It's not what you take but the way that you take it that can produce different results in women who take hormone replacement therapy (HRT), according to new research on the association between HRT and heart attacks, published the European Heart Journal [1] today.

The study is the largest to look at the effects of HRT since the Women's Health Initiative trial was stopped early after finding that HRT increased the risk of women developing a range of conditions including breast cancer and thromboembolism.

The research is an observational study of 698,098 healthy Danish women, aged 51-69, who were followed between 1995-2001. It has found that overall there was no increased risk of heart attacks in current users of HRT compared to women who had never taken it.

However, it did find that in younger women (aged 51-54) who were taking HRT during the period of the study, their risk of heart attacks was about a quarter (24%) more than in women who had never taken HRT. In addition, in younger women there was an increasing risk with longer duration of HRT, which was not seen in the older age groups.

The study also found that the type of HRT and the way that the women took it made a difference to the risk of heart attacks. Continuous HRT (a continuous combination of oestrogen and progesterone) carried a 35% increased risk of heart attacks compared with women who had never used HRT. But if HRT was taken on a cyclical basis (oestrogen, followed by a combination of oestrogen and progesterone) there was a tendency for these women to have a reduced risk of heart attacks compared to women who had never used HRT, and this was also seen if a synthetic hormone, tibolone, was used. If the method of taking the oestrogen was via a patch or gel on the skin or in the vagina, the risk of heart attack reduced by more than a third (38% and 44% respectively).

Dr Ellen Løkkegaard, a gynaecologist at the Rigshospitalet in Copenhagen, Denmark, who led the study, said: "Our finding of lower risk with a cyclic combined regimen, which gives monthly bleeding, than with continuous combined oestrogen/progesterone therapy, which does not cause bleeding, is potentially of great clinical importance. Also, the decreased risk of myocardial infarction with vaginal treatment is a very interesting finding that has not been tested before in large scale observational studies."

She said that the study produced similar results to the WHI study (a randomised controlled trial) for comparable HRT treatments, and that this suggested that the results from her study for the other, non-comparable treatments were valid.

"Our study does not change indications and duration recommendations for HRT. But the main message is that when hormone therapy is indicated for a woman, then a cyclic combined regimen should be preferred, and that application via the skin or the vagina is associated with a decreased risk of myocardial infarction.

"From the previous studies on HRT we have no reason to believe that these recommendations increase the risk of other diseases influenced by hormone therapy, such as breast cancer, venous thromboembolism and stroke. Actually, we believe they could reduce the risk."

Since the WHI trial was stopped, no further randomised controlled trials of HRT have been started.

"This study is the first, big observational study that addresses the influence of various regimens, doses and routes of administration," said Dr Løkkegaard. "In this 'post randomised era' where randomised studies on HRT are not easily performed, it provides important new information."