HRT 'is safe' and can 'cut heart attack deaths'

"HRT can cut heart attack risk, study shows," The Guardian reported today, while the Daily Telegraph said that women should "'no longer be worried' about taking HRT to combat symptoms of the menopause".

The story is based on research which found that recently menopausal women who took hormone replacement therapy (HRT) for 10 years were less likely to die or suffer heart failure or heart attack than women who had never taken it. The study also found that HRT was not associated with any increase in the risk of breast cancer, stroke or deep vein thrombosis.

The study was limited by its relatively small size (compared with previous HRT research), involving only 1,006 women. Because of this, its findings should be viewed with some caution as they could be the result of chance.

The risks and benefits of HRT have been the subject of much controversy over the last decade, with some but not all studies indicating a slightly higher risk of heart disease, stroke and breast cancer, while conversely, a decreased risk of osteoporosis and colon cancer. Additionally, the positive effect HRT can have on a woman’s quality of life also has to be considered.

Most experts agree that if HRT is used on a short-term basis (no more than five years), the benefits outweigh the risks. If you are taking HRT, discuss your individual risks with your GP and review them on an annual basis, especially if you are taking it for longer, particularly for more than 10 years when the risk-benefit ratio becomes less clear.

Where did the story come from?

The study was carried out by researchers from Hvidovre Hospital, Arhus University Hospital, Svendborg Hospital, Hillerod Hospital and Rigshospitalet, all in Denmark. It was funded by the University of Aarhus, a charitable foundation, and two pharmaceutical companies which make HRT and which also provided the study drug free of charge.

The study was published in the peer-reviewed Journal of Family Planning and Reproductive Healthcare.

The study was reported uncritically in the media, although both the BBC and the Daily Telegraph included dissenting comments from independent experts.

Studies such as these should be interpreted with caution. Much of what has been reported on the risks and benefits of HRT is both contradictory and controversial.

Reported findings may be the result of chance. As was the case with this study, researchers often pool the results of studies in order to include enough subjects to reduce the possibility of chance results. But this method does reduce the weight of evidence.

What kind of research was this?

This was a study reporting the long-term observations from a randomised controlled trial. This reported the 10-year effect of HRT on cardiovascular events and on overall mortality in recently menopausal women. It was an open label trial, which means that there was no blinded control group and that the researchers and the women involved knew whether they were in the HRT or the control group. An open-label trial may be unavoidable in some circumstances but there is a risk that the results may be influenced by conscious or subconscious bias.

The researchers pointed out that the risks and benefits of HRT have been the subject of much discussion. While some earlier observational studies showed it reduces the risk of cardiovascular disease, later research with confounders accounted for showed no benefit. This has led to the theory that the differences in these results may be accounted for by the length of time after reaching the menopause that a woman starts HRT.

Women taking HRT for long periods have been shown to have a slightly increased risk of breast and ovarian cancer.

What did the research involve?

The original trial was first intended to test the effects of HRT on osteoporosis. Between 1990 and 1993, researchers recruited 1,006 healthy, white and recently menopausal women aged between 45 and 58. Women were excluded from the trial if they had had bone disease, uncontrolled chronic disease, cancer, alcohol or drug addiction or had used HRT within the previous three months.

They were randomly allocated to receive HRT (502) or no treatment (504). Women who still had their wombs were given combined HRT (which includes the hormone progesterone to protect against endometrial cancer, which is cancer of the lining of the womb) and those who had had a hysterectomy received oestrogen-only HRT.

All the women underwent a physical examination and biochemical screening at baseline. They were subsequently seen by researchers after six months, one year and two, three, five and 10 years.

The planned duration of the study was 20 years, but after about 11 years all the women were advised to stop treatment after adverse effects of HRT were reported in other trials. Researchers continued to follow the women for a further 5.7 years, with an average follow-up time of 15.8 years.

In 2008, researchers looked at overall mortality rates among the two groups of women and also whether they had been admitted to hospital for heart failure or a heart attack. They obtained this information from national death and hospital discharge registers and combined it into a “composite” endpoint including death, admission to hospital for myocardial infarction or heart failure. They also obtained data on breast and other cancers and admission to hospital for a pulmonary embolism (a blockage of the main artery between heart and lung) or deep vein thrombosis.

They analysed the data using standard statistical methods. 

What were the basic results?

After five years, 75% of the women were still following their allocated treatment for 80% of the time.

After 10 years no results were statistically significant except the first listed:

• 16 women who had been taking HRT had either died or been admitted to hospital with heart failure or heart attack, compared with 33 in the control group (hazard ratio [HR] 0.48, 95% confidence interval [CI] 0.26 to 0.87).
• 15 women taking HRT had died compared with 26 in the control group (HR 0.57, 95% CI 0.30 to 1.08).
• Heart failure was diagnosed in 1 woman in the HRT group and 7 in the control group (HR 0.14, 95% CI 0.02 to 1.16).
• Heart attack was diagnosed in 1 woman in the HRT group and 4 in the control group (HR 0.25, 95% CI 0.03 to 2.21).
• The reduction in cardiovascular events was not associated with an increase in any cancer (36 in treated group versus 39 in control group, HR 0.92, 95% CI 0.58 to 1.45) or in breast cancer (10 in treated group versus 17 in control group, HR 0.58, 95% CI 0.27 to 1.27).
• The hazard ratio for deep vein thrombosis (2 in treated group versus 1 in control group) was 2.01 (95% CI 0.18 to 22.16) and for stroke (11 in treated group versus 14 in control group) it was 0.77 (95% CI 0.35 to 1.70).
• After 16 years the differences between the two groups in mortality rates and admissions to hospital for heart failure and heart attack was still present and not associated with an increase in any cancer.

How did the researchers interpret the results?

The researchers said that the findings suggest that starting HRT early after menopause reduces the combined risk of death, heart failure and heart attack without any apparent increase in the risk of cancer or stroke.

Conclusion

The results of this study, which followed women for nearly 16 years, does not provide much of a useful addition to the existing research on HRT and the findings should be viewed with caution. It had several limitations, mainly due to its small size, therefore a chance finding of significance cannot be ruled out.

• It was an open label trial with no placebo. As the researchers pointed out, knowledge of which group the women were in may have affected medical diagnoses.
• Only three-quarters of the women stayed in the group to which they were allocated, whether treatment or control.
• It is difficult to interpret the figures given at 16 years of follow-up since it is uncertain whether or not women continued with HRT after being advised to discontinue after 11 years.
• The study was not specifically designed to look at cancer or other risks so its results for breast and other risks may not be reliable.
• The results apply to white women and may not apply to other ethnic groups.

The primary endpoint for this study was a composite of death, admission to hospital for myocardial infarction or heart failure. This was specified before the study started. However, the results for this outcome demonstrate wide confidence intervals and there were small numbers of events in either group. This suggests that larger studies would be needed if a more precise estimate of the risk were required. It seems unlikely that such a study would be conducted now as far fewer women currently choose HRT compared with the 1990s and other treatments for osteoporosis are available.

The current consensus of expert opinion on the risks and benefits of HRT would appear to be still valid. That is, if HRT is used on a short-term basis (no more than five years), the benefits outweigh the risks. If you are taking HRT, discuss your individual risks with your GP and review them on an annual basis, especially if taking it for more than 10 years when the risk-benefit ratio becomes less clear.