to assess primary prevention (EPAT; WHI-2002). No differences with the whole analysis were seen after excluding the EPAT or the WHI studies, although the findings for stroke became less strong (RR=1.16; 95% CI 0.94 to 1.44). The risk of pulmonary embolus increased from 2.29 (95% CI 1.57 to 3.35) to 2.88 (95% CI 1.21 to 6.82) when considering only the secondary prevention trials.
DISCUSSION
Postmenopausal HRT is commonly used to prevent coronary disease in women, based on biological plausibility and observational data (Keating 1999). A meta-analysis in 1992, including data mainly from observational studies, showed an increased life expectancy in women taking HRT, taking adverse events into account (Grady 1992).Hemminki’s review of trials published before 1997 found an odds ratio of 1.34 (95% confidence intervals 0.55, 3.30) but was too small to be conclusive, and the quality of trials was variable as were the various HRT treatments used (Hemminki 1997). A second report by Hemminki provided an interesting meta-analysis of pooled data from 17 HRT drug applications to the Ministry of Social Affairs and Health of Finland which demonstrated no clear effect of HRT on CV survival (Hemminki 2000).
This discrepancy between observational and trials data has been the subject of growing debate since the publication of the definitive RCTs (Lawlor 2004). Possible explanations are: different level of risk of the study populations, being higher in general in clinical trials than in observational studies; insufficient adjustment for lifestyle and socio-economic factors in observational studies; insufficient consideration of methodological flaws in experimental studies. In addition, it seems unlikely that the intervention on one single factor, rather than on multiple risk factors, would produce significant changes in the incidence of major CV events.
When considering all the trials, both primary and secondary prevention, the results of the current systematic review do not show protection from subsequent CV events in post-menopausal women taking HRT. Only two studies included in our analysis were aimed to assess whether postmenopausal women without previous CV disease would benefit from HRT (EPAT, WHI-2002). Nevertheless, the primary outcome of the EPAT study (EPAT) was not CV events, but an intermediate outcome: the intima-media thickness of the carotid artery. The results regarding this outcome favoured HRT, but when CV events were taken into account, no benefits were seen. Another additional study (Angerer 2002) after one year of HRT, failed to demonstrate any slowing of progression of subclinical atherosclerosis (measured as intima-media thickness in carotid arteries) in postmenopausal women at increased risk. It had been hoped that long term outcomes would be available but WISDOM, intended to study women till 2016 has been stopped early owing to scientific and practical reasons (White, 2002).
After the publication of the WHI study (WHI-2002), the question of whether healthy women should take HRT to prevent CV disease seems to be easier to answer. The WHI study is the first randomised primary prevention trial of postmenopausal hormone replacement. The data and safety monitoring board recommended stopping the trial because women receiving HRT had an increased risk of invasive breast cancer. Overall, the results of the WHI study are consistent with the body of evidence on the effects of HRT. Risk of stroke and venous thromboembolism and myocardial infarction were also increased in women assigned to the HRT in the WHI.
AUTHORS’ CONCLUSIONS
Implications for practice
Treatment with HRT for the sole purpose of preventing CV events in post-menopausal women (with or without CV disease) is not effective.
Among women taking HRT for other reasons (e.g. menopausal symptoms) but with other risk factors for venous thromboembolic events, HRT should be discouraged as there is evidence that HRT causes an increased risk of these events.
Implications for research
The need to develop new treatments to control perimenopausal symptoms is essential given these findings from the RCTs. Future observational studies examining effects of treatments should be interpreted cautiously given these findings.
PLAIN LANGUAGE SUMMARY.
Hormone therapy has no heart-protective benefit to healthy postmenopausal women or to those with heart disease
The authors analysed the data from the 10 clinical trials - two involved healthy women and eight involved women with heart disease. Altogether the trials included about 24,000 women who had been randomly assigned to take either hormones or placebos (dummy pill) every day for approximately five years. The authors found no evidence that hormone therapy provides heart-related benefits to postmenopausal women with or without heart disease. Rather, women taking hormones had a higher incidence of non-fatal heart attacks, stroke, and blood clots in the leg and lung than the women taking placebos.
ACKNOWLEDGEMENTS
All authors are members of the Red Temática de Investigación en Medicina Basada en la Evidencia FIS G03/090 and Dr. Rafael Gabriel and Dr. Luis M. Sánchez are members of the Red Temática de Investigación en Epidemiología Cardiovascular:Proyecto ERICE. FIS G03/065. The authors want to thank the personnel at the Iberoamerican Cochrane Centre and the Cochrane Heart Group for their assistance with the preparation of this systematic review.
SOURCES OF SUPPORT
Internal sources
Instituto de Salud Carlos III (Contrato Investigadores del SNS), Spain.
Hospital Universitario de la Princesa (Madrid), Spain.
Centro Cochrane Iberoamericano (Barcelona), Spain.
Hospital Universitario la Paz (Madrid), Spain.
Spanish Foundation of Rheumatology, Spain.
External sources
Agencia de Evaluació de Tecnologies Mèdiques de Catalunya, Spain.
Red Tematica de Investigacion en Medicina Basada en la Evidencia FIS G03/090, Spain.
Red Tematica de Investigacion en Medicina Basada en Epidemiologia Cardiovascular: Proyecto ERICE FIS G03/065, Spain.
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
| Methods | Randomised controlled trial of 2 years of follow-up | |
| Participants | 222 post-menopausal women (mean age 62.2) without previous coronary artery disease | |
| Interventions |
|
|
| Outcomes | Primary: intima thickness Secondary: Major CV events All causes of death Side effects |
|
| Notes | 25% Losses of follow-up. | |
| Risk of bias | ||
| Item | Authors judgement | Description |
| Allocation concealment? | Yes | A - Adequate |
| Methods | Randomised controlled trial of 3.2 years of follow-up | |
| Participants | 309 post-menopausal women (mean age 65.8) with previous coronary artery disease | |
| Interventions |
|
|
| Outcomes | All causes of death Major CV events CV deaths Revascularization procedures other CV outcomes Side effects |
|
| Notes | Losses of follow-up evenly distributed. | |
| Risk of bias | ||
| Item | Authors’ judgement | Description |
| Allocation concealment? | Yes | A - Adequate |
| Methods | Randomised controlled trial of 1.3 years of follow-up | |
| Participants | 140 women with previous venous thromboembolism | |
| Interventions | A) 2 mg stradiol ans 1 mg of norethisterone acetate | |
| Outcomes | venous thromboembolism | |
| Notes | terminated after report of increased risk of venous thromboembolism | |
| Risk of bias | ||
| Item | Authors’ judgement | Description |
| Allocation concealment? | Yes | A - Adequate |
| Methods | Randomised controlled trial of 1 year of follow-up | |
| Participants | 60 post-menopausal women (mean age 59.4) with previous coronary artery disease | |
| Interventions |
|
|
| Outcomes | All causes of death Major CV events CV deaths Revascularization procedures |
|
| Notes | 23% Losses of follow-up | |
| Risk of bias | ||
| Item | Authors’ judgement | Description |
| Allocation concealment? | Yes | A - Adequate |
| Methods | Randomised controlled trial of 3.1 years of follow-up | |
| Participants | 2763 post- menopausal women (mean age 66.7) with previous coronary artery disease | |
| Interventions |
|
|
| Outcomes | All causes of death Major CV events CV deaths Revascularization procedures other CV outcomes Side effects |
|
| Notes | Vital status known to all. No losses to follow-up. | |
| Risk of bias | ||
| Item | Authors’ judgement | Description |
| Allocation concealment? | Yes | A - Adequate |
| Methods | Randomised, blinded, placebo controlled trial of 4.1 years duration (HERS) and follow-up for 2.7 years | |
| Participants | 2321 women consented for follow-up in HERS II | |
| Interventions | Open label hormone therapy in HERS II | |
| Outcomes | Primary outcome: Non fatal myocardial infarction and CHD death Secondary cardiovascular events: coronary revascularization, hospitalisation for unstable angina or congestive heart failure, ventricular arrhythmia, sudden death, stroke, ischemic attack, peripheral arterial diseases Non cardiovascular outcomes: thromboembolics events, cancer and al causes of death |
|
| Notes | Cardiovascular and Non cardiovascular Disease Outcomes from the HERS II | |
| Risk of bias | ||
| Item | Authors’ judgement | Description |
| Allocation concealment? | Yes | A - Adequate |
| Methods | Randomised controlled trial of 2 years of follow-up | |
| Participants | 1017 postmenopausal women with first myocardial infarction | |
| Interventions |
|
|
| Outcomes | Major CV events CV deaths |
|
| Notes | ||
| Risk of bias | ||
| Item | Authors’ judgement | Description |
| Allocation concealment? | Yes | A - Adequate |
| Methods | Randomised controlled trial of 5 years of follow-up | |
| Participants | 423 postmenopausal women with documented coronary disease | |
| Interventions |
|
|
| Outcomes | All deaths, cardiovascular deaths, nonfatal myocardial infarction, stroke, PCI or CABG surgery, pulmonary embolus or deep vein thrombosis | |
| Notes | 20% losses of follow-up | |
| Risk of bias | ||
| Item | Authors’ judgement | Description |
| Allocation concealment? | Yes | A - Adequate |
| Methods | Randomised controlled trial of 3.1 years of follow-up | |
| Participants | 664 post-menopausal women (mean age 71) with previous ischemic stroke | |
| Interventions |
|
|
| Outcomes | All causes of death Major CV events CV deaths Side effects |
|
| Notes | No losses to follow-up | |
| Risk of bias | ||
| Item | Authors’ judgement | Description |
| Allocation concealment? | Yes | A - Adequate |
| Methods | Randomised controlled trial of 5.2 years of follow-up | |
| Participants | 16608 postmenopausal women aged 50-79 years with an intact uterus at baseline | |
| Interventions |
|
|
| Outcomes | Primary outcomes: non fatal myocardial infarction and CHD death Secondary outcomes: stroke, pulmonary embolism, cancer and all causes of death |
|
| Notes | ||
| Risk of bias | ||
| Item | Authors’ judgement | Description |
| Allocation concealment? | Unclear | B - Unclear |
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| AITKEN | Did not record clinical outcomes. |
| ALOIA | Did not record clinical outcomes. |
| ANGERER | Did not record clinical outcomes. |
| Barret Connor | The intervention can not be considered “sensu stricto” HRT (women are treated with Raloxifene, a new oestrogen receptor modulator) |
| CHART | Did not record clinical outcomes. |
| CHRISTENSEN | Did not record clinical outcomes. |
| CHRISTIANSEN (a) | Did not record clinical outcomes. |
| CHRISTIANSEN (b) | Did not record clinical outcomes. |
| CHRISTIANSEN (c) | Did not record clinical outcomes. |
| COOPE | Did not record clinical outcomes. |
| DERMAN | Did not record clinical outcomes. |
| GALLAGHER | Did not record clinical outcomes. |
| GENANT | Did not record clinical outcomes. |
| HASSAGER | Did not record clinical outcomes. |
| Heckbert 1997 | Case control study |
| JENSEN | Did not record clinical outcomes. |
| LINDSAY | Did not record clinical outcomes. |
| LUFKIN | Did not record clinical outcomes. |
| MARSLEW | Did not record clinical outcomes. |
| MOLANDERM | Did not record clinical outcomes. |
| MUNK-JENSEN | Did not record clinical outcomes. |
| NACHTIGALL | Did not record clinical outcomes. |
| PEPI | Did not record clinical outcomes. |
| RESCH | Did not record clinical outcomes. |
| RIGGS | Did not record clinical outcomes. |
| RIIS | Did not record clinical outcomes. |
| SVENDSEN | Did not record clinical outcomes. |
| TONSTAD | Did not record clinical outcomes. |
| WIMALAWANSA | Did not record clinical outcomes. |
Characteristics of ongoing studies [ordered by study ID]
| Trial name or title | Oestrogen in the prevention of the Terinfartion Trial |
| Methods | |
| Participants | 1017 postmenopausal women with bfirs Myocardial Infarction |
| Interventions |
|
| Outcomes | |
| Starting date | 2000 |
| Contact information | Kahn MA |
| Notes | Secondary prevention |
| Trial name or title | Postmenopausal Hormone Therapy in Unstable Angina |
| Methods | |
| Participants | Postmenopausal women with unstable angina |
| Interventions |
|
| Outcomes | Ischemic episodes |
| Starting date | 1999 |
| Contact information | Steven P Schulman John Hopkins Hospital Baltimore, Maryland USA Tel: +01 410 955 7378 |
| Notes |
| Trial name or title | The Papworth HRT Atherosclerosis Survival Enquiry |
| Methods | |
| Participants | 400 women with ischemic heart disease |
| Interventions |
|
| Outcomes | Death MI Hospitalisations for unstable angina in 2 years |
| Starting date | |
| Contact information | Dr. Sarah C Clarke Box No 76 Papworth Hospital CB3 8RE UK |
| Notes | Secondary prevention (It should be completed) |
| Trial name or title | Women’s hormone intervention secondary prevention study |
| Methods | |
| Participants | 4,000-4,800 postmenopausal women who have recently had myocardial infarction |
| Interventions | HRT |
| Outcomes | All-cause mortality over a period of 4 years |
| Starting date | |
| Contact information | Malcom.Whitehead@kingshc.nhs.uk |
| Notes | Secondary prevention |
| Trial name or title | Women’s International Study of Long Duration Oestrogen After Menopause |
| Methods | |
| Participants | 34,000 post-menopausal healthy women |
| Interventions | Estrogen + Progestin |
| Outcomes | CV events Side effects Quality of life |
| Starting date | 2001. 10 years of follow up |
| Contact information | M.R.VICKERS@mds.qmw.ac.uk |
| Notes | Primary and secondary prevention |
DATA AND ANALYSES
Comparison 1. HRT vs placebo (in primary prevention).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Death (all causes) | 2 | 16830 | Risk Ratio (M-H, Fixed, 95% CI) | 1.00 [0.84, 1.21] |
| 2 Death (CV cause) | 2 | 16830 | Risk Ratio (M-H, Fixed, 95% CI) | 1.16 [0.70, 1.92] |
| 3 Non-fatal MI | 2 | 16830 | Risk Ratio (M-H, Fixed, 95% CI) | 1.32 [1.02, 1.71] |
| 4 Stroke | 2 | 16830 | Risk Ratio (M-H, Fixed, 95% CI) | 1.44 [1.10, 1.89] |
| 5 Combined CV events and outcomes | 2 | 16830 | Risk Ratio (M-H, Fixed, 95% CI) | 1.20 [1.05, 1.36] |
| 6 Venous thromboembolism | 1 | 16608 | Risk Ratio (M-H, Fixed, 95% CI) | 2.15 [1.61, 2.86] |
| 7 Pulmonary embolus | 1 | 16608 | Risk Ratio (M-H, Fixed, 95% CI) | 2.15 [1.41, 3.28] |
Comparison 2. HRT vs placebo (secondary prevention only).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Death (all causes) | 7 | 7453 | Risk Ratio (M-H, Fixed, 95% CI) | 1.08 [0.94, 1.25] |
| 2 Death (CV cause) | 7 | 7453 | Risk Ratio (M-H, Fixed, 95% CI) | 1.00 [0.82, 1.23] |
| 3 Non-fatal MI | 6 | 7393 | Risk Ratio (M-H, Fixed, 95% CI) | 1.01 [0.85, 1.20] |
| 4 Stroke | 7 | 7453 | Risk Ratio (M-H, Fixed, 95% CI) | 1.15 [0.97, 1.36] |
| 5 Combined CV events and outcomes | 6 | 6433 | Risk Ratio (M-H, Fixed, 95% CI) | 0.96 [0.89, 1.04] |
| 6 Venous thromboembolism | 7 | 7533 | Risk Ratio (M-H, Fixed, 95% CI) | 2.03 [1.36, 3.04] |
| 7 Pulmonary embolus | 5 | 6905 | Risk Ratio (M-H, Fixed, 95% CI) | 2.07 [1.04, 4.10] |
Comparison 3. HRT vs placebo (in primary or secondary prevention).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Death (all causes) | 9 | 24283 | Odds Ratio (M-H, Fixed, 95% CI) | 1.06 [0.94, 1.19] |
| 2 Death (CV cause) | 9 | 24283 | Odds Ratio (M-H, Fixed, 95% CI) | 1.04 [0.85, 1.26] |
| 3 Non-fatal MI | 8 | 24223 | Odds Ratio (M-H, Fixed, 95% CI) | 1.11 [0.95, 1.28] |
| 4 Stroke | 9 | 24283 | Odds Ratio (M-H, Fixed, 95% CI) | 1.25 [1.07, 1.45] |
| 5 Combined CV events and outcomes | 8 | 23266 | Odds Ratio (M-H, Fixed, 95% CI) | 1.04 [0.96, 1.14] |
| 6 Venous thromboembolism | 8 | 24141 | Odds Ratio (M-H, Fixed, 95% CI) | 2.13 [1.68, 2.70] |
| 7 Pulmonary embolus | 6 | 23513 | Odds Ratio (M-H, Fixed, 95% CI) | 2.14 [1.49, 3.07] |
Comparison 4. Oestrogen vs placebo (in primary and secondary prevention).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Death (all causes) | 3 | 1903 | Odds Ratio (M-H, Fixed, 95% CI) | 0.96 [0.69, 1.33] |
| 2 Death (CV causes) | 3 | 1903 | Odds Ratio (M-H, Fixed, 95% CI) | 0.70 [0.44, 1.12] |
| 3 Non-fatal MI | 3 | 1903 | Odds Ratio (M-H, Fixed, 95% CI) | 1.26 [0.84, 1.90] |
| 4 Stroke | 3 | 1903 | Odds Ratio (M-H, Fixed, 95% CI) | 1.21 [0.84, 1.74] |
| 5 Combined CV events and outcomes | 3 | 888 | Odds Ratio (M-H, Fixed, 95% CI) | 0.74 [0.53, 1.02] |
| 6 Venous thromboembolism | 2 | 1681 | Odds Ratio (M-H, Fixed, 95% CI) | 0.97 [0.28, 3.38] |
| 7 Pulmonary embolus | 2 | 1681 | Odds Ratio (M-H, Fixed, 95% CI) | 0.98 [0.28, 3.39] |
Comparison 5. Oestrogen vs placebo (in primary prevention).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Death (all causes) | 1 | 222 | Odds Ratio (M-H, Fixed, 95% CI) | 0.33 [0.01, 8.20] |
| 2 Death (CV cause) | 1 | 222 | Odds Ratio (M-H, Fixed, 95% CI) | 0.33 [0.01, 8.20] |
| 3 Non-fatal MI | 1 | 222 | Odds Ratio (M-H, Fixed, 95% CI) | 1.0 [0.06, 16.19] |
| 4 Stroke | 1 | 222 | Odds Ratio (M-H, Fixed, 95% CI) | 5.09 [0.24, 107.27] |
| 5 Combined CV events | 1 | 222 | Odds Ratio (M-H, Fixed, 95% CI) | 1.51 [0.25, 9.24] |
Comparison 6. Oestrogen vs placebo (in secondary prevention).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Death (all causes) | 2 | 1681 | Odds Ratio (M-H, Fixed, 95% CI) | 0.97 [0.70, 1.35] |
| 2 Death (CV causes) | 2 | 1681 | Odds Ratio (M-H, Fixed, 95% CI) | 0.72 [0.45, 1.15] |
| 3 Non-fatal MI | 2 | 1681 | Odds Ratio (M-H, Fixed, 95% CI) | 1.27 [0.84, 1.92] |
| 4 Stroke | 2 | 1681 | Odds Ratio (M-H, Fixed, 95% CI) | 1.17 [0.81, 1.70] |
| 5 Combined CV events and outcomes | 2 | 666 | Odds Ratio (M-H, Fixed, 95% CI) | 0.72 [0.51, 1.00] |
| 6 Venous thromboembolism | 2 | 1681 | Odds Ratio (M-H, Fixed, 95% CI) | 0.97 [0.28, 3.38] |
| 7 Pulmonary embolism | 2 | 1681 | Odds Ratio (M-H, Fixed, 95% CI) | 0.98 [0.28, 3.39] |
Comparison 7. Combined therapy vs Placebo (in primary or secondary prevention).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Death (all causes) | 7 | 22382 | Odds Ratio (M-H, Fixed, 95% CI) | 1.07 [0.94, 1.22] |
| 2 Death (CV cause) | 6 | 22380 | Odds Ratio (M-H, Fixed, 95% CI) | 1.13 [0.91, 1.41] |
| 3 Non-fatal MI | 5 | 22320 | Odds Ratio (M-H, Fixed, 95% CI) | 1.08 [0.92, 1.27] |
| 4 Stroke | 6 | 22380 | Odds Ratio (M-H, Fixed, 95% CI) | 1.26 [1.06, 1.49] |
| 5 Combined CV events and outcomes | 6 | 22377 | Odds Ratio (M-H, Fixed, 95% CI) | 1.07 [0.98, 1.17] |
| 6 Venous thromboembolism | 6 | 22460 | Odds Ratio (M-H, Fixed, 95% CI) | 2.19 [1.72, 2.79] |
| 7 Pulmonary embolus | 4 | 21832 | Odds Ratio (M-H, Fixed, 95% CI) | 2.29 [1.37, 3.33] |
Comparison 8. Combined therapy vs Placebo (in primary prevention).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Death (all causes) | 1 | Odds Ratio (M-H, Fixed, 95% CI) | Totals not selected | |
| 2 Death (CV cause) | 1 | Odds Ratio (M-H, Fixed, 95% CI) | Totals not selected | |
| 3 Non-fatal myocardial infarction | 1 | Odds Ratio (M-H, Fixed, 95% CI) | Totals not selected | |
| 4 Stroke | 1 | Odds Ratio (M-H, Fixed, 95% CI) | Totals not selected | |
| 5 Combined CV events and outcomes | 1 | Odds Ratio (M-H, Fixed, 95% CI) | Totals not selected | |
| 6 Venous thromboembolism | 1 | Odds Ratio (M-H, Fixed, 95% CI) | Totals not selected | |
| 7 Pulmonary embolus | 1 | Odds Ratio (M-H, Fixed, 95% CI) | Totals not selected |
Comparison 9. Combined therapy vs Placebo (in secondary prevention).
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Death (all causes) | 5 | 5772 | Odds Ratio (M-H, Fixed, 95% CI) | 1.13 [0.95, 1.35] |
| 2 Death (CV cause) | 5 | 5772 | Odds Ratio (M-H, Fixed, 95% CI) | 1.11 [0.87, 1.42] |
| 3 Non-fatal myocardial infarction | 4 | 5712 | Odds Ratio (M-H, Fixed, 95% CI) | 0.96 [0.78, 1.17] |
| 4 Stroke | 5 | 5772 | Odds Ratio (M-H, Fixed, 95% CI) | 1.16 [0.94, 1.44] |
| 5 Combined CV events | 5 | 5772 | Odds Ratio (M-H, Fixed, 95% CI) | 0.99 [0.88, 1.11] |
| 6 Venous thromboembolism | 5 | 5852 | Odds Ratio (M-H, Fixed, 95% CI) | 2.24 [1.45, 3.46] |
| 7 Pulmonary embolus | 3 | 3224 | Odds Ratio (M-H, Fixed, 95% CI) | 2.88 [1.21, 6.82] |
Analysis 1.1. Comparison 1 HRT vs placebo (in primary prevention), Outcome 1 Death (all causes).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 1 HRT vs placebo (in primary prevention)
Outcome: 1 Death (all causes)
 |
Analysis 1.2. Comparison 1 HRT vs placebo (in primary prevention), Outcome 2 Death (CV cause).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 1 HRT vs placebo (in primary prevention)
Outcome: 2 Death (CV cause)
 |
Analysis 1.3. Comparison 1 HRT vs placebo (in primary prevention), Outcome 3 Non-fatal MI.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 1 HRT vs placebo (in primary prevention)
Outcome: 3 Non-fatal MI
 |
Analysis 1.4. Comparison 1 HRT vs placebo (in primary prevention), Outcome 4 Stroke.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 1 HRT vs placebo (in primary prevention)
Outcome: 4 Stroke
 |
Analysis 1.5. Comparison 1 HRT vs placebo (in primary prevention), Outcome 5 Combined CV events and outcomes.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 1 HRT vs placebo (in primary prevention)
Outcome: 5 Combined CV events and outcomes
 |
Analysis 1.6. Comparison 1 HRT vs placebo (in primary prevention), Outcome 6 Venous thromboembolism.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 1 HRT vs placebo (in primary prevention)
Outcome: 6 Venous thromboembolism
 |
Analysis 1.7. Comparison 1 HRT vs placebo (in primary prevention), Outcome 7 Pulmonary embolus.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 1 HRT vs placebo (in primary prevention)
Outcome: 7 Pulmonary embolus
 |
Analysis 2.1. Comparison 2 HRT vs placebo (secondary prevention only), Outcome 1 Death (all causes).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 2 HRT vs placebo (secondary prevention only)
Outcome: 1 Death (all causes)
 |
Analysis 2.2. Comparison 2 HRT vs placebo (secondary prevention only), Outcome 2 Death (CV cause).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 2 HRT vs placebo (secondary prevention only)
Outcome: 2 Death (CV cause)
 |
Analysis 2.3. Comparison 2 HRT vs placebo (secondary prevention only), Outcome 3 Non-fatal MI.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 2 HRT vs placebo (secondary prevention only)
Outcome: 3 Non-fatal MI
 |
Analysis 2.4. Comparison 2 HRT vs placebo (secondary prevention only), Outcome 4 Stroke.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 2 HRT vs placebo (secondary prevention only)
Outcome: 4 Stroke
 |
Analysis 2.5. Comparison 2 HRT vs placebo (secondary prevention only), Outcome 5 Combined CV events and outcomes.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 2 HRT vs placebo (secondary prevention only)
Outcome: 5 Combined CV events and outcomes
 |
Analysis 2.6. Comparison 2 HRT vs placebo (secondary prevention only), Outcome 6 Venous thromboembolism.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 2 HRT vs placebo (secondary prevention only)
Outcome: 6 Venous thromboembolism
 |
Analysis 2.7. Comparison 2 HRT vs placebo (secondary prevention only), Outcome 7 Pulmonary embolus.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 2 HRT vs placebo (secondary prevention only)
Outcome: 7 Pulmonary embolus
 |
Analysis 3.1. Comparison 3 HRT vs placebo (in primary or secondary prevention), Outcome 1 Death (all causes).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 3 HRT vs placebo (in primary or secondary prevention)
Outcome: 1 Death (all causes)
 |
Analysis 3.2. Comparison 3 HRT vs placebo (in primary or secondary prevention), Outcome 2 Death (CV cause).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 3 HRT vs placebo (in primary or secondary prevention)
Outcome: 2 Death (CV cause)
 |
Analysis 3.3. Comparison 3 HRT vs placebo (in primary or secondary prevention), Outcome 3 Non-fatal MI.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 3 HRT vs placebo (in primary or secondary prevention)
Outcome: 3 Non-fatal MI
 |
Analysis 3.4. Comparison 3 HRT vs placebo (in primary or secondary prevention), Outcome 4 Stroke.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 3 HRT vs placebo (in primary or secondary prevention)
Outcome: 4 Stroke
 |
Analysis 3.5. Comparison 3 HRT vs placebo (in primary or secondary prevention), Outcome 5 Combined CV events and outcomes.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 3 HRT vs placebo (in primary or secondary prevention)
Outcome: 5 Combined CV events and outcomes
 |
Analysis 3.6. Comparison 3 HRT vs placebo (in primary or secondary prevention), Outcome 6 Venous thromboembolism.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 3 HRT vs placebo (in primary or secondary prevention)
Outcome: 6 Venous thromboembolism
 |
Analysis 3.7. Comparison 3 HRT vs placebo (in primary or secondary prevention), Outcome 7 Pulmonary embolus.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 3 HRT vs placebo (in primary or secondary prevention)
Outcome: 7 Pulmonary embolus
 |
Analysis 4.1. Comparison 4 Oestrogen vs placebo (in primary and secondary prevention), Outcome 1 Death (all causes).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 4 Oestrogen vs placebo (in primary and secondary prevention)
Outcome: 1 Death (all causes)
 |
Analysis 4.2. Comparison 4 Oestrogen vs placebo (in primary and secondary prevention), Outcome 2 Death (CV causes).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 4 Oestrogen vs placebo (in primary and secondary prevention)
Outcome: 2 Death (CV causes)
 |
Analysis 4.3. Comparison 4 Oestrogen vs placebo (in primary and secondary prevention), Outcome 3 Nonfatal MI.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 4 Oestrogen vs placebo (in primary and secondary prevention)
Outcome: 3 Non-fatal MI
 |
Analysis 4.4. Comparison 4 Oestrogen vs placebo (in primary and secondary prevention), Outcome 4 Stroke.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 4 Oestrogen vs placebo (in primary and secondary prevention)
Outcome: 4 Stroke
 |
Analysis 4.5. Comparison 4 Oestrogen vs placebo (in primary and secondary prevention), Outcome 5 Combined CV events and outcomes.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 4 Oestrogen vs placebo (in primary and secondary prevention)
Outcome: 5 Combined CV events and outcomes
 |
Analysis 4.6. Comparison 4 Oestrogen vs placebo (in primary and secondary prevention), Outcome 6 Venous thromboembolism.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 4 Oestrogen vs placebo (in primary and secondary prevention)
Outcome: 6 Venous thromboembolism
 |
Analysis 4.7. Comparison 4 Oestrogen vs placebo (in primary and secondary prevention), Outcome 7 Pulmonary embolus.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 4 Oestrogen vs placebo (in primary and secondary prevention)
Outcome: 7 Pulmonary embolus
 |
Analysis 5.1. Comparison 5 Oestrogen vs placebo (in primary prevention), Outcome 1 Death (all causes).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 5 Oestrogen vs placebo (in primary prevention)
Outcome: 1 Death (all causes)
 |
Analysis 5.2. Comparison 5 Oestrogen vs placebo (in primary prevention), Outcome 2 Death (CV cause).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 5 Oestrogen vs placebo (in primary prevention)
Outcome: 2 Death (CV cause)
 |
Analysis 5.3. Comparison 5 Oestrogen vs placebo (in primary prevention), Outcome 3 Non-fatal MI.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 5 Oestrogen vs placebo (in primary prevention)
Outcome: 3 Non-fatal MI
 |
Analysis 5.4. Comparison 5 Oestrogen vs placebo (in primary prevention), Outcome 4 Stroke.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 5 Oestrogen vs placebo (in primary prevention)
Outcome: 4 Stroke
 |
Analysis 5.5. Comparison 5 Oestrogen vs placebo (in primary prevention), Outcome 5 Combined CV events.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 5 Oestrogen vs placebo (in primary prevention)
Outcome: 5 Combined CV events
 |
Analysis 6.1. Comparison 6 Oestrogen vs placebo (in secondary prevention), Outcome 1 Death (all causes).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 6 Oestrogen vs placebo (in secondary prevention)
Outcome: 1 Death (all causes)
 |
Analysis 6.2. Comparison 6 Oestrogen vs placebo (in secondary prevention), Outcome 2 Death (CV causes).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 6 Oestrogen vs placebo (in secondary prevention)
Outcome: 2 Death (CV causes)
 |
Analysis 6.3. Comparison 6 Oestrogen vs placebo (in secondary prevention), Outcome 3 Non-fatal MI.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 6 Oestrogen vs placebo (in secondary prevention)
Outcome: 3 Non-fatal MI
 |
Analysis 6.4. Comparison 6 Oestrogen vs placebo (in secondary prevention), Outcome 4 Stroke.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 6 Oestrogen vs placebo (in secondary prevention)
Outcome: 4 Stroke
 |
Analysis 6.5. Comparison 6 Oestrogen vs placebo (in secondary prevention), Outcome 5 Combined CV events and outcomes.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 6 Oestrogen vs placebo (in secondary prevention)
Outcome: 5 Combined CV events and outcomes
 |
Analysis 6.6. Comparison 6 Oestrogen vs placebo (in secondary prevention), Outcome 6 Venous thromboembolism.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 6 Oestrogen vs placebo (in secondary prevention)
Outcome: 6 Venous thromboembolism
 |
Analysis 6.7. Comparison 6 Oestrogen vs placebo (in secondary prevention), Outcome 7 Pulmonary embolism.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 6 Oestrogen vs placebo (in secondary prevention)
Outcome: 7 Pulmonary embolism
 |
Analysis 7.1. Comparison 7 Combined therapy vs Placebo (in primary or secondary prevention), Outcome 1 Death (all causes).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 7 Combined therapy vs Placebo (in primary or secondary prevention)
Outcome: 1 Death (all causes)
 |
Analysis 7.2. Comparison 7 Combined therapy vs Placebo (in primary or secondary prevention), Outcome 2 Death (CV cause).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 7 Combined therapy vs Placebo (in primary or secondary prevention)
Outcome: 2 Death (CV cause)
 |
Analysis 7.3. Comparison 7 Combined therapy vs Placebo (in primary or secondary prevention), Outcome 3 Non-fatal MI.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 7 Combined therapy vs Placebo (in primary or secondary prevention)
Outcome: 3 Non-fatal MI
 |
Analysis 7.4. Comparison 7 Combined therapy vs Placebo (in primary or secondary prevention), Outcome 4 Stroke.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 7 Combined therapy vs Placebo (in primary or secondary prevention)
Outcome: 4 Stroke
 |
Analysis 7.5. Comparison 7 Combined therapy vs Placebo (in primary or secondary prevention), Outcome 5 Combined CV events and outcomes.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 7 Combined therapy vs Placebo (in primary or secondary prevention)
Outcome: 5 Combined CV events and outcomes
 |
Analysis 7.6. Comparison 7 Combined therapy vs Placebo (in primary or secondary prevention), Outcome 6 Venous thromboembolism.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 7 Combined therapy vs Placebo (in primary or secondary prevention)
Outcome: 6 Venous thromboembolism
 |
Analysis 7.7. Comparison 7 Combined therapy vs Placebo (in primary or secondary prevention), Outcome 7 Pulmonary embolus.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 7 Combined therapy vs Placebo (in primary or secondary prevention)
Outcome: 7 Pulmonary embolus
 |
Analysis 8.1. Comparison 8 Combined therapy vs Placebo (in primary prevention), Outcome 1 Death (all causes).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 8 Combined therapy vs Placebo (in primary prevention)
Outcome: 1 Death (all causes)
 |
Analysis 8.2. Comparison 8 Combined therapy vs Placebo (in primary prevention), Outcome 2 Death (CV cause).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 8 Combined therapy vs Placebo (in primary prevention)
Outcome: 2 Death (CV cause)
 |
Analysis 8.3. Comparison 8 Combined therapy vs Placebo (in primary prevention), Outcome 3 Non-fatal myocardial infarction.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 8 Combined therapy vs Placebo (in primary prevention)
Outcome: 3 Non-fatal myocardial infarction
 |
Analysis 8.4. Comparison 8 Combined therapy vs Placebo (in primary prevention), Outcome 4 Stroke.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 8 Combined therapy vs Placebo (in primary prevention)
Outcome: 4 Stroke
 |
Analysis 8.5. Comparison 8 Combined therapy vs Placebo (in primary prevention), Outcome 5 Combined CV events and outcomes.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 8 Combined therapy vs Placebo (in primary prevention)
Outcome: 5 Combined CV events and outcomes
 |
Analysis 8.6. Comparison 8 Combined therapy vs Placebo (in primary prevention), Outcome 6 Venous thromboembolism.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 8 Combined therapy vs Placebo (in primary prevention)
Outcome: 6 Venous thromboembolism
 |
Analysis 8.7. Comparison 8 Combined therapy vs Placebo (in primary prevention), Outcome 7 Pulmonary embolus.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 8 Combined therapy vs Placebo (in primary prevention)
Outcome: 7 Pulmonary embolus
 |
Analysis 9.1. Comparison 9 Combined therapy vs Placebo (in secondary prevention), Outcome 1 Death (all causes).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 9 Combined therapy vs Placebo (in secondary prevention)
Outcome: 1 Death (all causes)
 |
Analysis 9.2. Comparison 9 Combined therapy vs Placebo (in secondary prevention), Outcome 2 Death (CV cause).
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 9 Combined therapy vs Placebo (in secondary prevention)
Outcome: 2 Death (CV cause)
 |
Analysis 9.3. Comparison 9 Combined therapy vs Placebo (in secondary prevention), Outcome 3 Non-fatal myocardial infarction.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 9 Combined therapy vs Placebo (in secondary prevention)
Outcome: 3 Non-fatal myocardial infarction
 |
Analysis 9.4. Comparison 9 Combined therapy vs Placebo (in secondary prevention), Outcome 4 Stroke.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 9 Combined therapy vs Placebo (in secondary prevention)
Outcome: 4 Stroke
 |
Analysis 9.5. Comparison 9 Combined therapy vs Placebo (in secondary prevention), Outcome 5 Combined CV events.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 9 Combined therapy vs Placebo (in secondary prevention)
Outcome: 5 Combined CV events
 |
Analysis 9.6. Comparison 9 Combined therapy vs Placebo (in secondary prevention), Outcome 6 Venous thromboembolism.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 9 Combined therapy vs Placebo (in secondary prevention)
Outcome: 6 Venous thromboembolism
 |
Analysis 9.7. Comparison 9 Combined therapy vs Placebo (in secondary prevention), Outcome 7 Pulmonary embolus.
Review: Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women
Comparison: 9 Combined therapy vs Placebo (in secondary prevention)
Outcome: 7 Pulmonary embolus
 |
WHAT’S NEW
Last assessed as up-to-date: 31 January 2005.
| Date | Event | Description |
|---|---|---|
| 8 September 2008 | Amended | Converted to new review format. |
HISTORY
Protocol first published: Issue 3, 2000
Review first published: Issue 2, 2005
| Date | Event | Description |
|---|---|---|
| 1 February 2005 | New citation required and conclusions have changed | Substantive amendment |
Footnotes
DECLARATIONS OF INTEREST
None known
NOTES
The Peninsula Technology Assessment Group (PenTAG) at Peninsula Medical School, Exeter, UK and the Cochrane Heart Group have been awarded a 3-year grant from the National Institute for Health Research to update existing Cochrane systematic reviews relevant to public health, primary care and rehabilitation.
This review is scheduled to be updated in the first year of the program. Publication of the updated review is anticipated by issue 2, 2009 at the latest.
References to studies included in this review
- EPAT {published data only} .*; Hodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A, Mahrer PR, et al. Estrogen in the Prevention of Atherosclerosis. A Randomized, Double-Blind, Placebo-Controlled Trial. Annals of Internal Medicine. 2001;135(11):939–53. doi: 10.7326/0003-4819-135-11-200112040-00005. [DOI] [PubMed] [Google Scholar]
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