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Meta-Analysis
. 2015 Mar 10;2015(3):CD002229.
doi: 10.1002/14651858.CD002229.pub4.

Hormone therapy for preventing cardiovascular disease in post-menopausal women

Henry M P Boardman  1 , Louise Hartley, Anne Eisinga, Caroline Main, Marta Roqué i Figuls, Xavier Bonfill Cosp, Rafael Gabriel Sanchez, Beatrice Knight
Affiliations
Meta-Analysis

Hormone therapy for preventing cardiovascular disease in post-menopausal women

Henry M P Boardman et al. Cochrane Database Syst Rev. .

Abstract

Background: Evidence from systematic reviews of observational studies suggests that hormone therapy may have beneficial effects in reducing the incidence of cardiovascular disease events in post-menopausal women, however the results of randomised controlled trials (RCTs) have had mixed results. This is an updated version of a Cochrane review published in 2013.

Objectives: To assess the effects of hormone therapy for the prevention of cardiovascular disease in post-menopausal women, and whether there are differential effects between use in primary or secondary prevention. Secondary aims were to undertake exploratory analyses to (i) assess the impact of time since menopause that treatment was commenced (≥ 10 years versus < 10 years), and where these data were not available, use age of trial participants at baseline as a proxy (≥ 60 years of age versus < 60 years of age); and (ii) assess the effects of length of time on treatment.

Search methods: We searched the following databases on 25 February 2014: Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE and LILACS. We also searched research and trials registers, and conducted reference checking of relevant studies and related systematic reviews to identify additional studies.

Selection criteria: RCTs of women comparing orally administered hormone therapy with placebo or a no treatment control, with a minimum of six months follow-up.

Data collection and analysis: Two authors independently assessed study quality and extracted data. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for each outcome. We combined results using random effects meta-analyses, and undertook further analyses to assess the effects of treatment as primary or secondary prevention, and whether treatment was commenced more than or less than 10 years after menopause.

Main results: We identified six new trials through this update. Therefore the review includes 19 trials with a total of 40,410 post-menopausal women. On the whole, study quality was good and generally at low risk of bias; the findings are dominated by the three largest trials. We found high quality evidence that hormone therapy in both primary and secondary prevention conferred no protective effects for all-cause mortality, cardiovascular death, non-fatal myocardial infarction, angina, or revascularisation. However, there was an increased risk of stroke in those in the hormone therapy arm for combined primary and secondary prevention (RR 1.24, 95% CI 1.10 to 1.41). Venous thromboembolic events were increased (RR 1.92, 95% CI 1.36 to 2.69), as were pulmonary emboli (RR 1.81, 95% CI 1.32 to 2.48) on hormone therapy relative to placebo.The absolute risk increase for stroke was 6 per 1000 women (number needed to treat for an additional harmful outcome (NNTH) = 165; mean length of follow-up: 4.21 years (range: 2.0 to 7.1)); for venous thromboembolism 8 per 1000 women (NNTH = 118; mean length of follow-up: 5.95 years (range: 1.0 to 7.1)); and for pulmonary embolism 4 per 1000 (NNTH = 242; mean length of follow-up: 3.13 years (range: 1.0 to 7.1)).We performed subgroup analyses according to when treatment was started in relation to the menopause. Those who started hormone therapy less than 10 years after the menopause had lower mortality (RR 0.70, 95% CI 0.52 to 0.95, moderate quality evidence) and coronary heart disease (composite of death from cardiovascular causes and non-fatal myocardial infarction) (RR 0.52, 95% CI 0.29 to 0.96; moderate quality evidence), though they were still at increased risk of venous thromboembolism (RR 1.74, 95% CI 1.11 to 2.73, high quality evidence) compared to placebo or no treatment. There was no strong evidence of effect on risk of stroke in this group. In those who started treatment more than 10 years after the menopause there was high quality evidence that it had little effect on death or coronary heart disease between groups but there was an increased risk of stroke (RR 1.21, 95% CI 1.06 to 1.38, high quality evidence) and venous thromboembolism (RR 1.96, 95% CI 1.37 to 2.80, high quality evidence).

Authors' conclusions: Our review findings provide strong evidence that treatment with hormone therapy in post-menopausal women overall, for either primary or secondary prevention of cardiovascular disease events has little if any benefit and causes an increase in the risk of stroke and venous thromboembolic events.

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Conflict of interest statement

No potential conflicts of interest.

Figures

1
1
Figure 1: Process of study selection for the review
2
2
Process of study selection for the updated review
3
3
Figure 3: Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
4
4
Figure 4: Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
5
5
Funnel plot of comparison: Hormone therapy versus placebo in primary and secondary prevention, outcome: 5.1 Death (all‐causes).
1.1
1.1. Analysis
Comparison 1 Hormone therapy versus placebo in primary prevention, Outcome 1 Death (all‐causes).
1.2
1.2. Analysis
Comparison 1 Hormone therapy versus placebo in primary prevention, Outcome 2 Death (cardiovascular causes).
1.3
1.3. Analysis
Comparison 1 Hormone therapy versus placebo in primary prevention, Outcome 3 Non‐fatal myocardial infarction.
1.4
1.4. Analysis
Comparison 1 Hormone therapy versus placebo in primary prevention, Outcome 4 Stroke.
1.5
1.5. Analysis
Comparison 1 Hormone therapy versus placebo in primary prevention, Outcome 5 Angina.
1.6
1.6. Analysis
Comparison 1 Hormone therapy versus placebo in primary prevention, Outcome 6 Venous thromboembolism.
1.7
1.7. Analysis
Comparison 1 Hormone therapy versus placebo in primary prevention, Outcome 7 Pulmonary embolism.
1.8
1.8. Analysis
Comparison 1 Hormone therapy versus placebo in primary prevention, Outcome 8 Revascularisation.
2.1
2.1. Analysis
Comparison 2 Hormone therapy versus placebo in secondary prevention, Outcome 1 Death (all‐causes).
2.2
2.2. Analysis
Comparison 2 Hormone therapy versus placebo in secondary prevention, Outcome 2 Death (cardiovascular causes).
2.3
2.3. Analysis
Comparison 2 Hormone therapy versus placebo in secondary prevention, Outcome 3 Non‐fatal myocardial infarction.
2.4
2.4. Analysis
Comparison 2 Hormone therapy versus placebo in secondary prevention, Outcome 4 Stroke.
2.5
2.5. Analysis
Comparison 2 Hormone therapy versus placebo in secondary prevention, Outcome 5 Angina.
2.6
2.6. Analysis
Comparison 2 Hormone therapy versus placebo in secondary prevention, Outcome 6 Venous thromboembolism.
2.7
2.7. Analysis
Comparison 2 Hormone therapy versus placebo in secondary prevention, Outcome 7 Pulmonary embolism.
2.8
2.8. Analysis
Comparison 2 Hormone therapy versus placebo in secondary prevention, Outcome 8 Revascularisation.
3.1
3.1. Analysis
Comparison 3 Hormone therapy versus placebo in both primary and secondary prevention, Outcome 1 Death (all‐causes).
3.2
3.2. Analysis
Comparison 3 Hormone therapy versus placebo in both primary and secondary prevention, Outcome 2 Death (cardiovascular causes).
3.3
3.3. Analysis
Comparison 3 Hormone therapy versus placebo in both primary and secondary prevention, Outcome 3 Non‐fatal myocardial infarction.
3.4
3.4. Analysis
Comparison 3 Hormone therapy versus placebo in both primary and secondary prevention, Outcome 4 Stroke.
3.5
3.5. Analysis
Comparison 3 Hormone therapy versus placebo in both primary and secondary prevention, Outcome 5 Angina.
3.6
3.6. Analysis
Comparison 3 Hormone therapy versus placebo in both primary and secondary prevention, Outcome 6 Venous thromboembolism.
3.7
3.7. Analysis
Comparison 3 Hormone therapy versus placebo in both primary and secondary prevention, Outcome 7 Pulmonary embolism.
3.8
3.8. Analysis
Comparison 3 Hormone therapy versus placebo in both primary and secondary prevention, Outcome 8 Revascularisation.
3.9
3.9. Analysis
Comparison 3 Hormone therapy versus placebo in both primary and secondary prevention, Outcome 9 Death (all‐causes): by year on treatment.
3.10
3.10. Analysis
Comparison 3 Hormone therapy versus placebo in both primary and secondary prevention, Outcome 10 Death (all‐causes): cumulatively by year on treatment.
4.1
4.1. Analysis
Comparison 4 Subgroup analysis of timing hypothesis (<10 years versus >10 years since menopause), Outcome 1 Death (all‐causes).
4.2
4.2. Analysis
Comparison 4 Subgroup analysis of timing hypothesis (<10 years versus >10 years since menopause), Outcome 2 Coronary heart disease (death from cardiovascular causes and non‐fatal myocardial infarction).
4.3
4.3. Analysis
Comparison 4 Subgroup analysis of timing hypothesis (<10 years versus >10 years since menopause), Outcome 3 Stroke.
4.4
4.4. Analysis
Comparison 4 Subgroup analysis of timing hypothesis (<10 years versus >10 years since menopause), Outcome 4 Venous thromboembolism.
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References

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Jensen 1989 {published data only}
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Kim 1996 {published data only}
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Komulainen 1999 {published data only}
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Lindsay 1984 {published data only}
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Madsen 2003 {published data only}
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Marsden 2002 {published data only}
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Moriyama 2008 {published data only}
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Mosca 2009 {published data only}
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Obel 1993 {published data only}
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OPAL 2006 {published data only (unpublished sought but not used)}
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PEPI 1995 {published data only}
    1. Barrett‐Connor E, Slone S, Greendale G, Kritz‐Silverstein D, Espeland M, Johnson S, et al. The Postmenopausal Estrogen/Progestin Interventions Study: primary outcomes in adherent women. Maturitas 1997;27(3):261‐74. - PubMed
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Prentice 2008 {published data only}
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Soma 1991 {published data only}
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Steiner 2007 {published data only}
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Walter 1977 {published data only}
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WHIMS 2009 {published data only}
    1. Casanova R, Espeland M, Goveas J, Davatzikos C, Gaussoin S, Maldjian J, et al. Application of machine learning methods to describe the effects of conjugated equine estrogens therapy on region‐specific brain volumes. Magnetic Resonance Imaging 2011;29:546‐53. - PMC - PubMed
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Wimalawansa 1995 {published data only}
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Yeboah 2008 {published data only}
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References to studies awaiting assessment

NCT00154180 {published data only}
    1. NCT00154180. Kronos Early Estrogen Prevention Study (KEEPS). www.clinicaltrials.gov/ct2/show/NCT00154180 (accessed 15 March 2013). [NCT00154180]
    1. Naftolin F. The kronos early estrogen prevention study (KEEPS). Climacteric 2011;14:35‐6. - PubMed
    1. Naftolin F, Harman SM, Black D, Brinton E, Budoff M, et al. Adverse events during four years of daily oral conjugated estrogen or transdermal estradiol plus cyclic oral progesterone treatment in recently menopausal women: The KRONOS early estrogen prevention study (KEEPS). Menopause 2012;19(12):1402‐3.

References to ongoing studies

NCT00114517 {published data only}
    1. Howard H. The early versus late intervention trial with estradiol (ELITE). Climacteric 2011;14:35.
    1. NCT00114517. ELITE: early versus late intervention trial with estradiol. www.clinicaltrials.gov/ct2/show/NCT00114517 (accessed 15 March 2013). [NCT00114517]

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