Assessing the relative risks of HRT

GPs must look beyond the media panics to the real data on HRT, says Dr Sarah Gray

Over the past five years, since the first major publication of the Women’s Health Initiative (WHI), the clinical use of postmenopausal HRT has reduced significantly. This has been reinforced by the findings of the Million Women Study (MWS).

Sensational reporting of associated risks has made both women and their medical advisors much more cautious and even fearful of its use.

Benefits for symptom relief have not been denied, and benefits for bone health were strengthened by the WHI results. On 4 April 2007, JAMA reported a further analysis of the data from the WHI. This appeared to contradict some of the previously reported cardiovascular risks.

Only two weeks later the MWS published new data regarding risks of ovarian cancer associated with the use of HRT. Once again there is mass confusion.

GPs need to understand what these new findings mean in the real world and what difference they make to clinical practice.

Women’s Health Initiative
The WHI was set up in 1991 to test the hypothesis that postmenopausal HRT had a role in primary prevention of cardiovascular disease. This followed observational data from large cohorts of women that appeared to show a protective effect, with women taking HRT showing a much lower incidence of CHD. This was of major importance because  CHD is the top-ranking cause of death among women, exceeding breast cancer by a factor of 10 and gynaecological cancer by a factor of 25.

In the WHI, 16,608 women were randomised to a combined oestrogen and progestogen regimen (0.625mg conjugated equine oestrogens (CEE) with 2.5mg medroxyprogesterone acetate (MPA)) or placebo.

The global index was a predetermined ‘basket’ of significant outcomes that comprised CHD, venous thromboembolism stroke, breast cancer, hip fracture and total mortality.

This trial was stopped after 5.2 years because of a rise in the global index and to everyone’s surprise was reported as showing a headline figure of a 29 per cent increased risk of CHD.

In a second trial, 10,739 women who had had a hysterectomy were randomised to 0.625mg CEE or placebo. This trial did not show the same rise in global index and it continued to run for another two years, publishing its report in 2004.

A number of factors need to be appreciated. First, that the population of women randomised had an average age of 63 (range 50–79) and that many symptomatic women were ex-cluded on the basis that relief of oestrogen deficiency symptoms would unblind them. Third, that 36 per cent were being treated for hypertension and 34 per cent had a BMI >30.

It has been appreciated that this population was different from those symptomatic perimenopausal women in whom we would initiate hormone therapy for symptom relief in clinical practice.

Sub group analysis within the two trials suggested a reduction in CHD risk in women aged 50–59 for the CEE trial and in women less than 10 years since menopause in the CEE+MPA study. The small numbers of younger women and low incidence did not allow a significant outcome to be established.

Therefore data from the two groups have been amalgamated in this study. Details of 24,317 women in whom menopausal age was either known or could be assumed were included.

The WHI investigators have reanalysed the data relating to CHD, stroke, total mortality and global index and looked at the influence of age and years since menopause. 

Their figures show a non-significant reduction in cardiac risk for women starting HRT less than 10 years since menopause with a trend to increase over time to reach a significant 28 per cent increase at more than 20 years.

The trend has significance at the p=0.02 level. Significance is generally accepted at p=0.05 (5 per cent risk of the result being due to chance).

However, the Wall Street Journal reported that after submission of this paper the JAMA reviewers requested that a higher burden of proof be required. Significance required is usually predetermined not modified post hoc. 

These hazard ratios translate to an absolute risk reduction of -6 per 10,000 person years for women less than 10 years since menopause. Risk increases of +4 for women (10–19 years since menopause) and +17 for women over 20 years  since menopause (per 10,000 women years) were derived.

Relating this to age rather than time difference creates absolute risks of -2 per 10,000 age 50–59 and -1 at age 60–69 (both decreases) and +19 at 70–79 (an increase). This must be reassuring for patients and deserves greater emphasis.

The study did not contain sufficient numbers of women to calculate for the narrower and more typical age bands of 50–54 or less than five years since menopause.

The study showed an in-creased relative risk of stroke of 32 per cent which does not vary with age or years since menopause. Screening for stroke risk is therefore an important component of the risk analysis at any age, but additional attributable risk for healthy younger women will be small.

Total mortality is not increased  although there is a non-significant trend with reduction in younger women.

Window of opportunity
The effect of oestrogen on coronary arteries appears to be a trade-off between its beneficial effects on the endothelium and lipids and its negative effects on coagulation and inflammation.

Once vessels are diseased, regression does not occur, but there may be a preventative benefit when started early. The study provides no information about long-term use of HRT.

Further confusion
The MWS have reported an increase in ovarian cancer diagnosis and death in women taking HRT. This is an observational trial that has been subject to criticism and its breast cancer conclusions have appeared to overestimate risk in comparison with the randomised trials.

To date the issue of ovarian cancer risk has remained unproven. The study reports an  additional incidence of one ovarian cancer per 2,500 women taking HRT for five years, leading to one additional death in approximately 3,300 women.

Where are we now?
CHD is the greatest cause of death to women. Risk reduction would be welcome, but even the confidence that there is no risk increase is much appreciated.

Benefits for symptoms, quality of life and bone protection, an absence of cardiac risk and potential risks of stroke, VTE, breast endometrial and now ovarian cancer must be explained. An informed decision can then be made.

Dr Gray is a GP specialist in women’s health in Truro, Cornwall

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