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. Dr J Romain ( BMJ 4.8.2007 335:239-244)
The use of HRT to control moderate to severe menopausal symptoms is well established.
Long term use for disease prevention in postmenopausal women is in dispute.
1997 US Women’s Health Initiative Study
Assessed prevention of cardiovascular disease in women 50-79yrs on HRT.
On combined HRT;
- Increased risk of stroke, PE, breast cancer and coronary events in elderly (70-79 yrs).
- Decreased risk of hip fracture, colon Ca
when compared to women taking placebo.
Oestrogen only; increased risk of stroke
Risks largely outweighed benefits
Began recruiting 1999; UK, Aus and NZ
Designed to assess the balance of long term risks and benefits of hormone replacement therapy (combined vs placebo and oestrogen vs combined)
Aim for particular emphasis on cardiovascular disease and dementia
Recruiting in general practice
Postmenopausal women aged 50-69 yrs, oldest women first
Main exclusion criteria;
-Hx breast or other Ca, endometrial probs, IHD, CVA/TIA’s, HRT within last 6 months
Randomised to conjugated equine oestrogen alone (hysterectomy patients) or that and medroxyprogesterone acetate
Aim for 10yrs treatment, ideally double-blind but vaginal bleeding triggered investigation
12 week run-in period. 80% compliance cut-off
Seen at 4, 14, 27, 40, 52 weeks, then 6/12
Information collected on all outcomes, adverse events, and other medical history to check that patients remained eligible.
- major cardiovascular disease
- osteoporotic fractures
- breast cancer
- breast cancer mortality, other cancers
- venous thromboembolism
- cerebrovascular disease
Ideally 22,300. Provided 80% power at 5% significance to detect 29% reduction from an expected probability of a primary outcome event in the placebo group
Also power to detect;
- 20% reduction in all osteoporotic fractures
- 40% increase in breast cancer
Intention-to-treat principle when assessing treatment effects, with P<0.05 used to define statistical significance
To account for the prospective nature of the data, event rates were calculated (per 10 000 women-years) as the number of events divided by the relevant accumulated person-time
The results are reported as, respectively, rates and hazard ratios for the effect of combined therapy versus either placebo or oestrogen therapy (with 95% confidence intervals), with associated likelihood ratio tests for significance
226,282 women were eligible
Trial closed early in Oct 2002 due to publication of results from womens health initiative study- 155,204 women invited by this time
56,583 attended, 14,203 agreed to enter and 8980 entered at time of closure.
At end of run-in 5692 started trial
Mean age 62.8 yrs
Average of 15 years post menopause
Baseline characteristics similar in each group (% of women prev using HRT etc.)
Due to early closure follow up median of 11.9 months
Total 6498 women years
- total number of events low due to early closure
- no data on dementia as first follow-up due after 2 years
Combined VS Placebo
Significantly increased rates of cardiovascular events (P=0.016) and VTE in combined group (P=<0.001)
-all but 2 women over 64yrs
-all had 1 or more cardiovascular risks
Non significant reduction in rates of oseoporotic fractures (P=0.07)
Rates of cerebrovascular disease, breast cancer and other cancers did not differ.
Combined VS Oestrogen Alone
Numbers a lot smaller in this group; n=1641 compared to n=4385
Suggestion in combined group of increase in cardiovascular events (P=0.40) and VTE (P=0.19)
15 deaths during trial
Non-significant increase in combined group compared with placebo
No excess of serious adverse events in either of the randomised comparisons.
Data suggests that women starting or restarting combined oestrogen and progestogen therapy an average of 15 years after menopause are at increased risk of cardiovascular disease and venous thromboembolism, at least in the early years of treatment
Trend towards a decreased risk of osteoporotic fracture
Results for early cardiovascular and thromboembolic disease;
oestrogen only therapy may have similar, but smaller, short term effects compared to combined
results consistent with the findings of the combined therapy arm of the women's health initiative study
Supports conclusion that combined therapy should not be given for cardiovascular disease prevention in older postmenopausal women
Early increased risk of cardiovascular events in BOTH trials is compatible with the hypothesis that administration of hormone replacement therapy, particularly combined oestrogen and progestogen therapy, to women many years after menopause, who are likely to have established atherosclerosis, may cause disruption of the plaque surface, with subsequent platelet adhesion, clotting, and further arterial narrowing.
Value of Study
Contribution to the body of knowledge about hormone replacement therapy started in older postmenopausal women of a mean age of 63 years
participants are likely to be representative of the general population of women of this age and the results applicable to this older age group
Limitations- early closure and therefore reduced recruitment and power. Few women in younger age groups. Only two types of HRT assessed.
results of WISDOM, help test the hypothesis that starting long term hormone replacement therapy in elderly, often asymptomatic, women in their 60s might reduce major morbidities, in particular cardiovascular disease. This does NOT seem likely.
Currently it is rare to start taking therapy at this age
Cannot draw conclusions for women taking HRT around time of menopause
However there may be no increased benefit, and indeed some risk, for women commencing HRT many years after menopause for few or no menopausal symptoms.
If there is a ‘window’ of benefit this is likely to vary with arterial risk factors and obesity