Early postmenopausal HT* does not prevent vascular deterioration

There is good evidence that post-menopausal hormone therapy (HT) increases heart attacks and strokes. However, most of the patients in the randomised trials that provided that evidence started HT or placebo 10 years or so after the menopause, and some had pre-existing heart disease.  Perhaps HT started earlier in healthy women is preventive.  This “timing hypothesis” is popular with HT manufacturers.

The Kronos Early Estrogen Prevention Study (KEEPS) tested the timing hypothesis by studying healthy women within three years of the menopause. They were divided into three groups and treated for 48 months as follows:

1) oral conjugated equine estrogens (o-CEE), 0.45 mg/day, plus progesterone 200 mg for 12 days/month.

2) transdermal 17β-estradiol (t-E2), 50 mcg/day, plus progesterone 200 mg for 12 days/month.

3) placebo.

The primary endpoint was change in carotid artery intima-media thickness (CIMT), a measure of the vascular damage which precedes heart attacks and strokes. The trial was randomised, double blind, registered here before starting, and follow-up of the 727 participants was completed two years ago – I grumbled about the delay in publication here. The results have just been published in the Annals of Internal Medicine here, or Keeps trial report.

HT doesn’t protect the arteries.  Here is the change in CIMT over time in the three groups. Larger change means more artery wall thickening, a sign of damage.  Arteries in all three groups deteriorated over time but, although the deterioration was slightly greater in the two HT groups, the difference was not statistically significant.

The trial was too small to say much about substantive health outcomes – one woman died of an unspecified pelvic maligancy in the o-CEE group, and there was one non-fatal heart attack in the t-E2 group. There were no deaths or heart attacks in controls, and no strokes in the whole trial.

It’s a nice paper. It shows the power of good trial design – double blind, registered, sample size achieved, primary endpoint pre-defined and analysis by intention to treat.

The authors, mostly supporters of the timing hypothesis, were disappointed, but the many women who will avoid taking HT in the vain hope of preventing heart disease should not be.

The best advice remains – if you must take HT, take it for symptoms only, in the lowest dose and for the shortest time possible.

Jim Thornton

*Hormone replacement therapy (HRT) changed to hormone therapy (HT) Jan 2016