Can HRT in early menopause cut heart disease risk?

Behind the Headlines

Friday April 1 2016

HRT is used to relieve symptoms of menopause such as hot flushes

HRT may reduce fatty plaques in blood vessels

"Women who take HRT drugs soon after going through menopause are 'less likely to suffer heart disease','' the Daily Mail reports.

A new study found that early adopters of hormone replacement therapy (HRT) might slow their progression toward atherosclerosis (hardening and thickening of the arteries) which can increase the risk of heart diseaseheart attacks or strokes.

However, the study in question did not follow the women long enough to see if this would have a significant impact on heart health outcomes.

This study found women taking HRT (specifically, an oestrogen pill with or without progesterone vaginal gel) less than six years after their menopause began, had slower rates of artery wall thickening than women taking a dummy placebo pill. Artery wall thickening is a sign of atherosclerosis progression.

Artery wall thickening was the main way atherosclerosis progression was tested, but other measures showed no difference, so the results were a mixed bag.

Women taking HRT 10 or more years after menopause showed no difference in atherosclerosis progression compared with a placebo, suggesting the timing of HRT use post-menopause was important.

The 643 women in the study, its randomised double-blind design, and average follow-up of five years, help build confidence in the study.

The main ambiguity is whether the differing rates of artery thickening observed here are big enough to have an impact on a woman's risk of heart attack or stroke over the longer term. 

The risks and benefits of taking HRT should be discussed with your GP if you have any concerns.

 

Where did the story come from?

The study was carried out by researchers from Keck School of Medicine at the University of Southern California and was funded by National Institute on Aging, National Institutes of Health.

A section declaring potential conflicts of interest among the study authors was missing from the main article text. The methods section said that Teva Pharmaceuticals, Watson Laboratories and Abbott Laboratories provided the hormone products used in the study free of charge, but: "no company had any role in the collection or analysis of data or in the preparation or review of the manuscript or the trial protocol".

The study was published in the peer-reviewed New England Medical Journal of Medicine.

The general body of the Mail's reporting was accurate, but its headline was a bit of a stretch. While slower rates of artery wall thickening are never a bad thing, it doesn't automatically mean that heart disease risk is reduced for all. The paper also helpfully introduced further context around HRT being linked to breast and ovarian cancer, as well as current national guidance.

 

What kind of research was this?

This was a double-blind randomised control trial testing whether the timing of HRT after menopause increased the risk of atherosclerosis. Atherosclerosis is a gradual clogging and thickening of your artery walls with fat that raises your risk of heart attacks and strokes.

A double-blind RCT is one of the best ways to establish whether HRT causes atherosclerosis. A downside is that RCTs are very expensive, so tend to be short. For example, setting up an RCT that tracks women from menopause to their death, potentially 40 to 50 years later, would be prohibitively expensive in most cases. 

The expense means that researchers have to find ways of looking for shorter-term effects (often referred to biomarkers) that would give them an idea of longer-term health. In this study, they chose the thickness of the wall in the carotid artery on the relatively safe assumption that a thickening was a sign of atherosclerosis progression, which in itself raises the risk of heart attacks and strokes later on. 

 

What did the research involve?

The researchers first divided 643 healthy postmenopausal women into two groups: those within six years of their last period (early post-menopause) and those 10 years after (late post-menopause).

Each group was then split again into those randomly assigned HRT or a placebo for two to five years.

The specific HRT was estradiol (a widely used HRT treatment that contains oestrogen) at 1mg per day with or without 45mg progesterone vaginal gel administered sequentially. Women in the placebo group received a matching placebo gel.

Participants were healthy postmenopausal women without diabetes, without clinical evidence of cardiovascular disease, had no regular periods for at least six months or who had surgically induced menopause.

The main outcome was the rate of change in the thickness of the carotid artery wall measured every six months through ultrasound scans. A secondary measure of interest was an assessment of coronary atherosclerosis using a CT scan.

The participants, investigators, staff, imaging specialists, and data monitors were unaware of the treatment assignments – a double, if not triple-blind, study.

 

What were the basic results?

For women less than six years after their last period, average artery thickness increased 0.0078mm per year while using a placebo. By comparison, the increased thickening was less in women using HRT, at 0.0044mm per year, a statistically significant difference. Both groups had thickening artery walls, but the HRT group had slightly less.

For women 10 or more years after their last period, the artery thickening results for HRT and placebo weren't too different, at 0.0088 and 0.0100mm per year respectively, a non-significant difference.

Other measures of cardiovascular health, like CT scans of artery calcium, abnormal blood vessel narrowing and atherosclerotic plaque formation, did not differ between placebo and HRT group, irrespective of time since menopause.

Serious side effects did not differ significantly between any of the groups.

 

How did the researchers interpret the results?

The study authors conclude: "Oral estradiol therapy [HRT] was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within six years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum."

 

Conclusion

This double-blind RCT found that women taking HRT less than six years after the menopause had slower artery wall thickening than those taking a placebo. This represented the main measure of atherosclerosis progression tested; other measures showed no difference, so the results were not as conclusive as they could have been.

Women taking HRT 10 or more years after menopause also showed no difference in atherosclerosis progression compared with a placebo, further complicating the picture.

An important limitation of this study is the lack of a patient relevant endpoint, such as cardiovascular events or mortality. Previous studies from the 1980s have indicated that hormone therapy is linked to a reduction in heart disease in postmenopausal women, but had problems in the design of the research. As subsequent research failed to support the idea that hormone therapy prevents heart disease, it will be important to have well-designed studies with clinical outcomes.

The number of women in the study, its randomised double-blind design, and average follow-up of five years help to build confidence in the study.

The main ambiguity is whether the differing rates of artery thickening observed here are big enough to have an impact on a person's risk of heart attack or stroke. 

The differences of 0.0078mm versus 0.0044mm per year for placebo and HRT groups were statistically convincing, but it's much less clear if they are clinically important.

The researchers themselves describe the difference as "preclinical", suggesting they think these differences aren’t a problem yet. However, they don't comment on whether their accumulated value over multiple decades – which would happen if these women lived into their 70s or older – would be a significant risk booster.

The assumption in the media was that, over the longer term, this faster rate of thickening might result in an important increased risk of heart disease, but this isn't yet concrete and needs further unpicking. The other factor to bear in mind is that measures of early disease progression and risk, such as CT scans of the arteries, showed no differences.

Hence, we have a mixed bag of results. They clearly show a link between the timing of HRT after menopause, but the link between HRT and reducing risks of heart attack and stroke is a little more fragile.

HRT can help many women with severe symptoms of menopause, providing relief, and its considerable benefits should not be overlooked. But this comes with a known increased risk of breast and ovarian cancer.

The risks and benefits of taking HRT should always be taken into account and discussed with your GP if you have any concerns.  

Analysis by Bazian. Edited by NHS Choices. Follow NHS Choices on TwitterJoin the Healthy Evidence forum.

Analysis by Bazian

Edited by NHS Choices

Links to the headlines

Women who take HRT drugs soon after going through menopause are 'less likely to suffer heart disease'. Daily Mail, March 30 2016

Links to the science

Hodis HH, Mack WJ, Henderson VW, et al. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. New England Journal of Medicine. Published online March 31 2016

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