Trial set out to balance risks and benefits in hormone use

By ANGELA GREGORY health reporter

* Why was the trial so important?

It was the first randomised controlled trial to confirm that the widely used combined oestrogen plus progestogen therapy increased the risk of incidence of breast cancer.

* What is combination HRT?

It is a medication which contains a combination of oestrogens and progestogens to treat menopausal symptoms such as severe hot flushes, vaginal dryness and osteoporosis in women with an intact uterus.

* What are some of the side effects?

They include blood clots, nausea, abdominal pain, breast tenderness irregular bleeding and headaches.

* Why was the trial done?

Researchers wanted to balance the risks and benefits for hormone use in healthy post-menopausal women.

* How was the trial set up?

United States clinical centres in 1993-1998 recruited 16,608 post-menopausal women, with uterus intact, aged between 50 and 79 years.

The trial's planned duration was 8 1/2 years, but it was stopped about three years early.

The researchers chose the most commonly prescribed combined hormone preparation in the US.

About half the participants received placebos, and the others a conjugated equine oestrogens, 0.625mg a day, plus medroxyprogesterone acetate, 2.5 mg/d in one tablet.

* Do New Zealand women take this combined HRT?

Yes, that particular combination is available in New Zealand in a single pill form called Premia 2.5 Continuous.

Overall, tens of thousands of women in the country take some form of combined HRT drug therapy.

Premia 2.5 Continous should not be confused with the widely used oestrogen-only medication Premarin.

* Why was the trial stopped?

The trial was stopped early because of strong evidence the health risks were exceeding the benefits after use of the combined HRT for an average 5.2 years.

The trial data and safety monitoring board recommended it end, particularly because the test statistic for invasive breast cancer exceeded the stopping boundary.

* What exactly did the trial find?

Over one year, 10,000 women taking the combination drug might experience seven more coronary heart disease events, eight more strokes and eight more invasive breast cancers between them than the same number taking the placebo.

The elevated risk of coronary heart disease was largely limited to the first year of therapy.

The study also found benefits such as six fewer women developing colo-rectal cancers and five fewer suffering hip fractures.

Combining all the monitored outcomes, women taking oestrogen plus progestogen might expect 19 more events per year per 10,000 women than women taking the placebo.

* What about oestrogen-only HRT?

Oestrogen-only medications have been thought to increase the risk of cancer of the uterus but are thought to be less associated with an increased risk of breast cancer than combined therapies.

A parallel trial of oestrogen-alone therapy in women who have had a hysterectomy is being continued, and the planned end of this trial is March 2005. By then the average follow-up will be about 8 1/2 years.

* What are medical professionals saying?

Women are being reminded to discuss HRT treatment with their doctor. It can be complex and must be individualised to meet their specific needs if they want help with managing menopause.

The Journal of the American Medical Association, which published the study, recommends clinicians stop prescribing combination HRT for long-term use.

It also says the risks in short-term use should be balanced against the severity of symptoms and benefit of treatment.

* What are the research limitations?

This trial tested only one drug regime, so the results do not necessarily apply to lower dosages of these drugs.

The trial could not distinguish the effects of oestrogen from those of progestogen.

* How did the early stopping affect the results?

It decreased the precision of estimates of long-term treatment effects.

A longer intervention period might have shown more pronounced benefit for fractures and might have yielded a more precise test of the hypothesis that treatment reduces colo-rectal cancer.

Nonetheless, it appears unlikely that any benefit for coronary heart disease would have emerged by continuing the trial to its planned termination.

* What does the Ministry of Health say?

The ministry sent out revised guidelines for HRT in June and July to make it clear that, contrary to some earlier claims, HRT does not have a role in the prevention of heart disease.

* Are we doing similar research here?

A major Wellington study on long-term HRT may be halted in the wake of the US concerns.

The study's medical director, Dr Bev Lawton, said two independent international committees overseeing the trial were meeting urgently to consider the implications of the US study.

The Wellington School of Medicine study is part of the Women's International Study of Long-Duration Oestrogen after Menopause (Wisdom), which involves 22,000 women in Britain, Ireland, Australia and New Zealand.

A decision is expected next week, but women should continue with the study in the meantime, Dr Lawton said.

She said 150 New Zealand women, some of whom had had their uteruses removed, were taking part in blind trials of oestrogen, a combination of oestrogen and progestogen HRT, and placebos.

The school began recruiting women last year, and had planned to monitor up to 2200 women over a decade.

Dr Lawton has fielded dozens of calls from women concerned about the risks of the combined oestrogen and progestogen HRT, but said there was no need to panic as the relative risks were small.

* What is the reaction elsewhere?

Australia has issued a warning against the long-term use of hormone replacement therapy, but is urging women not to panic.

An Australian Government-appointed committee of medical experts has called for a review of the use of combination HRT and of all ongoing Australian trials using HRT to treat chronic disease.

However, the committee stressed that combination HRT remained an appropriate short-term treatment for symptoms of menopause.

nzherald.co.nz/health