Hormone replacement therapy and cardiovascular disease revisited

John C Stevenson 

National Heart & Lung Institute, Imperial College London, Royal Brompton Hospital, London, UK

Correspondence: Dr John C Stevenson, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. Email: j.stevenson{at}imperial.ac.uk

Controversy still rages about whether hormone replacement therapy(HRT) confers cardiovascular benefit or harm. There is a wealthof biological evidence that estrogen has a beneficial effect,supporting a large body of epidemiological evidence demonstratingreduction in coronary events with HRT. A large randomized placebo-controlledclinical trial of preventive strategies for coronary heart disease(CHD) in postmenopausal women, the Women’s Health Initiative(WHI), included HRT arms. The published preliminary findingsof this trial showed a significant increase in coronary events,stroke, venous thromboembolism and breast cancer with estrogen–progestogen,leading to the conclusion that HRT was unsafe to use other thanfor short-term relief of menopausal symptoms. But subsequentpublications of the more complete data from WHI have shown nosignificant increase in CHD, and a tendency to a reduction inthose initiating HRT below age 60 years. This is important becauseother therapeutic strategies for the primary prevention of CHD,such as aspirin and statins, are not of proven benefit in women,in contrast to men. Subsequent WHI findings have not shown aclear increase in breast cancer, and any potential increasefrom HRT is similar to that seen with many lifestyle factorsand other commonly used medications. The preliminary WHI resultsdo not reflect accurately true benefits and risks, and HRT shouldremain a potential preventive treatment for CHD.

Cardiovascular disease, and particularly coronary heart disease(CHD), is the leading cause of death of women in developed countries.The risk increases following menopause, and hormone replacementtherapy (HRT) has long been thought to help protect againstthis risk.

A workshop under the auspices of the International Menopause Society (IMS) was held in Italy in February to review and update current thinking about HRT and cardiovascular disease. A consensus resulting from this workshop will be published in due course. But consensus and position statements on this topic have been recently published,^1–3 so why was this workshop needed?The confusion surrounding the benefits and risks of HRT continuesunabated, and nowhere is it better illustrated than in the cardiovascularfield.

For years HRT was thought to be beneficial for the prevention of CHD in postmenopausal women. This belief was founded on the demonstration of beneficial biological effects of estrogen on metabolic risk factors for CHD and on vascular function, and supported by the effects on clinical CHD outcomes consistently observed in a large number of epidemiological studies.⁴ Thus there was sound clinical evidence from population studies backed by biological plausibility. HRT was not licensed for use in the prevention of CHD, but it was considered an additional benefit when the treatment was given for relief of menopausal symptoms or for the prevention of postmenopausal osteoporosis. To try to define the risks and benefits of strategies that could potentially prevent CHD in postmenopausal women, the US National Institutes of Health set up a series of randomized clinical trials known as the Women’s Health Initiative (WHI), including HRT arms using estrogen plus progestogen or unopposed estrogen in hysterectomized women. The preliminary publication⁵ in 2002 of the findings from the estrogen–progestogen arm of the WHI showed that HRT caused an increase in CHD events, stroke and venous thromboembolism, as well as breast cancer, and the conclusion was that HRT was too dangerous to be used for any disease prevention but should be confined to short-term use for menopausal symptom relief. Cardiologists, who traditionally have shown little interest in female health, were happy to dismiss HRT as a potential preventive treatment for CHD following this publication, in much the same way that bone physicians were happy to dismiss HRT for the prevention of postmenopausal osteoporosis. The authors claimed in this paper that there was a significant increase in CHD events with estrogen plus progestogen compared with placebo, and that ‘no noteworthy interaction with age’ was seen. However, when the full results of the WHI trial were subsequently published, there was no significant difference between estrogen plus progestogen and placebo on CHD events.⁶ The estrogen-alone arm of the WHI also showed no significant difference between treatment and placebo for coronary events,⁷ and again it was stated that there was no interaction with age at initiation. However, a further publication⁸ of the full results of this arm was suggestive of a reduction in CHD events with estrogen compared with placebo, and a composite outcome of myocardial infarction, coronary death and coronary interventions was significantly lower in women initiating HRT aged below 60 years. In addition, a post hoc study of coronary calcification scores in women from this age group who participated in the WHI showed a significant decrease in those previously assigned to estrogen compared with those assigned to placebo.⁹ A further publication¹⁰ in 2007 combined the cardiovascular data from the two HRT arms of WHI. Surprisingly, the data for CHD differed slightly from the ‘final’ data previously published. Even more surprisingly, the authors now concluded that chronological and menopausal age at initiation of therapy had an effect on CHD outcomes, with the younger women, closer to menopause, showing a lower event rate. So in contrast to their early report that age had no effect, they now acknowledged that it did. It thus appears that HRT may confer benefit for CHD prevention when initiated below age 60 or within 10 years of the onset of the menopause. The consensus statement¹ from the British Menopause Society in 2008 reached this conclusion, and a consensus statement³ from the IMS published later that year also reflected this opinion, concluding that HRT initiated in women below age 60 does not increase CHD risk and may even decrease it. This is in agreement with previous observational data and with primate studies.¹¹

Should we now start to point our cardiological colleagues in the direction of HRT for consideration in the prevention of CHD in postmenopausal women, specifically those deemed at increased future risk? They will of course know from the WHI that HRT increases the risk of breast cancer⁵ and therefore cannot be used, except for a short time to relieve menopausal symptoms, which is not their concern. Indeed this view has been reinforced repeatedly by our regulatory authority, heavily influenced by the findings of the Million Women Study (MWS).¹² Yet subsequent publications from WHI showed no increased risk of breast cancer from estrogen plus progestogen when appropriately adjusted for confounding variables,¹³ and a significant decrease in breast cancer incidence in women who were adherent to estrogen-alone therapy compared with placebo.¹⁴ So the large randomized clinical trials do not support an increased risk of breast cancer with HRT use. The findings of the MWS, a heavily criticized questionnaire survey,¹⁵ are in complete contrast to WHI and indeed dissimilar to most other observational studies. So the breast cancer risk remains unresolved, and any increased risk that might exist is similar to or even less than that seen due to many lifestyle factors or commonly used medications.¹⁶ Stroke risk may be slightly increased with HRT use when initiated in older women, but again the findings from WHI are somewhat inconsistent.¹⁰ It wouldgenerally appear that the risk is minimal or non-existent inwomen starting HRT below 60 years.

Many cardiologists may feel that they do not need to consider HRT as they have other strategies for preventing CHD in women. Attention to lifestyle factors such as diet, physical exercise and smoking will reduce CHD incidence in both men and women.¹⁷ Similarly, control of blood pressure and diabetes are also important preventive measures. But some therapies, while effective in men, are not effective in women. Thus the use of low-dose aspirin has been ineffective in preventing CHD events in women.¹⁸ Similarly, statins have not been effective in reducing CHD events in women as they have in men.¹⁹ Furthermore, the increased risk of breast cancer seen with statins is of similar magnitude to that reported with HRT.²⁰ Yet, are cardiologists aware of this, and why is our regulatory authority not recommending only short-term use of statins in women for this very reason? It would appear that HRT is more effective and as safe as any other therapeutic option for the primary prevention of CHD in postmenopausal women, provided the treatment is started at a suitable time postmenopause and at a suitable dose. While with the current evidence it may not be justifiable to put women onto HRT for this indication, it should certainly come into discussions of benefits and risks of HRT as a positive effect. Of more importance, if a woman is taking HRT, it does not need to be stopped on the grounds of cardiovascular safety when she passes her 60th birthday. Further studies are needed to establish what types and doses of HRT are optimal for CHD prevention. Two studies, KEEPS and ELITE,^21,22 are currently ongoing in the USA to address someof these issues. Unfortunately both have some design flaws andmay not give us full or satisfactory answers. But will thereever be funding to perform more studies? One thing is clear.It is time to stop quoting so-called safety concerns about HRTfrom the WHI 2002 publication. Its findings have been supersededand its erroneous conclusions re-interpreted.

JCS has received research grants from Organan and Wyeth, andhas served on advisory boards and/or received honoraria forlectures from Astrazeneca, Bayer-Schering, Novo Nordisk, Orion,Proctor & Gamble, Servier, Solvay, Theramex and Wyeth.

Accepted: March 16, 2009.

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