(This sheet is summary of links to the above website as of July 2004)

Hormone Replacement Therapy and Cardiovascular Disease

Prepared by the Medical Issues Committee, National Heart Foundation of Australia.

The Heart Foundation would like to thank Professor Richard Harper and Dr Gishel New who contributed to the development of this paper.

Summary of Heart Foundation position

1.       At present, there is no definite evidence to suggest a benefit of ‘unopposed’ oestrogen or combined (oestrogen and progestin) hormone replacement therapy (HRT) in the primary and secondary prevention of cardiovascular disease (CVD) events in women.

2.       Additional interventional studies will be concluded shortly which should further clarify the effects of HRT on coronary heart disease (CHD) risk, as well as other risks and benefits.

3.       In women without manifest CHD in whom HRT is being considered as a treatment for menopausal symptoms and/or to reduce the risk of osteoporosis, a decision to treat should be based on an individualised assessment of the potential health benefits versus the cardiovascular and non-cardiovascular health risks.

4.       Women with manifest CHD who are considering HRT should be advised that there may be a slightly higher risk of cardiovascular complications in the first year of use.

5.       Women with manifest CHD who have been taking HRT for over a year and who have not experienced cardiovascular complications can be advised that, from a cardiovascular perspective, it is probably safe for them to continue with therapy.

6.       In order to reduce CVD risk, lifestyle advice should be offered to all women and established lipid modifying and antihypertensive drug therapies should be considered according to the individual’s overall risk status and evidence based guidelines.

7.       Overall, the recommendations on usage of HRT must be made within the context of other indicators such as postmenopausal symptoms and taking into consideration other potential effects on cancer and osteoporosis.

Background

This paper presents the National Heart Foundation of Australia’s position on hormone replacement therapy (HRT) and cardiovascular disease (CVD) based on a summary of the key available evidence.

The principally recognised clinical indications for the use of HRT relate to alleviation of menopausal symptoms and the prevention and management of osteoporosis. However, it has been frequently asserted that HRT in postmenopausal women prevents coronary heart disease (CHD) events and can be used for this purpose. ^1,2  Such recommendations, however, have been made in the absence of robust interventional trial evidence, and have been based on the plausibility of biological mechanisms and observational data (NHMRC 1995 – level III and IV ratings).

Recent editorials ^3,4 and reviews ^5,6,7,8 recommend caution in prescribing HRT for both primary and secondary prevention of CHD. This caution is largely based on assessments taking into account:

·         Potential risks of HRT

-      At present, there is no definite evidence to suggest a benefit of ‘unopposed’ oestrogen or combined (oestrogen and progestin) HRT in the primary and secondary prevention of CVD events in women.

-     Further interventional studies will be concluded shortly and should further clarify the effects of HRT on CHD risk as well as other risks and benefits.

-          A possible increased risk of breast cancer associated with HRT; this issue remains controversial and will not be resolved until the magnitude of such a risk can be weighed against the magnitude of any HRT-mediated reduction in CHD mortality.

-          A concern that HRT may have adverse effects on blood pressure and thrombosis; these concerns have been lessened by more recent research.

-          Concerns regarding the effects of the combination between HRT and smoking: there is a lack of evidence on this relationship and the potential effects and risks are unknown at this point in time.

·         Uncertainty as to whether the potential cardioprotective effects of oestrogen therapy are applicable to all formulations and routes of administration and are not neutralised by the use of progestins.

·         Concerns regarding the efficacy and magnitude of the effect of HRT because of results from recently reported randomised controlled trials.

The more recent publication of results from the HERS study ⁹, has provided the only randomised trial (level II) evidence to date examining clinical cardiac endpoints. This study showed no overall benefit from HRT in the secondary prevention of CHD over the study period. This finding has refocussed debate on the appropriateness of using HRT for the primary and secondary prevention of CVD, which needs to take into account the best evidence available and consider the benefits and risks of using HRT for CVD prevention.

Biological mechanisms linking HRT and CVD risk

The role of oestrogen replacement in post-menopausal women is less clear than would have been anticipated from the current understanding of the physiological effects of oestrogens on lipids and the cardiovascular system. Plausible biological mechanisms by which oestrogen may influence cardiovascular risk include favourable effects on lipid levels and haemostasis (e.g. decreasing levels of fibrinogen), antioxidant properties and favourable effects on the vascular wall and response to endothelial injury.7

HRT increase high-density lipoprotein (HDL) cholesterol and reduces low-density (LDL) cholesterol levels. A reduced lipoprotein (a) concentration and increased fibrinolysis during HRT may indicate a reduced risk of thrombosis. On the other hand oestrogen could have unfavourable effects on haemostasis, because it increases the levels of thrombin and fibrin.

Whether HRT has an effect on plaque composition and stabilisation is the subject of ongoing research.

Evidence: HRT and CHD

HRT and primary prevention of CHD

Observational studies

More than 30 epidemiological studies since 1974 have suggested that postmenopausal women using HRT may have as much as a 50% lower risk of CHD when compared with women not using these hormones.¹⁰  However, observations may be confounded by the more selective use of HRT by healthier women.

Of these studies more weight can be placed on cohort or prospective studies than cross sectional studies. The largest prospective study, the US Nurses Health Study,2 included more than 50 000 women. This study reported a 61% reduction in risk of CHD in women using HRT compared with non-users. However, despite the strengths of this study, it may have overestimated the protective effect of HRT as indicated above.

Randomised trials

Only a few randomised trials of women have been published to date. The only double-blinded randomised trial in primary prevention, in women, was the PEPI study.¹¹  This study demonstrated a benefit of both unopposed oestrogen and combined HRT on lipoproteins and fibrinogen levels with a neutral effect on blood pressure, weight gain, glucose and insulin levels. Although there was a beneficial effect on some surrogate markers (risk factors) for CVD, the study was limited because it was not powered sufficiently to detect a benefit in clinical endpoints.

Summary: HRT and primary prevention of CHD

On the basis of the limited research evidence, no definite conclusion regarding benefit from HRT in primary prevention of CHD can be made.

HRT and secondary prevention of CHD

Observational studies

Observational studies have reported a reduction in cardiovascular event rate (death, nonfatal myocardial infarction or nonfatal stroke)¹² in women on HRT following percutaneous coronary intervention (5 and 10 year survival),¹³ and following coronary artery bypass graft surgery (CABG).7

Randomised trials

Contrary to the observational reports in secondary prevention, the Estrogen Replacement and Atherosclerosis (ERA) Trial¹⁴ did not show a benefit of unopposed HRT on changes in mean, minimal coronary lumen diameter (particularly located and combined left coronary artery and right coronary artery measurements) after 3 years, compared with placebo.

The HERS study⁹ is the only randomised trial published to date, which has assessed clinical endpoints in women with established CHD. The study failed to show a beneficial effect on overall CHD events after an average of 4.1 years of treatment (relative risk 0.99; 95%CI- 0.80-1.22).  However, 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 the first year (71 CHD deaths in the hormone group compared with 58 CHD deaths in the placebo group).  After one year there was a tendency to decreasing risk of CHD events with HRT with fewer events in years 4 and 5.  Absolute CHD event rates were less, drop out rates greater and follow-up less than planned, limiting the power of the HERS study to address reliably the use of HRT.

Summary: HRT and secondary prevention of CHD

On the basis of current available evidence, it is recommended that:

·         HRT should not be commenced in women with existing CHD on this basis alone.

In those women with existing CHD who have been taking HRT for over a year, from a cardiovascular perspective it is probably safe to continue with therapy.

CHD risk reduction

General

In relation to CHD risk and its reduction in women, it is important to also address modifiable risk factor management through lifestyle advice and treatments as outlined in the relevant evidence based guidelines. Particular attention should be given to those at higher absolute risk of CHD. For further details refer to Heart Foundation professional information and guidelines regarding physical activity, healthy eating, hypertension, lipids and smoking.

Lipids

It should be noted that in contrast to HRT, lipid-modifying therapy has been shown to be of clear benefit to women both with and without manifest CHD, reducing CVD events in both the primary and secondary prevention of CHD. Although the studies were not powered specifically to show a mortality benefit in women in these cohorts, both the CARE¹⁵ (secondary prevention) and AFCAPS/TEXCAPS¹⁶ (primary prevention) showed a reduction in CHD events with the use of statins. Although the effect of treatment in women in the LIPID secondary prevention study was not statistically significant, there was no evidence of heterogeneity of effect compared with men.¹⁷  Therefore, as in men, treatment with statins or fibrates, rather than treatment with HRT, should be the primary therapeutic approach to dyslipidaemia for women.

Evidence: Stroke

Many studies have examined the relationship between HRT and the risk of stroke. These studies report that there is no significant association between postmenopausal hormone therapy and the risk of stroke¹⁸ A sixteen-year follow up report from the Nurses’ Health Study reaffirmed the lack of impact of HRT on stroke occurrence.¹⁹ 

A follow up study on 149 women in the HERS study with CHD who suffered a stroke, showed no significant effect of HRT in reducing the risk of stroke¹⁸. nor was there any effect in the 213 women in the HERS study who had suffered a peripheral arterial event.²⁰ However, the incidence of stroke is particularly related to age, and the elderly have been under-represented in studies.

‘Alternative’ hormone therapies

Phytoestrogens (plant oestrogens) and selective oestrogen receptor modulators (SERMS e.g. raloxifene and tamoxifen) are compounds that have similar chemical structure to oestrogen.  Preliminary work suggests some favourable, but probably not as marked effects on lipoproteins and the blood vessel wall compared with oestrogen.^{21 22}The effects on other tissues and organs such as breast and uterus are still unclear.

References