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)

Introduction

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

WISDOM

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

Participants

Recruiting in general practicePostmenopausal women aged 50-69 yrs, oldest women firstMain exclusion criteria;-Hx breast or other Ca, endometrial probs, IHD, CVA/TIA’s, HRT within last 6 monthsRandomised to conjugated equine oestrogen alone (hysterectomy patients) or that and medroxyprogesterone acetateAim for 10yrs treatment, ideally double-blind but vaginal bleeding triggered investigation

Data collection

12 week run-in period. 80% compliance cut-offSeen at 4, 14, 27, 40, 52 weeks, then 6/12Information collected on all outcomes, adverse events, and other medical history to check that patients remained eligible.

Outcome Measures

Primary Outcomes- major cardiovascular disease - osteoporotic fractures - breast cancerSecondary Outcomes- breast cancer mortality, other cancers- venous thromboembolism - cerebrovascular disease- dementia

Sample Size

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 groupAlso power to detect;- 20% reduction in all osteoporotic fractures- 40% increase in breast cancer

Statistical Method

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

Results

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 time56,583 attended, 14,203 agreed to enter and 8980 entered at time of closure.At end of run-in 5692 started trialMean age 62.8 yrsAverage of 15 years post menopauseBaseline characteristics similar in each group (% of women prev using HRT etc.)

Results

Due to early closure follow up median of 11.9 months

Total 6498 women years

Clinical Outcomes;

- 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)

Adverse Events

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.

Discussion

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

Discussion

Results for early cardiovascular and thromboembolic disease;

oestrogen only therapy may have similar, but smaller, short term effects compared to combinedresults consistent with the findings of the combined therapy arm of the women's health initiative studySupports conclusion that combined therapy should not be given for cardiovascular disease prevention in older postmenopausal women

Discussion

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.

Discussion

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

Conclusions

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

THE END!