Women warned against late start on HRT -- on dubious grounds

The study reported below would seem to be a very close replication of another much-criticized study that was prematurely terminated some years ago. Media report below followed by journal abstract. The basic point to note is again that only a tiny proportion of women (a fifth of one percent) in the study suffered any heart disease. Such low numbers are a very poor indicator of a causal relationship. As a sufferer from a REAL iatrogenic illness, I can assure everyone that a real iatrogenic illness is much more relentless than anything reported below. The time factor is however the big unknown. Many adverse outcomes of medication take years to emerge. But the study below simply has no information on that. I do understand why they had to stop the study after 12 months. Having ANY women dying on you would be too big a risk legally and heart attacks do take you perilously close to death. So the result basically is an unknown. But even if the adverse relationship is causal, most medications and most things we do every day do carry risks -- often much greater risks than described below. It should also be noted that even the authors below are not critical of women who go straight on to HRT after menopause. Apparently the few deaths they observed were among women who were in their 60s before they started taking HRT. That group would of course have a higher mortality anyhow. Note also that there is some very direct evidence that estrogen therapy is beneficial to the heart

WOMEN have again been advised not to start hormone replacement therapy many years beyond menopause, after a second major study showed it could increase the risk of heart attacks and blood clots. The study, which involved nearly 5700 women in Britain, Australia and New Zealand, found the risk of clots increased more than seven-fold. The risk of heart attack, stroke and other heart-related events was significantly higher among older women who were randomly assigned to take it an average of 15 years after menopause.

The reports' authors stress HRT is a safe, short-term treatment when initiated in younger women shortly after menopause, when it is used to reduce symptoms such as hot flushes. The latest findings, published today online by the British Medical Journal, echo the shock results of a 2002 US study that found women aged 50 to 79 who took a combined oestrogen and progestogen pill were at greater risk of stroke, breast cancer and clots in the lungs, compared with women given a dummy pill. That result overturned hopes that HRT could be used to reduce heart risk, and millions of women stopped taking HRT as a result.

Today's study was stopped in 2002 when the US results became known, by which point only one-quarter of the planned 22,300 subjects had been enrolled. The 5692 women who had joined the study, including 319 in Australia, had been followed up for barely one year, instead of the planned 10 years. Even with the limited data to analyse, the results showed that the increased risk from HRT translated to an extra 27 heart attacks or blood clots in a year per 10,000 women treated. Although there were only 11 heart attacks, clots or other cardiovascular events, all were recorded in women taking hormones.

On the other hand, bone fractures dropped by a third among women taking HRT compared with those who were not, although this finding was statistically doubtful due to the low numbers. Study co-author Alastair MacLennan, head of obstetrics and gynaecology at the University of Adelaide, said that as the trial was stopped before many younger women were recruited, it remained unclear what age cut-off should apply - in other words, when the benefits of starting a woman on HRT no longer outweighed the risks. "That's the $64,000 question," Professor MacLennan said. "People starting HRT under the age of 60 need not be at all concerned."

If women started HRT before this age and if "they need to take HRT for 15 years because of symptoms which may still be persisting, they are not putting themselves at risk". In a BMJ editorial published online today, senior lecturer in women's health at Auckland University Helen Roberts said HRT had "come full circle". Current advice was that women needing relief from menopausal symptoms should take the lowest dose to relieve them. "Healthy women in early menopause are at low absolute risk whether they take hormones or not, and they are unlikely to face substantially increased risks when using hormones for a few years," she says.


Main morbidities recorded in the women's international study of long duration oestrogen after menopause (WISDOM): a randomised controlled trial of hormone replacement therapy in postmenopausal women

By Madge R Vickers et al.


Objective: To assess the long term risks and benefits of hormone replacement therapy (combined hormone therapy versus placebo, and oestrogen alone versus combined hormone therapy).

Design: Multicentre, randomised, placebo controlled, double blind trial.

Setting: General practices in UK (384), Australia (91), and New Zealand (24).

Participants: Postmenopausal women aged 50-69 years at randomisation. At early closure of the trial, 56 583 had been screened, 8980 entered run-in, and 5692 (26% of target of 22 300) started treatment.

Interventions: Oestrogen only therapy (conjugated equine oestrogens 0.625 mg orally daily) or combined hormone therapy (conjugated equine oestrogens plus medroxyprogesterone acetate 2.5/5.0 mg orally daily). Ten years of treatment planned.

Main outcome measures: Primary outcomes: major cardiovascular disease, osteoporotic fractures, and breast cancer. Secondary outcomes: other cancers, death from all causes, venous thromboembolism, cerebrovascular disease, dementia, and quality of life.

Results: The trial was prematurely closed during recruitment, after a median follow-up of 11.9 months (interquartile range 7.1-19.6, total 6498 women years) in those enrolled, after the publication of early results from the women's health initiative study. The mean age of randomised women was 62.8 (SD 4.8) years. When combined hormone therapy (n=2196) was compared with placebo (n=2189), there was a significant increase in the number of major cardiovascular events (7 v 0, P=0.016) and venous thromboembolisms (22 v 3, hazard ratio 7.36 (95% CI 2.20 to 24.60)). There were no statistically significant differences in numbers of breast or other cancers (22 v 25, hazard ratio 0.88 (0.49 to 1.56)), cerebrovascular events (14 v 19, 0.73 (0.37 to 1.46)), fractures (40 v 58, 0.69 (0.46 to 1.03)), and overall deaths (8 v 5, 1.60 (0.52 to 4.89)). Comparison of combined hormone therapy (n=815) versus oestrogen therapy (n=826) outcomes revealed no significant differences.

Conclusions: Hormone replacement therapy increases cardiovascular and thromboembolic risk when started many years after the menopause. The results are consistent with the findings of the women's health initiative study and secondary prevention studies. Research is needed to assess the long term risks and benefits of starting hormone replacement therapy near the menopause, when the effect may be different.



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